fludara i.v. (2nd line nhl)

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Anlage 1 FLUDARA: Marketing Autorization Status (Schering) Fludara i.v. (2nd line NHL) Country Date 1 TURKEY 15.02.2000 2 LATVIA 12.04.2000 3 CZECH REPUBLIC 23.08.2000 4 LITHUANIA 30.08.2001 5 SLOVAKIA 25.10.2001 6 CANADA 30.10.2001 7 RUSSIAN FEDERATION 27.11.2001 8 HUNGARY 20.12.2001 9 SWITZERLAND 25.01.2002 10 ESTONIA 08.02.2002 11 GUATEMALA 12.06.2002 12 COLOMBIA 02.08.2002 13 URUGUAY 12.12.2002 14 ISRAEL 19.02.2003 15 PERU 17.03.2003 16 VENEZUELA 13.06.2003 17 SERBIA and MONTENEGRO 30.06.2003 18 THAILAND 10.07.2003 19 TAIWAN PROVINCE OF CHINA 29.07.2003 20 UKRAINE 20.11.2003 21 DOMINICAN REPUBLIC 23.01.2004 22 KOREA REPUBLIC OF 12.03.2004 23 ARGENTINA 27.05.2004 24 ARUBA 06.07.2004 25 JAMAICA 08.07.2004 26 ROMANIA 20.07.2004 27 MEXICO 16.02.2005 28 TRINIDAD And TOBAGO 06.07.2005 29 VIETNAM 07.10.2005

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Page 1: Fludara i.v. (2nd line NHL)

Anlage 1 FLUDARA: Marketing Autorization Status (Schering) Fludara i.v. (2nd line NHL) Country Date 1 TURKEY 15.02.20002 LATVIA 12.04.20003 CZECH REPUBLIC 23.08.20004 LITHUANIA 30.08.20015 SLOVAKIA 25.10.20016 CANADA 30.10.20017 RUSSIAN FEDERATION 27.11.20018 HUNGARY 20.12.20019 SWITZERLAND 25.01.200210 ESTONIA 08.02.200211 GUATEMALA 12.06.200212 COLOMBIA 02.08.200213 URUGUAY 12.12.200214 ISRAEL 19.02.200315 PERU 17.03.200316 VENEZUELA 13.06.200317 SERBIA and MONTENEGRO 30.06.200318 THAILAND 10.07.200319 TAIWAN PROVINCE OF CHINA 29.07.200320 UKRAINE 20.11.200321 DOMINICAN REPUBLIC 23.01.200422 KOREA REPUBLIC OF 12.03.200423 ARGENTINA 27.05.200424 ARUBA 06.07.200425 JAMAICA 08.07.200426 ROMANIA 20.07.200427 MEXICO 16.02.200528 TRINIDAD And TOBAGO 06.07.200529 VIETNAM 07.10.2005

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Bewertung und Extraktion von Therapiestudien Stand der Bearbeitung Bearbeiter Axel Heyll

Stand der Bearbeitung 08.01.2009 Nr. Feld Hinweise für die Bearbeitung

1 Quelle Dhodapkar MV et al., Blood 88: 41 – 48, 2001

2 Studientyp vom Autor bezeichnet als

Prospektive multizentrische Beobschtungsstudie

3 Studientyp nach Durchsicht

Zuordnung zu einem der folgenden Studientypen: □ Therapiestudie mit randomisierter Gruppenzuteilung □ Therapiestudie mit nicht-randomisierter

Gruppenzuteilung □ Therapiestudie mit Vergleichen über Zeit und Ort (z. B.

historische Kontrollen) X herapiestudie ohne Vergleichsgruppen (auch

Beobachtungsstudien und Anwendungsbeobachtungen) □ Fall-Kontrollstudien □ Fallserie □ Fallbericht / Kasuistik (case report) □ Nicht eindeutig zuzuordnen Falls Therapiestudie: □ mit Placebokontrolle(n) □ mit Aktivkontrolle(n) □ mit Dosisgruppen □ sonstige Kontrollgruppe(n): Nennen

4 Formale Evidenzkriterien gemäß SIGN

□ 1++: Qualitativ hochwertige Metaanalyse bzw. systematischer Review von RCTs oder RCT mit sehr geringem Risiko von Bias

□ 1+: Gut durchgeführte Metaanalyse bzw. systematischer Review von RCTs oder RCT mit geringem Risiko von Bias

□ 1-: Metaanalyse bzw. systematischer Review von RCTs oder RCT mit hohem Risiko von Bias

□ 2++: Qualitativ hochwertiger systematischer Review von Fallkontroll- oder Kohortenstudien oder Qualitativ hochwertige Fallkontroll- oder Kohortenstudie mit sehr geringem Risiko von Confounding, Bias oder Zufallsschwankungen und hoher Wahrscheinlichkeit, so dass der Zusammenhang kausal ist

X 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie mit niedrigem Risiko von Confounding, Bias oder Zufallsschwankungen und einer mittleren Wahrschein-lichkeit, so dass der Zusammenhang kausal ist

□ 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko von Confounding, Bias oder Zufallsschwankungen und

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Nr. Feld Hinweise für die Bearbeitung einem signifikanten Risiko, so dass der Zusammenhang nicht kausal ist

□ 3: Andere Studien wie Einzelfallberichte, Fallserien

□ 4: Expertenmeinung

5 Bezugsrahmen Therapieoptimierungsstudie einer US-amerikanischen Studiengruppe (SWOG), IIT, keine Interessenskonflikte angegeben

6 Indikation Waldenström Makroglobulinämie (lymphoplasmozytisches NHL nach WHO mit IgM-Paraproteinämie)

7 Primäre Fragestellung / primäre Zielsetzung(en)

Ansprechrate unter Studientherapie, Ermittlung von Prognosefaktoren für Überlebenszeit

8 Relevante Ein- und Ausschlusskriterien

Histologische und laborchemische Diagnose eines lymphoplasmozytischen NHL nach WHO mit IgM-Paraproteinämie

Allgemeinzustand 0 – 2 nach WHO Granulozyten > 1.500/µl, Thrombozyten > 100.000/µl

wenn nicht lymphombedingte Zytopenie Keine Chemotherapie innerhalb von 4 Wochen vor

Protokolleinschluss Alle Patienten mit diesen Einschlusskriterien wurden

registriert. Die Studienmedikation erhielten nur Patienten, die bereits bei Registrierung oder im weiteren Krankheitsverlauf eine Lymphom-bezogene Symptomatik und/oder einen Lymphomprogess entwickelten.

9 Prüfintervention Fludarabin 30 mg/m2 Tag 1 – 5, alle 4 Wochen, mindestens 4 Zyklen, bei Ansprechen bis zu 8 Zyklen

10 Vergleichsintervention Nein

11 Evtl. weitere Behandlungsgruppen

Nein

12 Subgruppen Enthält die Studie Subgruppen, die für die Fragestellung an die Kommission relevant sind? □ keine relevanten Subgruppen X prospektiv geplante Subgruppenauswertung

(wahrscheinlich) □ post hoc definierte oder in Auswertung gefundene

Subgruppen Unterscheidung bei Auswertung der Ansprechrate zwischen

vorbehandelten und nicht vorbehandelten Patienten

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13 Studiendesign Anzahl der Behandlungsarme 1 Typus: □ Parallelgruppendesign □ Cross-Over Design □ Prae-Post-Vergleich □ Sonstige:......................... Geplante Fallzahl (falls angegeben) Nicht angegeben Wurde eine Fallzahlplanung (Power-Kalkulation) durchgeführt? Entfällt, da keine Vergleichsintervention Waren Interimanalysen geplant? Nein

14 Zentren Anzahl der Zentren nicht angegeben Vergleichbarkeit der Studiendurchführung in den einzelnen Zentren beurteilen nicht angegeben

15 Randomisierung Keine Randomisation

16 Verblindung der Behandlung

□ Keine Verblindung (offene Behandlung) □ Patienten verblindet □ Behandler verblindet □ Beurteiler verblindet ( z.B. bei Bildgebung)

17 Beobachtungsdauer Median 30 Monate für Ansprechrate Median 41 Monate für Überleben

18 Primäre Zielkriterien Zielkriterien (outcomes) nennen, die von den Autoren als die primären bzw. Haupt-Zielkriterien genannt wurden. Ansprechrate Wurden relevante patientennahe Zielkriterien verwendet? Nein Mit welchen Instrumenten und in welcher Form erfolgte die Erfassung der Zielkriterien (z. B. Interview, Untersuchung, standardisierte Fragebögen, Referenzbeurteilung)? Nicht angegeben

19 Sekundäre Zielkriterien Überlebenszeit

20 Statistische Methoden für die Analyse der primären Endpunkte

Bezeichnung der verwendeten Test- bzw. Schätzprozeduren Signifikanz-/Konfidenzniveau Entfällt, kein Vergleich

21 Anzahl der behandelten Patienten

Erreichte Fallzahl. 231 Patienten registriert 182 behandelt mit Fludarabin Wurde die Studie vorzeitig beendet? (Gründe)

22 Zahl und Charakteristika der eingeschlossenen und ausgewerteten Patienten

Differenzierte Darstellung nach Behandlungsgruppen vorhanden? Darstellung des Patientenflusses nach CONSORT Sind die Ausfälle von Studienteilnehmern (Drop-outs) dokumentiert und begründet? Erfolgte eine Intention-to-treat- (ITT-) Analyse? Erfolgte eine Per Protocol- (PP-) Analyse? Gibt es Hinweise auf systematische und relevante

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Unterschiede zwischen den Drop-outs und den gemäß Studienprotokoll behandelten Patienten. Entfällt, kein Vergleich

23 Vergleichbarkeit der Behandlungsgruppen

Gibt es relevante Unterschiede zwischen den Behandlungsgruppen □ bei Studienbeginn (Baseline)? □ in der Durchführung der Intervention? Entfällt, kein Vergleich

24 Ergebnisse und ihre Darstellung

Ansprechrate insgesamt 36 %, 95 %-KI; 29 – 44%, Ansprechen definiert als Reduktion M-Gradient und Tumormasse um > 50 % Ansprechrate 38 % bei nicht vorbehandelten Patienten (n=118) und 33 % bei mit Alkylantien vorbehandelten Patienten (n=64)

25 Unerwünschte Therapiewirkung

Sind unerwünschte Ereignisse (UEs/AEs) berichtet? Ja, Tabelle 4 der Publikation Sind schwerwiegende UEs (SUEs/SAEs) berichtet? Ja Wurde der Bezug zur Behandlung beurteilt? Ja

26 Fazit der Autoren Beschreibung des Prognosefaktormodells, für Fragestellung der Expertengruppe nicht relevant Fludarabin ist wirksam bei Patienten mit oder ohne Vorbehandlung mit Alkylantien, aber die Studie begründet nicht, Fludarabin an Stelle von Alkylantien in der Erstlinientherapie zu bevorzugen,

27 Abschließende Bewertung durch den Bearbeiter

Völlige Übereinstimmung mit dem Resümee der Autoren

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Zu Feld 24 Ergebnisdarstellung für quantitative Zielkriterien (mit Beispiel)

Prüftherapie Kontrolle Zielkriterium

n x SD* n x SD*

Maß für Gruppen- unterschied

Schätzer und 95% Konfidenzintervall für Gruppenunterschied

p-Wert (optional)

VAS 117 20.4 7.4 123 15.6 4.5 Differenz** 4.8 (3.25 ; 6.35)

* ggf. aus SE umrechnen: nSESD ⋅= ** Es kann u.U. notwendig sein, die Richtung des angegebenen Unterschieds deutlich zu machen (z.B. „negative Angaben kennzeichnen eine Überlegenheit von Verum“) Ergebnisdarstellung für dichotome Zielkriterien (mit Beispiel)

Anzahl Patienten mit Ereignis / Anzahl aller Patienten Zielkriterium Verum Kontrolle

Maß für Gruppen- unterschied

Schätzer und 95% Konfidenzintervall für Gruppenunterschied

p-Wert (optional)

Erfolg 12 / 120 (10%) 8 / 127 (6.3%) Odds Ratio 1.65 (0.65 ; 4.2)

5

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Bewertung und Extraktion von Therapiestudien Stand der Bearbeitung Bearbeiter Prof. Dr. med. J. T. Hartmann

Datum der Bearbeitung 15.02.2007

Datum der Diskussion mit der Expertengruppe

Nr. Feld Hinweise für die Bearbeitung

1 Quelle Forstpointner R, Dreyling M, Repp R, Hermann S, Hanel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Bock HP, Wandt H, Unterhalt M, Hiddemann W. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 104: 3064-71, 2004.

2 Studientyp vom Autor bezeichnet als

Phase III, kontrolliert, randomisiert

3 Studientyp nach Durchsicht

Zuordnung zu einem der folgenden Studientypen: x Therapiestudie mit randomisierter Vergleichsgruppe □ Therapiestudie mit nicht-randomisierter

Vergleichsgruppe □ Therapiestudie mit Vergleichen über Zeit und Ort (z. B.

historische Kontrollen) □ Fallkontrollstudien □ Kohortenstudien □ Therapiestudie ohne Vergleichsgruppen (auch „Vorher-

Nachher-Studien“) □ Fallserie □ Fallbericht / Kasuistik (case report) □ Nicht eindeutig zuzuordnen

4 Formale Evidenzkriterien gemäß SIGN

Hier folgt eine formale Zuordnung zu den Evidenzstufen gemäß SIGN: □ 1++: Qualitativ hochwertige Metaanalyse bzw.

systematischer Review von RCTs oder RCT mit sehr geringem Risiko von Bias

□ 1+: Gut durchgeführte Metaanalyse bzw. systematischer Review von RCTs oder RCT mit geringem Risiko von Bias

x 1-: Metaanalyse bzw. systematischer Review von RCTs oder RCT mit hohem Risiko von Bias

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□ 2++: Qualitativ hochwertiger systematischer Review von

Fallkontroll- oder Kohortenstudien Qualitativ hochwertige Fallkontroll- oder Kohortenstudie mit sehr geringem Risiko von Confounding, Bias oder Zufallsschwankungen und hoher Wahrscheinlichkeit, dass der Zusammenhang kausal ist

□ 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie mit einem niedrigen Risiko von Confounding, Bias oder Zufallsschwankungen und einer mittleren Wahrschein-lichkeit, dass der Zusammenhang kausal ist

□ 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko von Confounding, Bias oder Zufallsschwankungen und einem signifikanten Risiko, dass der Zusammenhang nicht kausal ist

□ 3: Andere Studien wie Einzelfallberichte, Fallserien

□ 4: Expertenmeinung

5 Bezugsrahmen GLSG

6 Indikation Mantelzell-Lymphom und follikuläres Lymphom

7 Fragestellung / Zielsetzung Addition von Rituximab in Kombination mit FCM beim rezidivierten follikullären- und Mantelzellymphom

8 Relevante Ein- und Ausschlusskriterien

Typische Einschlusskriterien bzgl. der Hämatologie, Leber und Nierenfunktion. Alter> 18 Jahre, ECOG 0-2. Relaps oder refraktäres Mantelzelllymphom, FL, oder Lymphoplasmozytisches Lymphom (Pathologie-Review)

9 Prüfintervention Fludarabin 25 mg/m2 d1-3, Cyclophosphamid 200 mg/m2 d1-3, Mitoxantron 8mg/m2 d1, Wdh d28 max. 4 Zyklen (FCM), Rituximab 375mg/m2 am Tag vor FCM (alle 4 Wochen)

10 Vergleichsintervention FCM

11 Evtl. weitere Behandlungsgruppen

Entfällt

12 Studiendesign Offene, multizentrische, randomisierte Phase III-Studie

13 Zahl der Zentren 61

14 Randomisierung Offen

15 Concealment („Maskierung“ der Randomisierung)

Entfällt

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16 Verblindung der

Behandlung Erfolgte eine Verblindung der Behandlung? x Nein, offene Behandlung □ Patienten verblindet □ Behandler verblindet □ Patienten und Behandler verblindet Wie wurde die Verblindung durchgeführt?

17 Beobachtungsdauer Mittlere Beobachtungsdauer: 18 Monate

18 Primäre Zielkriterien Objektive Response-Rate (Anstieg um 20%, antizipiert unter FCM 57%, 1-seitig alpha 5%, 228 observationen), CR-, PR-Rate, TTF, AE’s

19 Sekundäre Zielkriterien

20 Anzahl der zu behandelnden Patienten

228 Beobachtungen

21 Zahl und Charakteristika der eingeschlossenen und ausgewerteten Patienten

Es wurde ein zentraler Pathologie-Review durchgeführt, der zu einer Änderung einiger Diagnosen führte. 147 Patienten randomisiert, 128 ausgewertet, 114 per protocol behandelt. Follikuläre Lyphome: 49%, MZL: 35%, Lymphoplasmozytisches Lymphom: 11%. Mittl. Alter 62 Jahre (35-80)

22 Vergleichbarkeit der Behandlungsgruppen

Ist gegeben

23 Ergebnisse Intent to treat-Auswertung. Ansprechen R-FCM: 82% (CR 36%, PR 45%) FCM: 61% (CR 14%, PR 47%) 2-Jahres Ueberlebenszeit: 63%# PFS: 13 Monate, für FCM vs. R-FCM: 16 Monate vs. 10 Monate (p=0.03) OS: 24 Monate vs. Not reached (p=0.003).

24 Unerwünschte Therapiewirkungen

Häufigste Nebenwirkungen waren hämatologischer Art, insbesondere Grad 3/4 Neutropenie (40%). Die Nicht-Hämatologischen Toxizitäten waren gering ausgeprägt. 4 Fälle von allergischen Reaktionen unter Rituximab, die zum Therapieabbruch führten. Keine Veränderung gegenüber dem bisherigen Stand.

25 Fazit der Autoren Rituximab additiv zu einer Fludarabinhaltigen Kombinationschemotherapie – hier FCM- ist hocheffektiv als Salvage-Therapie bei folikullärem, Mantelzell- und Lymphozytischen Lymphom.

26 Abschließende Bewertung durch x den Bearbeiter □ die Expertengruppe

Diese Studie zeigt eine verbesserte Wirksamkeit von Fludarabin-haltiger Chemotherapie in der Salvage-Therapie des low grade Lymphoms in Kombination mit Rituximab versus FCM allein. Einschränkend ist die kurze Beobachtungszeit und die Fallzahl.

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Bewertung und Extraktion von Therapiestudien Stand der Bearbeitung Bearbeiter Name

Stand der Bearbeitung Datum Nr. Feld Hinweise für die Bearbeitung

1 Quelle Forstpointner R et al.; Blood 108: 4003-4008, 2006

2 Studientyp vom Autor bezeichnet als

Prospektive, randomisierte, nicht-verblindete Phase 3 Studie

3 Studientyp nach Durchsicht

Zuordnung zu einem der folgenden Studientypen: X Therapiestudie mit randomisierter Gruppenzuteilung □ Therapiestudie mit nicht-randomisierter

Gruppenzuteilung □ Therapiestudie mit Vergleichen über Zeit und Ort (z. B.

historische Kontrollen) □ Therapiestudie ohne Vergleichsgruppen (auch

Beobachtungsstudien und Anwendungsbeobachtungen) □ Fall-Kontrollstudien □ Fallserie □ Fallbericht / Kasuistik (case report) □ Nicht eindeutig zuzuordnen Falls Therapiestudie: □ mit Placebokontrolle(n) X mit Aktivkontrolle(n) □ mit Dosisgruppen □ sonstige Kontrollgruppe(n): Nennen

4 Formale Evidenzkriterien gemäß SIGN

X 1++: Qualitativ hochwertige Metaanalyse bzw. systematischer Review von RCTs oder RCT mit sehr geringem Risiko von Bias

□ 1+: Gut durchgeführte Metaanalyse bzw. systematischer Review von RCTs oder RCT mit geringem Risiko von Bias

□ 1-: Metaanalyse bzw. systematischer Review von RCTs oder RCT mit hohem Risiko von Bias

□ 2++: Qualitativ hochwertiger systematischer Review von Fallkontroll- oder Kohortenstudien oder Qualitativ hochwertige Fallkontroll- oder Kohortenstudie mit sehr geringem Risiko von Confounding, Bias oder Zufallsschwankungen und hoher Wahrscheinlichkeit, so dass der Zusammenhang kausal ist

□ 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie mit niedrigem Risiko von Confounding, Bias oder Zufallsschwankungen und einer mittleren Wahrschein-lichkeit, so dass der Zusammenhang kausal ist

□ 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko von Confounding, Bias oder Zufallsschwankungen und

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Nr. Feld Hinweise für die Bearbeitung einem signifikanten Risiko, so dass der Zusammenhang nicht kausal ist

□ 3: Andere Studien wie Einzelfallberichte, Fallserien

□ 4: Expertenmeinung

5 Bezugsrahmen Therapieoptimierungsstudie einer deutschen Studiengruppe (GLSG), IIT, Der Seniorautor (W. Hiddemann) hat von der Herstellerfirma des Prüfmedikaments Rituximab (Roche) Honorare und Drittmittel für Forschung erhalten, die übrigen Autoren haben keine Interessenkonflikte angegeben

6 Indikation Follukläre NHL und Mantelzelllymphom

7 Primäre Fragestellung / primäre Zielsetzung(en)

Reduktion des Rezidivrisikos um 50 % durch Ritruximab-Erhaltung

8 Relevante Ein- und Ausschlusskriterien

Follikuläres NHL (FL) oder Mantelzelllymphom (MCL) nach WHO

Rezidiv oder primär refraktär Mindestens 18 Jahre alt

9 Prüfintervention Patienten erhielten zunächst 4 Kurse FCM (Fludarabin, Cyclophosphamid, Mitoxantrone) je nach erster Randomisation mit oder ohne Ristuximab. Patienten, die anschließend eine CR oder PR (Tumorreduktion um mindestens 50 %) erreicht hatten, wurden zum zweiten Mal randomisiert und erhielten entweder Rituximab 375 mg/m2 jeweils 4 Gaben in wöchentlichen Abständen 3 und 9 Monate nach Ende der Chemotherapie oder wurden nur beobachtet.

10 Vergleichsintervention s. o.

11 Evtl. weitere Behandlungsgruppen

Keine

12 Subgruppen Enthält die Studie Subgruppen, die für die Fragestellung an die Kommission relevant sind? X keine relevanten Subgruppen □ prospektiv geplante Subgruppenauswertung □ post hoc definierte oder in Auswertung gefundene

Subgruppen Subgruppen ggf. benennen

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13 Studiendesign Anzahl der Behandlungsarme Typus: X Parallelgruppendesign □ Cross-Over Design □ Prae-Post-Vergleich □ Sonstige:......................... Geplante Fallzahl (falls angegeben) Nicht angegeben Wurde eine Fallzahlplanung (Power-Kalkulation) durchgeführt? Ja Waren Interimanalysen geplant? Ja

14 Zentren Anzahl der Zentren 109 Vergleichbarkeit der Studiendurchführung in den einzelnen Zentren beurteilen Keine Angaben

15 Randomisierung Ausreichend beschrieben? Zentrale Randomisation durch Studienleitung über Telefon Erfolgte die Randomisierung maskiert, d.h. wurde sicher gestellt, dass die Randomisierungssequenz vor Behandlern und den Studienteilnehmern verborgen blieb (Concealment; z.B. durch zentrale telefonische Randomisierung)? Ja

16 Verblindung der Behandlung

X Keine Verblindung (offene Behandlung) □ Patienten verblindet □ Behandler verblindet □ Beurteiler verblindet ( z.B. bei Bildgebung)

17 Beobachtungsdauer Median 26 Monate

18 Primäre Zielkriterien Zielkriterien (outcomes) nennen, die von den Autoren als die primären bzw. Haupt-Zielkriterien genannt wurden. Rezidivrisiko bzw. Dauer der Remission Wurden relevante patientennahe Zielkriterien verwendet? Ja sekundärer Endpunkt war auch Überlebenszeit Mit welchen Instrumenten und in welcher Form erfolgte die Erfassung der Zielkriterien (z. B. Interview, Untersuchung, standardisierte Fragebögen, Referenzbeurteilung)? Keine Angabe

19 Sekundäre Zielkriterien Ansprechrate Überlebenszeit

20 Statistische Methoden für die Analyse der primären Endpunkte

Bezeichnung der verwendeten Test- bzw. Schätzprozeduren Log-Rang-Test Signifikanz-/Konfidenzniveau Berechnung für p=0,05

21 Anzahl der behandelten Patienten

Erreichte Fallzahl. n=194 (2. Randomisation Wurde die Studie vorzeitig beendet? (Gründe)

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Ja, 1. Randomisation nach 147 Patienten gestoppt, nachdem für R-FCM im Vergleich zu FCM ein signifikanter Vorteil (Überleben?) gefunden worden war, danach erhielten alle Patienten R-FCM, 2. Randomisation nach 194 Patienten gestoppt, nachdem signifikant geringeres Rezidivrisiko für R-Erhaltung gefunden worden war

22 Zahl und Charakteristika der eingeschlossenen und ausgewerteten Patienten

Differenzierte Darstellung nach Behandlungsgruppen vorhanden? Ja Darstellung des Patientenflusses nach CONSORT Nein Sind die Ausfälle von Studienteilnehmern (Drop-outs) dokumentiert und begründet? Nein, bei 14 von 19 nicht ausgewerteten Patienten unvollständige Dokumentation Erfolgte eine Intention-to-treat- (ITT-) Analyse? Ja Erfolgte eine Per Protocol- (PP-) Analyse? Nein Gibt es Hinweise auf systematische und relevante Unterschiede zwischen den Drop-outs und den gemäß Studienprotokoll behandelten Patienten.

23 Vergleichbarkeit der Behandlungsgruppen

Gibt es relevante Unterschiede zwischen den Behandlungsgruppen □ bei Studienbeginn (Baseline)? □ in der Durchführung der Intervention?

24 Ergebnisse und ihre Darstellung

Studienarm R-Erhaltung Beobachtung Patientenzahl n=80 n=82 Histologie FL/MCL 52/28 53/29 Endpunkte Dauer Remission Median / Monate nicht erreicht 17 p-Wert < 0,001 Überleben nach 3 Jahren 77 % 57 % p-Wert 0,1

25 Unerwünschte Therapiewirkung

Sind unerwünschte Ereignisse (UEs/AEs) berichtet? Ja Sind schwerwiegende UEs (SUEs/SAEs) berichtet? Nicht aufgetreten Wurde der Bezug zur Behandlung beurteilt? Ja

26 Fazit der Autoren Erhaltung mit Rituximab nach Chemotherapie verlängert Dauer der Remission

27 Abschließende Bewertung durch den Bearbeiter

Fazit der Autoren trifft zu, aber Dauer der Remission ist bei einer palliativen Therapie, wie im vorliegenden Fall nicht der für die Nutzenbewertung relevante Endpunkt. Entscheidend ist vielmehr, der Endpunkt Überlebenszeit für den kein signifikanter Unterschied im Gesamtkollektiv nachgewiesen werden konnte. Zudem hat ein Teil der Patienten im Rahmen der FCM-Therapie kein Rituximab erhalten, was aber inzwischen den Standard entspricht. Daten anderer Studien belegen, dass der Effekt einer

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Rituximab-Erhaltung bei Patienten ohne Zugabe von Rituximab zur vorausgegangenen Chemotherapie deutlich ausgeprägter ist. Die entscheidende Frage ist somit, ob eine Rituximaberhaltung nach Zweitlinientherapie mit R-FCM zu einer Verlängerung der Überlebenszeit führt. Dazu müsste die entsprechende Untergruppe ausgewertet werden. Wenn aber schon im Gesamtkollektiv die Differenz der Überlebenszeit nicht signifikant war, ist dies für die R-FCM-Untergruppe erst recht nicht zu erwarten.

Page 16: Fludara i.v. (2nd line NHL)

Zu Feld 24 Ergebnisdarstellung für quantitative Zielkriterien (mit Beispiel)

Prüftherapie Kontrolle Zielkriterium

n x SD* n x SD*

Maß für Gruppen- unterschied

Schätzer und 95% Konfidenzintervall für Gruppenunterschied

p-Wert (optional)

VAS 117 20.4 7.4 123 15.6 4.5 Differenz** 4.8 (3.25 ; 6.35)

* ggf. aus SE umrechnen: nSESD ⋅= ** Es kann u.U. notwendig sein, die Richtung des angegebenen Unterschieds deutlich zu machen (z.B. „negative Angaben kennzeichnen eine Überlegenheit von Verum“) Ergebnisdarstellung für dichotome Zielkriterien (mit Beispiel)

Anzahl Patienten mit Ereignis / Anzahl aller Patienten Zielkriterium Verum Kontrolle

Maß für Gruppen- unterschied

Schätzer und 95% Konfidenzintervall für Gruppenunterschied

p-Wert (optional)

Erfolg 12 / 120 (10%) 8 / 127 (6.3%) Odds Ratio 1.65 (0.65 ; 4.2)

6

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Bewertung und Extraktion von Therapiestudien Stand der Bearbeitung Bearbeiter Prof. Dr. med. J. T. Hartmann

Datum der Bearbeitung 15.02.2007

Datum der Diskussion mit der Expertengruppe

Nr. Feld Hinweise für die Bearbeitung

1 Quelle Foussard C, Colombat P, Maisonneuve H, Berthou C, Gressin R, Rousselet MC, Rachieru P, Pignon B, Mahe B, Ghandour C, Desablens B, Casassus P, Lamy T, Delwail V, Deconinck E. Long-term follow-up of a randomized trial of fludarabine-mitoxantrone, compared with cyclophosphamide, doxorubicin, vindesine, prednisone (CHVP), as first-line treatment of elderly patients with advanced, low-grade non-Hodgkin's lymphoma before the era of monoclonal antibodies. Ann Oncol 16: 466-72, 2005.

2 Studientyp vom Autor bezeichnet als

Phase III, randomisiert

3 Studientyp nach Durchsicht

Zuordnung zu einem der folgenden Studientypen: x Therapiestudie mit randomisierter Vergleichsgruppe □ Therapiestudie mit nicht-randomisierter

Vergleichsgruppe □ Therapiestudie mit Vergleichen über Zeit und Ort (z. B.

historische Kontrollen) □ Fallkontrollstudien □ Kohortenstudien □ Therapiestudie ohne Vergleichsgruppen (auch „Vorher-

Nachher-Studien“) □ Fallserie □ Fallbericht / Kasuistik (case report) □ Nicht eindeutig zuzuordnen

4 Formale Evidenzkriterien gemäß SIGN

Hier folgt eine formale Zuordnung zu den Evidenzstufen gemäß SIGN: □ 1++: Qualitativ hochwertige Metaanalyse bzw.

systematischer Review von RCTs oder RCT mit sehr geringem Risiko von Bias

□ 1+: Gut durchgeführte Metaanalyse bzw. systematischer Review von RCTs oder RCT mit geringem Risiko von Bias

x 1-: Metaanalyse bzw. systematischer Review von RCTs oder RCT mit hohem Risiko von Bias

Page 18: Fludara i.v. (2nd line NHL)

□ 2++: Qualitativ hochwertiger systematischer Review von

Fallkontroll- oder Kohortenstudien Qualitativ hochwertige Fallkontroll- oder Kohortenstudie mit sehr geringem Risiko von Confounding, Bias oder Zufallsschwankungen und hoher Wahrscheinlichkeit, dass der Zusammenhang kausal ist

□ 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie mit einem niedrigen Risiko von Confounding, Bias oder Zufallsschwankungen und einer mittleren Wahrschein-lichkeit, dass der Zusammenhang kausal ist

□ 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko von Confounding, Bias oder Zufallsschwankungen und einem signifikanten Risiko, dass der Zusammenhang nicht kausal ist

□ 3: Andere Studien wie Einzelfallberichte, Fallserien

□ 4: Expertenmeinung

5 Bezugsrahmen Dr. E. Deconinck, Hematology Department, CHU Besancon, France

6 Indikation Ältere Patienten mit nicht vorbehandeltem, fortgeschrittenem indolentem B-Non-Hodgkin’s Lymphom

7 Fragestellung / Zielsetzung Effizienz und Toxizität von Fludararbin/Mitoxantron (FM) versus Cyclophosphamid/Vincristin/Doxorubicin/Prednison (CHVP)

8 Relevante Ein- und Ausschlusskriterien

Typische Einschlusskriterien bzgl. der Hämatologie, Leber und Nierenfunktion. Alter: 55-75 Jahre. Nicht vorbehandelte, indolente Lymphome (nach REAL-Klassifikation): zentraler histologischer Review.

9 Prüfintervention FM Fludarabin 20 mg/m2/d i.v. Tag 1-5 und Mitoxantron 10 mg/m2 Tag 1 Wdh. an Tag 28 6 Zyklen, dann 3 x alle 2 Monate 1 Zyklus Anpassung der Dosierung an hämatologische, Leber- und Nierentoxizität

10 Vergleichsintervention CHVP Cyclophosphamid 750 mg/m2 Tag 1, Doxo 25 mg/m2 Tag 1, Vindesine 3 mg/m2 Tag 1, Prednison 50 mg/m2 p.o. Tag 1-5 Wdh. an Tag 28 6 Zyklen, dann 3 x alle 2 Monate 1 Zyklus Anpassung der Dosierung an hämatologische, Leber- und Nierentoxizität

11 Evtl. weitere Behandlungsgruppen

Entfällt

12 Studiendesign Offene, zweiarmige Phase III-Studie

13 Zahl der Zentren 18 französische Zentren

14 Randomisierung Offen

Page 19: Fludara i.v. (2nd line NHL)

15 Concealment („Maskierung“ der Randomisierung)

Entfällt

16 Verblindung der Behandlung

Erfolgte eine Verblindung der Behandlung? x Nein, offene Behandlung □ Patienten verblindet □ Behandler verblindet □ Patienten und Behandler verblindet Wie wurde die Verblindung durchgeführt?

17 Beobachtungsdauer 7 Jahre

18 Primäre Zielkriterien Objektive Response-Rate, CR-,PR-Rate,

19 Sekundäre Zielkriterien RR nach 7 Zyklen, FFS, OS

20 Anzahl der zu behandelnden Patienten

Keine Angabe, Fallzahlkalkulation nach RR Rate nach 6 Zyklen (15% Differenz, 45% FM vs. 30% CHVP)

21 Zahl und Charakteristika der eingeschlossenen und ausgewerteten Patienten

155 Patienten wurden primär eingeschlossen. Es wurde ein zentraler Pathologie-Review durchgeführt. Danach wurden 11 Patienten ausgeschlossen. 144 Patienten wurden ausgewertet. Mittleres Alter 66 Jahre

22 Vergleichbarkeit der Behandlungsgruppen

Gleichmässige Verteilung in den Gruppen, etwas mehr Grad 1 FL in der FM-Gruppe (32% versus 22%).

23 Ergebnisse Nach 6 Zyklen FM versus CHVP: CR 34% versus 6% PR 45% versus 63% Failure 10 versus 26% (p=0.0001) Medianes Follow-up: 53 Monate 4-J-FFS-Rate 42 versus 10% (p=0.0001) 7-OS-Rate 53% (ohne Unterschied zwischen den Behandlungsarmen.

24 Unerwünschte Therapiewirkungen

Grad III/IV Alopezie: 41% CHVP versus 9% FM (p=0.001) Grad III/IV Infektionen: 5% versus 14% (n.s.) Grad III/IV Neutropenie: 54% versus 64% (n.s.)

25 Fazit der Autoren FM ist gut durchführbar und wirksam in der Erst-Linienbehandlung des indolenten Lymphoms bei älteren Patienten, assoziiert mit höherer Remissionsrate und längerem progressionsfreies Überleben als CHVP-Therapie. Eine PCP-Prophylaxe wird für das Fludarabin-haltige Regime empfohlen.

26 Abschließende Bewertung durch x den Bearbeiter □ die Expertengruppe

Behandlung älterer Patienten mit fortgeschrittenem, indolentem Lymphom ist mit der Kombination aus FM + PCP-Prophylaxe mit hoher Effizienz und guter Verträglichkeit verbunden.

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Bewertung und Extraktion von Therapiestudien Stand der Bearbeitung Bearbeiter Prof. Dr. med. J. T. Hartmann

Datum der Bearbeitung 15.02.2007

Datum der Diskussion mit der Expertengruppe

Nr. Feld Hinweise für die Bearbeitung

1 Quelle Hagenbeek A, Eghbali H, Monfardini S, Vitolo U, Hoskin PJ, Wolf-Peeters C, Maclennan K, Staab-Renner E, Kalmus J, Schott A, Teodorovic I, Negrouk A, van Glabbeke M, Marcus R. Phase III intergroup study of fludarabine phosphate compared with cyclophosphamide, vincristine, and prednisone chemotherapy in newly diagnosed patients with stage III and IV low-grade malignant Non-Hodgkin's lymphoma. J Clin Oncol 24: 1590-6, 2006.

2 Studientyp vom Autor bezeichnet als

Phase III Studie

3 Studientyp nach Durchsicht

Zuordnung zu einem der folgenden Studientypen: x Therapiestudie mit randomisierter Vergleichsgruppe □ Therapiestudie mit nicht-randomisierter

Vergleichsgruppe □ Therapiestudie mit Vergleichen über Zeit und Ort (z. B.

historische Kontrollen) □ Fallkontrollstudien □ Kohortenstudien □ Therapiestudie ohne Vergleichsgruppen (auch „Vorher-

Nachher-Studien“) □ Fallserie □ Fallbericht / Kasuistik (case report) □ Nicht eindeutig zuzuordnen

4 Formale Evidenzkriterien gemäß SIGN

Hier folgt eine formale Zuordnung zu den Evidenzstufen gemäß SIGN: □ 1++: Qualitativ hochwertige Metaanalyse bzw.

systematischer Review von RCTs oder RCT mit sehr geringem Risiko von Bias

x 1+: Gut durchgeführte Metaanalyse bzw. systematischer Review von RCTs oder RCT mit geringem Risiko von Bias

□ 1-: Metaanalyse bzw. systematischer Review von RCTs oder RCT mit hohem Risiko von Bias

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2

□ 2++: Qualitativ hochwertiger systematischer Review von

Fallkontroll- oder Kohortenstudien Qualitativ hochwertige Fallkontroll- oder Kohortenstudie mit sehr geringem Risiko von Confounding, Bias oder Zufallsschwankungen und hoher Wahrscheinlichkeit, dass der Zusammenhang kausal ist

□ 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie mit einem niedrigen Risiko von Confounding, Bias oder Zufallsschwankungen und einer mittleren Wahrschein-lichkeit, dass der Zusammenhang kausal ist

□ 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko von Confounding, Bias oder Zufallsschwankungen und einem signifikanten Risiko, dass der Zusammenhang nicht kausal ist

□ 3: Andere Studien wie Einzelfallberichte, Fallserien

□ 4: Expertenmeinung

5 Bezugsrahmen EORTC Lymphoma-Group, British National Lymphoma Investigation Group, Dutch-Belgian Working Party on Hemato-Oncology; Kein Hinweis auf inhaltlich relevante Interessenskonflikte

6 Indikation Stadium III und IV Niedrig maligne Non-Hodgkin Lymphome, Vergleich von Fludarabin Phosphat mit dem Kombinationsregime Cyclophosphamid, Vincristin und Prednison (CVP) in einer unbehandelten Patientengruppe

7 Fragestellung / Zielsetzung 15-% Differenz in der 4-Jahres-Progressionsrate. α-Fehler 0,05, beta-Fehler 0,2, Fallzahlkalkulation 163 Patienten/Behandlungsarm (Gesamtpatientenzahl 326)

8 Relevante Ein- und Ausschlusskriterien

Patienten mit Alter > 18 Jahre, unbehandelt, mit „low-grade“ Lymphom der Gruppen A, B oder C der „International Working Formulation“ (WF), Ann Arbor Stadium III oder IV, eingeschlossen nodale und Waldeyer’scher Rachenring-Lokalisationen, mindestens eine messbare Tumormasse, WHO Status 0-2.

9 Prüfintervention Vergleich von Fludarabin Phosphat (25 mg/m2/d i.v. an Tag 1-5, Wh alle 4 Wochen bis zu maximal 8 Zyklen versus CVP (Cyclophosphamid 750 mg/m2 i.v. an Tag 1, Vincristin Sulfat 1,2 mg/m2/i.v. (2 mg maximal) an Tag 1 und Prednison oder Prednisolon 40 mg/m2 p.o. an Tag 1-5, Wh alle 4 Wochen bis zu 8 Zyklen

10 Vergleichsintervention s.o.

11 Evtl. weitere Behandlungsgruppen

Entfällt

12 Studiendesign 2-armig, randomisiert, keine Daten zum Crossover, aber anzunehmen.

13 Zahl der Zentren 60

14 Randomisierung Randomisierung über die EORTC-Zentrale (Brüssel, Belgien)

15 Concealment („Maskierung“ der

Ja

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3

Randomisierung)

16 Verblindung der Behandlung

Erfolgte eine Verblindung der Behandlung? x Nein, offene Behandlung □ Patienten verblindet □ Behandler verblindet □ Patienten und Behandler verblindet Wie wurde die Verblindung durchgeführt?

17 Beobachtungsdauer 79 Monate

18 Primäre Zielkriterien 4-Jahres-pogressionsfreie Rate (Differenz antizipiert 15%)

19 Sekundäre Zielkriterien Remissionsrate (komplette/partielle Remission), TTP,Überleben

20 Anzahl der zu behandelnden Patienten

Fallzahlplanung siehe oben

21 Zahl und Charakteristika der eingeschlossenen und ausgewerteten Patienten

Es wurden 381 Patienten randomisiert. 194 Patienten in den Fludarabin-, 187Patienten in den CVP-Arm. Es folgte eine „intention-to-treat“ Analyse (ITT). Im Flowchart über die Dispositionen der Patienten sind keine systematischen oder relevanten Unterschiede zwischen den „Drop outs“und den gemäss dem Studienprotokoll behandelten Patienten zu erkennen. Die „Safety-Population“ beinhaltete 188 Patienten im Fludarabin- und 179 Patienten im CVP-Arm. Eine Darstellung des Patientenflusses nach dem Consort-Flussdiagramm ist in der Publikation gegeben.

22 Vergleichbarkeit der Behandlungsgruppen

Die Patientencharakteristika sind getrennt nach Studienarm dargestellt, betreffend Alter, Geschlecht, Ann-Arbor-Stadium, Histologie, LDH-Level, Knochenmarkbefall,WHO Performance-Status. Eine statistische Auswertung liegt nicht vor. Aufgrund der histologischen Vorgaben sind 19,1% der Patienten im Fludarabin-Arm sowie 21,4% der Patienten im CVP-Arm als Protokollverletzer zu werten. Grobe Abweichung bzgl. der Verteilungen ergeben sich sonst nicht. Aus dem Manuskript ist anzunehmen, dass die Patienten bis auf die Intervention gleichbehandelt wurden, allerdings handelt es sich um eine Multicenterstudie mit Einschluss von 60 Studienzentren, und dieser Aspekt ist in der Publikation nicht abgebildet.

23 Ergebnisse Es sind die Ergebnisse der ITT-Population dargestellt. Diese bezieht auch die etwa 20-%-ige Protokollviolation bzgl. der Histologie mit ein, im wesentlichen durch den Einschluss von CLL- sowie Mantelzell-Lymphomen. Die Responserate wurde durch Fludarabin signifikant verbessert. Die CR-Rate lag bei 38,6 versus 15,0%. Es ergaben sich keine statistischen Unterschiede in der „Time to progression“ oder „Time to treatment failure“ oder in im Gesamtüberleben. Die Gesamtansprechrate betrug 70% unter Fludarabin und 51,9% und CVP. Es ergaben sich bzgl. des Ansprechens keine Unterschiede zwischen Patienten, die bzgl. der „Watch and wait policy“ verfolgt wurden oder eine sofortige Behandlung im Rahmen es Protokolls erhielten.

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24 Unerwünschte Therapiewirkungen

Die Therapie mit Fludarabin war mit einer höheren Rate an Grad III/IV hämatologischen Toxizitäten verbunden (WHO-Klassifikation). Allerdings kamen es nicht zu häufigeren Infektionen unter den Patienten, die Fludarabin erhielten. Insgesamt brachen 13 Patienten im Fludarabin-Arm die Therapie aufgrund der Toxizität ab, ein Patient im CVP-Arm.

25 Fazit der Autoren Bei Patienten mit low-grade Non-Hodgkin-Lymphomen wurden mit Fludarabin höhere Gesamtansprechraten sowie höhere komplette Remissionsraten verglichen mit CVP-behandelten Patienten beobachtet. Es ergaben sich keine Unterschiede zwichen TTP, TTF und OS. Fludarabin ist eine hochaktive Mono-Therapie in dieser Patientengruppe.

26 Abschließende Bewertung durch x den Bearbeiter □ die Expertengruppe

Das primäre Studienziel wurde in dieser randomisierten Phase-3-Gruppe nicht erreicht. Es fanden sich Vorteile zugunsten Fludarabin bzgl. der objektiven Remissionsrate sowie der kompletten Remission, die sich aber im Rahmen des Beobachtungszeitraums nicht in einen Vorteil im progressionfreien Überleben oder Gesamtüberleben widerspiegelten (wie in dieser Patientengruppe mit langsamen Progressionsverlauf häufig). Die Nebenwirkungsrate war, was die hämatologische Toxizität angeht, im Fludarabin-Arm erhöht.

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Bewertung und Extraktion von Therapiestudien Stand der Bearbeitung Bearbeiter Prof. Dr. med. J. T. Hartmann

Datum der Bearbeitung 26.02.2007

Datum der Diskussion mit der Expertengruppe

Nr. Feld Hinweise für die Bearbeitung

1 Quelle Klasa RJ, Meyer RM, Shustik C, Sawka CA, Smith A, Guevin R, Maksymiuk A, Rubinger M, Samosh M, Laplante S, Grenier JF. Randomized phase III study of fludarabine phosphate versus cyclophosphamide, vincristine, and prednisone in patients with recurrent low-grade non-Hodgkin's lymphoma previously treated with an alkylating agent or alkylator-containing regimen. J Clin Oncol 20: 4649-54, 2002.

2 Studientyp vom Autor bezeichnet als

Randomisiert, Phase III

3 Studientyp nach Durchsicht

Zuordnung zu einem der folgenden Studientypen: x Therapiestudie mit randomisierter Vergleichsgruppe □ Therapiestudie mit nicht-randomisierter

Vergleichsgruppe □ Therapiestudie mit Vergleichen über Zeit und Ort (z. B.

historische Kontrollen) □ Fallkontrollstudien □ Kohortenstudien □ Therapiestudie ohne Vergleichsgruppen (auch „Vorher-

Nachher-Studien“) □ Fallserie □ Fallbericht / Kasuistik (case report) □ Nicht eindeutig zuzuordnen

4 Formale Evidenzkriterien gemäß SIGN

Hier folgt eine formale Zuordnung zu den Evidenzstufen gemäß SIGN: □ 1++: Qualitativ hochwertige Metaanalyse bzw.

systematischer Review von RCTs oder RCT mit sehr geringem Risiko von Bias

x 1+: Gut durchgeführte Metaanalyse bzw. systematischer Review von RCTs oder RCT mit geringem Risiko von Bias

□ 1-: Metaanalyse bzw. systematischer Review von RCTs oder RCT mit hohem Risiko von Bias

Page 25: Fludara i.v. (2nd line NHL)

□ 2++: Qualitativ hochwertiger systematischer Review von

Fallkontroll- oder Kohortenstudien Qualitativ hochwertige Fallkontroll- oder Kohortenstudie mit sehr geringem Risiko von Confounding, Bias oder Zufallsschwankungen und hoher Wahrscheinlichkeit, dass der Zusammenhang kausal ist

□ 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie mit einem niedrigen Risiko von Confounding, Bias oder Zufallsschwankungen und einer mittleren Wahrschein-lichkeit, dass der Zusammenhang kausal ist

□ 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko von Confounding, Bias oder Zufallsschwankungen und einem signifikanten Risiko, dass der Zusammenhang nicht kausal ist

□ 3: Andere Studien wie Einzelfallberichte, Fallserien

□ 4: Expertenmeinung

5 Bezugsrahmen Industriegesponsert: Unterstützt von Berlex, Kanada

6 Indikation low-grade NHL und CLL, vorbehandelt

7 Fragestellung / Zielsetzung Überlegenheit einer Fludarabin-Therapie gegenüber der Therapie mit CVD im 18-Monats-PFS

8 Relevante Ein- und Ausschlusskriterien

Histologie gemäss inter. Working formulation WHO PS >=2 Alter >18 Jahre Übliche Parameter für Nieren-Leber und hämatologische Funktion

9 Prüfintervention FLU: Fludarabin 25 mg/m2 d1-5 alle 4 Wochen

10 Vergleichsintervention CVP (Cyclophosphamid 750 mg/m2 d1/Vincristin 1,2 mg/m2 d1/Prednison 40 mg/m2 d1-5) alle 3 Wochen

11 Evtl. weitere Behandlungsgruppen

Entfällt

12 Studiendesign Randomisation in 2 Behandlungsarme Stratifikation in Vortherapien (Zahl), Alter, Art der Vortherapie (Antrazyklin vs. Nicht-Antrazyklin)

13 Zahl der Zentren 18

14 Randomisierung Ja

15 Concealment („Maskierung“ der Randomisierung)

Maskiert

Page 26: Fludara i.v. (2nd line NHL)

16 Verblindung der

Behandlung Erfolgte eine Verblindung der Behandlung? x Nein, offene Behandlung □ Patienten verblindet □ Behandler verblindet □ Patienten und Behandler verblindet Wie wurde die Verblindung durchgeführt?

17 Beobachtungsdauer Mittlere Beobachtungsdauer 42 Monate

18 Primäre Zielkriterien PFS nach 18 Monaten (20% Differenz zugunsten Fludarabin), Alpha 5%, beta 20%,

19 Sekundäre Zielkriterien Ansprechraten CR/PR/PD Toxizität Überleben QoL und „Soziale Funktion“ (nicht genau angegeben, ob mit Fragebogen erfasst) Zeit bis zum Einsatz einer folgenden Chemotherapie

20 Anzahl der zu behandelnden Patienten

N=180 über 3 Jahre

21 Zahl und Charakteristika der eingeschlossenen und ausgewerteten Patienten

91 Patienten aufgrund langsamer Rekrutierung 98% in Stad. III/IV für beide Gruppen, gleichverteilt. Es gibt keine statistischen Unterschiede in der Verteilung der Gruppen. Alle eingeschlossenen Patienten wurden ausgewertet.

22 Vergleichbarkeit der Behandlungsgruppen

Es liegen die Angaben, getrennt nach Behandlungsgruppen, in tabellarischer Form nachvollziehbar vor für Alter, Geschlecht, Histologie, Stage Ann-Arbor, WHO PS, Anzahl der Vortherapien, durchschnittliche Zeit von der Diagnose, Monate von der letzten Therapie. Es gibt keine relevanten Unterschiede zwischen den Behandlungsgruppen.

23 Ergebnisse CR/PR Fludarabin: 9 / 55% CR/PR CVP: 7 % / 45%: Medianes PFS Fludarabin: 11 Monate vs. CVP: 9,2 Monate (p=0,03) 2-Jahres PFS: Fludarabin 30% vs. CVP: 13% Zeit bis zum Einsatz einer folgenden Chemotherapie unter Fludarabin 15,3 Monate vs. CVP 11,2 Monate QoL ohne signifikanten Unterschied in beiden Gruppen. Höhere Scores bzgl. „social function“ zugunsten Fludarabin (p=0.008).

24 Unerwünschte Therapiewirkungen

Fludarabin verursacht mehr Grad III/IV Neutropenie (22 vs. 11%) Mehr Neurotoxizität, Alopezie in CVP-Gruppe Keine unbekannten Toxizitäten

25 Fazit der Autoren Die Fludarabin-Monotherapie verbessert PTS, TFS und „social function scores“ bei rezidivierten, fortgeschrittenen low grade Lymphomen.

Page 27: Fludara i.v. (2nd line NHL)

26 Abschließende Bewertung durch X den Bearbeiter □ die Expertengruppe

Gut durchgeführte und dokumentierte Phase III-Studie, die die Wirksamkeit von Fludarabin gegenüber CVP beim rezidivierten, fortgeschrittenen low grade Lymphom im randomisierten Vergleich belegt. Die längere Nachbeobachtungszeit mit höherer Anzahl von Ereignissen kompensiert die geringere Zahl eingeschlossener Patienten.

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Bewertung und Extraktion von Therapiestudien Stand der Bearbeitung Bearbeiter Prof. Dr. med. J. T. Hartmann

Datum der Bearbeitung 15.02.2007

Datum der Diskussion mit der Expertengruppe

Nr. Feld Hinweise für die Bearbeitung

1 Quelle Lazzarino M, Orlandi E, Baldanti F, Furione M, Pagnucco G, Astori C, Arcaini L, Viglio A, Paulli M, Gerna G, Bernasconi C. The immunosuppression and potential for EBV reactivation of fludarabine combined with cyclophosphamide and dexamethasone in patients with lymphoproliferative disorders. Br J Haematol 107: 877-82, 1999.

2 Studientyp vom Autor bezeichnet als

Phase II, unkontrolliert

3 Studientyp nach Durchsicht

Zuordnung zu einem der folgenden Studientypen: □ Therapiestudie mit randomisierter Vergleichsgruppe □ Therapiestudie mit nicht-randomisierter

Vergleichsgruppe □ Therapiestudie mit Vergleichen über Zeit und Ort (z. B.

historische Kontrollen) □ Fallkontrollstudien □ Kohortenstudien x Therapiestudie ohne Vergleichsgruppen (auch „Vorher-

Nachher-Studien“) □ Fallserie □ Fallbericht / Kasuistik (case report) □ Nicht eindeutig zuzuordnen

4 Formale Evidenzkriterien gemäß SIGN

Hier folgt eine formale Zuordnung zu den Evidenzstufen gemäß SIGN: □ 1++: Qualitativ hochwertige Metaanalyse bzw.

systematischer Review von RCTs oder RCT mit sehr geringem Risiko von Bias

□ 1+: Gut durchgeführte Metaanalyse bzw. systematischer Review von RCTs oder RCT mit geringem Risiko von Bias

□ 1-: Metaanalyse bzw. systematischer Review von RCTs oder RCT mit hohem Risiko von Bias

Page 29: Fludara i.v. (2nd line NHL)

□ 2++: Qualitativ hochwertiger systematischer Review von

Fallkontroll- oder Kohortenstudien Qualitativ hochwertige Fallkontroll- oder Kohortenstudie mit sehr geringem Risiko von Confounding, Bias oder Zufallsschwankungen und hoher Wahrscheinlichkeit, dass der Zusammenhang kausal ist

x 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie mit einem niedrigen Risiko von Confounding, Bias oder Zufallsschwankungen und einer mittleren Wahrschein-lichkeit, dass der Zusammenhang kausal ist

□ 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko von Confounding, Bias oder Zufallsschwankungen und einem signifikanten Risiko, dass der Zusammenhang nicht kausal ist

□ 3: Andere Studien wie Einzelfallberichte, Fallserien

□ 4: Expertenmeinung

5 Bezugsrahmen Prof. Lazzarino, Institute of Hematology, Policlinico San Matteo, Pavia, Italy

6 Indikation Patienten mit lymphoproliferativen Erkrankungen.

7 Fragestellung / Zielsetzung Frage nach der Immunsuppression und möglicher EBV-Reaktivierung von Fludarabin kombiniert mit Cyclophosphamid und Dexamethason

8 Relevante Ein- und Ausschlusskriterien

Typische Einschlusskriterien bzgl. der Hämatologie, Leber und Nierenfunktion. „erwachsene Patienten“ mit low-grade NHL oder CLL EBV-Serologie positiv

9 Prüfintervention Fludarabin 25 mg/m2/d Tag 1-3, Cyclophosphamid 350 mg/m2 d1-3 i.v., Dexamethason 20 mg/d po d1-3 Wh an Tag 28 für max. 6 Zyklen. Anpassung der Dosierung an hämatologische, Leber- und Nierentoxizität. PCP-Prophylaxe Kein GCSF

10 Vergleichsintervention Entfällt

11 Evtl. weitere Behandlungsgruppen

Entfällt

12 Studiendesign Offene, einarmige Phase II Studie

13 Zahl der Zentren Nicht angegeben

14 Randomisierung Entfällt

15 Concealment („Maskierung“ der Randomisierung)

Entfällt

16 Verblindung der Behandlung

Erfolgte eine Verblindung der Behandlung? x Nein, offene Behandlung □ Patienten verblindet □ Behandler verblindet □ Patienten und Behandler verblindet

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Wie wurde die Verblindung durchgeführt?

17 Beobachtungsdauer 114 Monate

18 Primäre Zielkriterien RR (CR, PR), EBV-Reaktivierung, CD4/8 Zellzahl, histologische Transformation in high grade NHL

19 Sekundäre Zielkriterien

20 Anzahl der zu behandelnden Patienten

24 Patienten

21 Zahl und Charakteristika der eingeschlossenen und ausgewerteten Patienten

24 Patienten, vorbehandelt, mittleres Alter 56 Jahre, Mittlere Zahl an Vortherapien 2 (1-4). Mittleres Intervall von Diagnosestellung: 44 Monate 21 Patienten mit low-grade NHL 3 Patienten mit CLL

22 Vergleichbarkeit der Behandlungsgruppen

Entfällt

23 Ergebnisse 22 Patienten (91%) erhielten 5 oder 6 Zyklen, 2 Patienten Stop aufgrund von Toxizität (n=24) Overall RR: 79% (36% CR, 50% PR)

24 Unerwünschte Therapiewirkungen

CD4 Zellzahl (n=19): Abfall auf ein Minimum nach dem 6. Zyklus (max. 484 CD4+/ul, min. 198 CD4+/ul) Im 12 Monate Follow-up: 229 CD4+/ul (n=9) 16 Infektionen bei 11/24 Patienten, keine Hospitalisierung notwendig EBV-Kopien: Peak am Ende der Therapie, wenn die CD4 Zellen ein Minimum erreicht haben. Im Follow-up sinken die Kopien mit steigender CD4-Zellzahl. Insgesamt 6/24 Patienten (25%) Transformation im Mittel 39 Monate nach Diagnosestellung und 8 Monate nach Fludarabin-Therapie (von 5 Non-Respondern 2 mit Transformation)..

25 Fazit der Autoren Fludarabin mit Cyclophosphamid und Dexamethason führt zu einem deutlichen Abfall der CD-4 Zellzahl. Dies war jedoch nicht assoziiert mit einer höheren Rate an opportunistischen Infektionen. Die untersuchten Fälle zeigen keine höhere Rate an EBV-assoziierten histologische Transformationen. Die beobachtete EBV-Reaktivierung war nach Therapieabschluss regredient.

26 Abschließende Bewertung durch x den Bearbeiter □ die Expertengruppe

Eine PCP-Prophylaxe erscheint sinnvoll unter Fludarabin-Therapie, insbesondere wenn kombiniert mit Steroiden. Darunter ist die Fludarabin assoziierte Immunsuppression nicht mit vermehrten opportunistischen Infektionen verbunden. Die Daten belegen auch die Effizienz einer Fludarabin-kombinieren Therapie bei low-grade NHL.

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1

Bewertung und Extraktion von Therapiestudien Stand der Bearbeitung Bearbeiter Axel Heyll

Stand der Bearbeitung 08.01.2009 Nr. Feld Hinweise für die Bearbeitung

1 Quelle Leblond V et al., Blood 98: 2640-2644, 2001

2 Studientyp vom Autor bezeichnet als

Randomisierte multizentrische Studie

3 Studientyp nach Durchsicht

Zuordnung zu einem der folgenden Studientypen: X Therapiestudie mit randomisierter Gruppenzuteilung □ Therapiestudie mit nicht-randomisierter

Gruppenzuteilung □ Therapiestudie mit Vergleichen über Zeit und Ort (z. B.

historische Kontrollen) □ Therapiestudie ohne Vergleichsgruppen (auch

Beobachtungsstudien und Anwendungsbeobachtungen) □ Fall-Kontrollstudien □ Fallserie □ Fallbericht / Kasuistik (case report) □ Nicht eindeutig zuzuordnen Falls Therapiestudie: □ mit Placebokontrolle(n) X mit Aktivkontrolle(n) □ mit Dosisgruppen □ sonstige Kontrollgruppe(n): Nennen

4 Formale Evidenzkriterien gemäß SIGN

□ 1++: Qualitativ hochwertige Metaanalyse bzw. systematischer Review von RCTs oder RCT mit sehr geringem Risiko von Bias

X 1+: Gut durchgeführte Metaanalyse bzw. systematischer Review von RCTs oder RCT mit geringem Risiko von Bias

□ 1-: Metaanalyse bzw. systematischer Review von RCTs oder RCT mit hohem Risiko von Bias

□ 2++: Qualitativ hochwertiger systematischer Review von Fallkontroll- oder Kohortenstudien oder Qualitativ hochwertige Fallkontroll- oder Kohortenstudie mit sehr geringem Risiko von Confounding, Bias oder Zufallsschwankungen und hoher Wahrscheinlichkeit, so dass der Zusammenhang kausal ist

□ 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie mit niedrigem Risiko von Confounding, Bias oder Zufallsschwankungen und einer mittleren Wahrschein-lichkeit, so dass der Zusammenhang kausal ist

□ 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko von Confounding, Bias oder Zufallsschwankungen und

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2

Nr. Feld Hinweise für die Bearbeitung einem signifikanten Risiko, so dass der Zusammenhang nicht kausal ist

□ 3: Andere Studien wie Einzelfallberichte, Fallserien

□ 4: Expertenmeinung

5 Bezugsrahmen Therapieoptimierungsstudie einer französischen Studiengruppe (French Cooperative Group on Chronic Lymhocytic Leukemia and Makroglobulinemia), IIT, keine angaben zu Interessenkonflikten

6 Indikation Waldenström Makroglobulinämie (lymphoplasmozytisches NHL nach WHO mit IgM-Paraproteinämie)

7 Primäre Fragestellung / primäre Zielsetzung(en)

Verdopplung der Ansprechrate durch Fludarabin im Vergleich zu CAP von 25% auf 50%

8 Relevante Ein- und Ausschlusskriterien

Alter 18 – 75 Jahre Histologische und laborchemische Diagnose eines

lymphoplasmozytischen NHL nach WHO mit IgM-Paraproteinämie

Rezidiv oder primär refraktär nach/auf Alkylantien-haltige Chemotherapie

9 Prüfintervention Fludarabin 25 mg/m2 Tag 1-5, alle 4 Wochen für 6 Kurse

10 Vergleichsintervention Cyclophosphamid 750 mg/m2 Tag 1, Doxorubicin 25 mg/m2 Tag 1 und Prednison 40 mg/m2 Tag 1 – 5, alle 4 Wochen für 6 Kurse

11 Evtl. weitere Behandlungsgruppen

Keine

12 Subgruppen Enthält die Studie Subgruppen, die für die Fragestellung an die Kommission relevant sind? X keine relevanten Subgruppen □ prospektiv geplante Subgruppenauswertung □ post hoc definierte oder in Auswertung gefundene

Subgruppen Subgruppen ggf. benennen

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13 Studiendesign Anzahl der Behandlungsarme Typus: X Parallelgruppendesign □ Cross-Over Design □ Prae-Post-Vergleich □ Sonstige:......................... Geplante Fallzahl (falls angegeben) 176 Patienten Wurde eine Fallzahlplanung (Power-Kalkulation) durchgeführt? Ja Waren Interimanalysen geplant? Ja

14 Zentren Anzahl der Zentren 37 Vergleichbarkeit der Studiendurchführung in den einzelnen Zentren beurteilen Nicht angegeben

15 Randomisierung Ausreichend beschrieben? Nicht beschrieben Erfolgte die Randomisierung maskiert, d.h. wurde sicher gestellt, dass die Randomisierungssequenz vor Behandlern und den Studienteilnehmern verborgen blieb (Concealment; z.B. durch zentrale telefonische Randomisierung)? Nicht beschrieben

16 Verblindung der Behandlung

X Keine Verblindung (offene Behandlung) □ Patienten verblindet □ Behandler verblindet □ Beurteiler verblindet ( z.B. bei Bildgebung)

17 Beobachtungsdauer Median 52 Monate für überlebende Patienten

18 Primäre Zielkriterien Zielkriterien (outcomes) nennen, die von den Autoren als die primären bzw. Haupt-Zielkriterien genannt wurden. Ansprechrate Wurden relevante patientennahe Zielkriterien verwendet? Ja als sekundärer Endpunkt auch Überlebenszeit Mit welchen Instrumenten und in welcher Form erfolgte die Erfassung der Zielkriterien (z. B. Interview, Untersuchung, standardisierte Fragebögen, Referenzbeurteilung)? Nicht angegeben

19 Sekundäre Zielkriterien Ereignisfreies Überleben Überleben

20 Statistische Methoden für die Analyse der primären Endpunkte

Bezeichnung der verwendeten Test- bzw. Schätzprozeduren Für primären Endpunkt nicht angegeben, für Überleben Log-Rang-Test Signifikanz-/Konfidenzniveau Für primären Endpunkt p=0,05

21 Anzahl der behandelten Patienten

Erreichte Fallzahl. 92

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Wurde die Studie vorzeitig beendet? (Gründe) Geplante Fallzahl nicht erreicht, keine Begründung angegeben

22 Zahl und Charakteristika der eingeschlossenen und ausgewerteten Patienten

Differenzierte Darstellung nach Behandlungsgruppen vorhanden? Ja Darstellung des Patientenflusses nach CONSORT Angaben zu möglicherweise ausgeschlossenen Patienten fehlen Sind die Ausfälle von Studienteilnehmern (Drop-outs) dokumentiert und begründet? S. o. Erfolgte eine Intention-to-treat- (ITT-) Analyse? Keine Angabe Erfolgte eine Per Protocol- (PP-) Analyse? S. o. Gibt es Hinweise auf systematische und relevante Unterschiede zwischen den Drop-outs und den gemäß Studienprotokoll behandelten Patienten. Angaben fehlen

23 Vergleichbarkeit der Behandlungsgruppen

Gibt es relevante Unterschiede zwischen den Behandlungsgruppen □ bei Studienbeginn (Baseline)? □ in der Durchführung der Intervention?

24 Ergebnisse und ihre Darstellung

Studienarm Fludarabin CAP Patientenzahl n=46 n=46 Endpunkte Dauer Remission Ansprechrate Reduktion M-Gradient und Tumorgröße > 50% 30 % 11% p-Wert 0,02 Remissionsdauer Median, Monate 19 3 p-Wert 0,02 Überleben Median, Monate 41 45 p-Wert 0,89

25 Unerwünschte Therapiewirkung

Sind unerwünschte Ereignisse (UEs/AEs) berichtet? Ja Sind schwerwiegende UEs (SUEs/SAEs) berichtet? Ja Wurde der Bezug zur Behandlung beurteilt? Ja

26 Fazit der Autoren Fludarabin war „aktivere“ Rezidivtherapie

27 Abschließende Bewertung durch den Bearbeiter

Es handelt sich um eine rein palliativ wirksame Therapie, deshalb sind die Endpunkte Ansprechrate oder Remissionsdauer nicht relevant. Entscheidend für die Nutzenbewertung ist vielmhr der Endpunkt Überlebenszeit. Bei einer gleichen Anzahl von Todesfällen in beiden Armen ergibt sich kein Hinweis auf eine überlegene Wirksamkeit von Fludarabin. Bei CAP handelt es sich um

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ein dosisreduziertes CHOP-Protokoll. Es kann deshalb vernutet werden, dass CHOP mindestens genau so wirksam, möglicherweise sogar noch wirksamer ist als Fludarabin bei Zweitlinientherapie nach Vorbehandlung mit Alkylantien

Page 36: Fludara i.v. (2nd line NHL)

Zu Feld 24 Ergebnisdarstellung für quantitative Zielkriterien (mit Beispiel)

Prüftherapie Kontrolle Zielkriterium

n x SD* n x SD*

Maß für Gruppen- unterschied

Schätzer und 95% Konfidenzintervall für Gruppenunterschied

p-Wert (optional)

VAS 117 20.4 7.4 123 15.6 4.5 Differenz** 4.8 (3.25 ; 6.35)

* ggf. aus SE umrechnen: nSESD ⋅= ** Es kann u.U. notwendig sein, die Richtung des angegebenen Unterschieds deutlich zu machen (z.B. „negative Angaben kennzeichnen eine Überlegenheit von Verum“) Ergebnisdarstellung für dichotome Zielkriterien (mit Beispiel)

Anzahl Patienten mit Ereignis / Anzahl aller Patienten Zielkriterium Verum Kontrolle

Maß für Gruppen- unterschied

Schätzer und 95% Konfidenzintervall für Gruppenunterschied

p-Wert (optional)

Erfolg 12 / 120 (10%) 8 / 127 (6.3%) Odds Ratio 1.65 (0.65 ; 4.2)

6

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1

Bewertung und Extraktion von Therapiestudien Stand der Bearbeitung Bearbeiter Prof. Dr. med. J. T. Hartmann

Datum der Bearbeitung 31.12.2007

Datum der Diskussion mit der Expertengruppe

Nr. Feld Hinweise für die Bearbeitung

1 Quelle Pro,-B; Hagemeister,-F-B; McLaughlin,-P; Romaguera,-J; Rodriguez,-M-A; Cabanillas,-F; Tiongson,-L-P; Younes,-A Phase 2- Study of Fludarabine and Paclitaxel in patients with recurrent low-grade non-Hodgkin`s lymphoma. Leuk-Lymphoma. 2006; 47(9): 1818-21

2 Studientyp vom Autor bezeichnet als

Phase II Studie

3 Studientyp nach Durchsicht

Zuordnung zu einem der folgenden Studientypen: � Therapiestudie mit randomisierter Vergleichsgruppe x Therapiestudie mit nicht-randomisierter

Vergleichsgruppe � Therapiestudie mit Vergleichen über Zeit und Ort (z. B.

historische Kontrollen) � Fallkontrollstudien � Kohortenstudien � Therapiestudie ohne Vergleichsgruppen (auch „Vorher-

Nachher-Studien“) � Fallserie � Fallbericht / Kasuistik (case report) � Nicht eindeutig zuzuordnen

4 Formale Evidenzkriterien gemäß SIGN

Hier folgt eine formale Zuordnung zu den Evidenzstufen gemäß SIGN: � 1++: Qualitativ hochwertige Metaanalyse bzw.

systematischer Review von RCTs oder RCT mit sehr geringem Risiko von Bias

� 1+: Gut durchgeführte Metaanalyse bzw. systematischer Review von RCTs oder RCT mit geringem Risiko von Bias

� 1-: Metaanalyse bzw. systematischer Review von RCTs oder RCT mit hohem Risiko von Bias

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2

� 2++: Qualitativ hochwertiger systematischer Review von

Fallkontroll- oder Kohortenstudien Qualitativ hochwertige Fallkontroll- oder Kohortenstudie mit sehr geringem Risiko von Confounding, Bias oder Zufallsschwankungen und hoher Wahrscheinlichkeit, dass der Zusammenhang kausal ist

x 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie mit einem niedrigen Risiko von Confounding, Bias oder Zufallsschwankungen und einer mittleren Wahrschein-lichkeit, dass der Zusammenhang kausal ist

� 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko von Confounding, Bias oder Zufallsschwankungen und einem signifikanten Risiko, dass der Zusammenhang nicht kausal ist

� 3: Andere Studien wie Einzelfallberichte, Fallserien

� 4: Expertenmeinung

5 Bezugsrahmen Department of Lymphoma and Myeloma, University of Texas, MD Anderso Cancer Centre, Houston, Texas

6 Indikation Rezidiviertes low grade NHL

7 Fragestellung / Zielsetzung Wirksamkeit von Fludarabin kombiniert mit Paclitaxel bei Patienten mit rezidiviertem low grade B-NHL

8 Relevante Ein- und Ausschlusskriterien

Rezidiviertes low grade B-NHL PS 0-2, Lebenserwartung > 3 Monate

9 Prüfintervention Fludarabin 20 mg/m2i.v. Tag 1-5 Paclitaxel 50 mg/m2 i.v./72 Std. kont. Wdh. Tag 29, insgesamt max. 6 Zyklen, wenn mindestens PR erreicht nach 2 Zyklen G-CSF nur bei neutropenem Fieber

10 Vergleichsintervention Kein Vergleich

11 Evtl. weitere Behandlungsgruppen

entfällt

12 Studiendesign Offene, nichtvergleichende, Phase II Studie

13 Zahl der Zentren 1

14 Randomisierung entfällt

15 Concealment („Maskierung“ der Randomisierung)

16 Verblindung der Behandlung

Erfolgte eine Verblindung der Behandlung? x Nein, offene Behandlung � Patienten verblindet � Behandler verblindet � Patienten und Behandler verblindet Wie wurde die Verblindung durchgeführt?

17 Beobachtungsdauer 84 Monate

18 Primäre Zielkriterien RR: PR, CR, PD

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„Failure free survival“, Gesamtüberleben

19 Sekundäre Zielkriterien Sh. oben: nicht als primäre und sekundäre Zielkriterien definiert

20 Anzahl der zu behandelnden Patienten

32 Patienten eingeschlossen: 3 wegen high-grade ausgeschlossen, 1 Patient wegen MALT (einziger Patient) ausgeschlossen 28 Patienten auswertbar

21 Zahl und Charakteristika der eingeschlossenen und ausgewerteten Patienten

Mittleres Alter: 53 Jahre (26-74) 78 % follikuläres Lymphom vorbehandelt, im Mittel eine vorherige Chemotherapie (range: 1-3)

22 Vergleichbarkeit der Behandlungsgruppen

entfällt

23 Ergebnisse Ausgewertet für Toxizität: n=28 Studienabbruch bei 2 Patienten wegen Toxizität: neutropenes Fieber und Sepsis, Myokardinfarkt nach dem 2. Zyklus mit Todesfolge. 34% Neutropenes Fieber 13% Infektion, 7% Mucositis 3% Neuropathie Ansprechraten: Overall RR: 57%: CR: 9/28, PR: 7/28 Median time to treatment failure: 10 Monate

24 Unerwünschte Therapiewirkungen

Myokardinfarkt nach dem 2. Zyklus mit Todesfolge sh. Oben

25 Fazit der Autoren Der erhöhten Hämatotoxizität könnte man mit einer regelmässigen G-CSF-Substitution entgegenwirken. Die Zugabe von Rituximab könnte die Ansprechraten und Remissionsdauern noch verlängern und sollte im Weiteren untersucht werden.

26 Abschließende Bewertung durch x den Bearbeiter � die Expertengruppe

Hohe Hämatotoxizität und hohe Zahl von neutropenem Fieber mit 34% plus einem Patienten mit Sepsis. Der Todesfall mit Myokardinfarkt wird in der Diskussion nicht bewertet. Kleine Fallzahl, die Kombination mit Paclitaxel scheint hämatotoxisch und in der Wirksamkeit nicht überlegen im Vergleich zu anderen Kombinationen/Fludarabin alleine.

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Bewertung und Extraktion von Therapiestudien Stand der Bearbeitung Bearbeiter Prof. Dr. med. J. T. Hartmann

Datum der Bearbeitung 27.12.2007

Datum der Diskussion mit der Expertengruppe

Nr. Feld Hinweise für die Bearbeitung

1 Quelle Sacchi,-S; Pozzi,-S; Marcheselli,-R; Federico,-M; Tucci,-A; Merli,-F; Orsucci,-L; Liberati,-M; Vallisa,-D; Brugiatelli,-M Rituximab in Combination with Fludarabine and Cyclophosphamide in the treatment of patients with recurrent follicular lymphoma. Cancer. 2007; 110(1): 121-8

2 Studientyp vom Autor bezeichnet als

Phase II Studie..

3 Studientyp nach Durchsicht

Zuordnung zu einem der folgenden Studientypen: � Therapiestudie mit randomisierter Vergleichsgruppe x Therapiestudie mit nicht-randomisierter

Vergleichsgruppe � Therapiestudie mit Vergleichen über Zeit und Ort (z. B.

historische Kontrollen) � Fallkontrollstudien � Kohortenstudien � Therapiestudie ohne Vergleichsgruppen (auch „Vorher-

Nachher-Studien“) � Fallserie � Fallbericht / Kasuistik (case report) � Nicht eindeutig zuzuordnen

4 Formale Evidenzkriterien gemäß SIGN

Hier folgt eine formale Zuordnung zu den Evidenzstufen gemäß SIGN: � 1++: Qualitativ hochwertige Metaanalyse bzw.

systematischer Review von RCTs oder RCT mit sehr geringem Risiko von Bias

� 1+: Gut durchgeführte Metaanalyse bzw. systematischer Review von RCTs oder RCT mit geringem Risiko von Bias

� 1-: Metaanalyse bzw. systematischer Review von RCTs oder RCT mit hohem Risiko von Bias

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� 2++: Qualitativ hochwertiger systematischer Review von

Fallkontroll- oder Kohortenstudien � Qualitativ hochwertige Fallkontroll- oder Kohortenstudie

mit sehr geringem Risiko von Confounding, Bias oder Zufallsschwankungen und hoher Wahrscheinlichkeit, dass der Zusammenhang kausal ist

x 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie mit einem niedrigen Risiko von Confounding, Bias oder Zufallsschwankungen und einer mittleren Wahrschein-lichkeit, dass der Zusammenhang kausal ist

� 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko von Confounding, Bias oder Zufallsschwankungen und einem signifikanten Risiko, dass der Zusammenhang nicht kausal ist

� 3: Andere Studien wie Einzelfallberichte, Fallserien

� 4: Expertenmeinung

5 Bezugsrahmen Multicenter Phase II Studie Prüfung der Sicherheit und Aktivität der Kombination von Rituximab/Fludarabin und Cyclophosphamid bei Patienten mit rezidiviertem follikulärem B-NHL.

6 Indikation Rezidiviertes follikuläres B-NHL

7 Fragestellung / Zielsetzung Prüfung der Sicherheit und Aktivität der Kombination von Rituximab/Fludarabin und Cyclophosphamid bei Patienten mit rezidiviertem follikulärem B-NHL

8 Relevante Ein- und Ausschlusskriterien

Rezidiviertes follikuläres B-NHL, Grad I-II (WHO) Stadium IIB oder bulky, III, IV Alter 18-70 Jahre PS 0-2

9 Prüfintervention Fludarabin 25 mg/m2i.v. d1, Cyclophosphamid 300 mg/m2 i.v. d2-3, Wdh. d22, insgesamt 4 Zyklen. Rituximab 375 mg/m2 Beginn nach 2 Wochen, dann an Tag 1 des nächsten Zyklus Cotrim-Prophylaxe, Aciclovir-Prophylaxe und G-CSF fakultativ

10 Vergleichsintervention Kein Vergleich

11 Evtl. weitere Behandlungsgruppen

entfällt

12 Studiendesign Offene, nichtvergleichende, multizentrische Phase II Studie

13 Zahl der Zentren 10

14 Randomisierung entfällt

15 Concealment („Maskierung“ der Randomisierung)

16 Verblindung der Behandlung

Erfolgte eine Verblindung der Behandlung? x Nein, offene Behandlung � Patienten verblindet � Behandler verblindet

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� Patienten und Behandler verblindet Wie wurde die Verblindung durchgeführt?

17 Beobachtungsdauer 8 Jahre

18 Primäre Zielkriterien Nicht als solche (primär/sekundär) definiert: Erfasste Daten: ab Behandlung PR, CR, Survival Remissionsdauer, TTP, Überleben

19 Sekundäre Zielkriterien Sh. Oben

20 Anzahl der zu behandelnden Patienten

54

21 Zahl und Charakteristika der eingeschlossenen und ausgewerteten Patienten

Mittleres Alter: 62 Jahre Vorbehandelte Patienten: 20% mit mindestens 2 vorherigen Chemotherapieregimen 29/45 Patienten waren positiv für bcl2 rearrangement 81% Stage III/IV

22 Vergleichbarkeit der Behandlungsgruppen

entfällt

23 Ergebnisse Ausgewertet für Toxizität: n=52 Hämatologische Toxizität: 3 Patienten wurden wegen prolongierter Neutropenie ausgeschlossen Grad III/IV Neutropenie: 40% Diagnose eines MDS bei einem Patienten nach 32 Monaten 92% vollendeten die geplante Therapie (n=49) Overall RR: 90%, CR: 74%, PR: 16%

24 Unerwünschte Therapiewirkungen

MDS bei einem Patienten (sh. Tox)

25 Fazit der Autoren Es werden hohe Therapieansprechraten erzielt bei geringer Toxizität. Trotz hoher Rate an Grad III/IV Neutropenien gab es selten manifeste Infekte. Vorschlag der Autoren: Das Therapieintervall sollte hier von 21 Tage auf einen 28-Tage Zyklus verlängert werden. Die Therapie sollte in einem randomisierten Vergleich geprüft werden.

26 Abschließende Bewertung durch x den Bearbeiter � die Expertengruppe

Kleine Fallzahlen.,Die Ergebnisse der Studie zeigen jedoch wiederholt die gute Wirksamkeit einer Fludarabin-basierten Therapie. Die relevante Hämatotoxizität muss bei Auftreten eines MDS bei einem Patienten erneut unterstrichen werden..

Page 43: Fludara i.v. (2nd line NHL)

Bewertung und Extraktion von Therapiestudien Stand der Bearbeitung Bearbeiter Prof. Dr. med. J. T. Hartmann

Datum der Bearbeitung 15.02.2007

Datum der Diskussion mit der Expertengruppe

Nr. Feld Hinweise für die Bearbeitung

1 Quelle Santini G, Nati S, Spriano M, Gallamini A, Pierluigi D, Congiu AM, Truini M, Rubagotti A, Chisesi T, Vimercati R, Rossi E, Sertoli MR, Mattei D, Marino G, Gobbi M. Fludarabine in combination with cyclophosphamide or with cyclophosphamide plus mitoxantrone for relapsed or refractory low-grade non-Hodgkin's lymphoma. Haematologica 86: 282-6, 2001.

2 Studientyp vom Autor bezeichnet als

Phase II, unkontrolliert

3 Studientyp nach Durchsicht

Zuordnung zu einem der folgenden Studientypen: □ Therapiestudie mit randomisierter Vergleichsgruppe □ Therapiestudie mit nicht-randomisierter

Vergleichsgruppe □ Therapiestudie mit Vergleichen über Zeit und Ort (z. B.

historische Kontrollen) □ Fallkontrollstudien □ Kohortenstudien Therapiestudie ohne Vergleichsgruppen (auch „Vorher-

Nachher-Studien“) □ Fallserie □ Fallbericht / Kasuistik (case report) □ Nicht eindeutig zuzuordnen

4 Formale Evidenzkriterien gemäß SIGN

Hier folgt eine formale Zuordnung zu den Evidenzstufen gemäß SIGN: □ 1++: Qualitativ hochwertige Metaanalyse bzw.

systematischer Review von RCTs oder RCT mit sehr geringem Risiko von Bias

□ 1+: Gut durchgeführte Metaanalyse bzw. systematischer Review von RCTs oder RCT mit geringem Risiko von Bias

□ 1-: Metaanalyse bzw. systematischer Review von RCTs oder RCT mit hohem Risiko von Bias

Page 44: Fludara i.v. (2nd line NHL)

□ 2++: Qualitativ hochwertiger systematischer Review von

Fallkontroll- oder Kohortenstudien Qualitativ hochwertige Fallkontroll- oder Kohortenstudie mit sehr geringem Risiko von Confounding, Bias oder Zufallsschwankungen und hoher Wahrscheinlichkeit, dass der Zusammenhang kausal ist

□ 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie mit einem niedrigen Risiko von Confounding, Bias oder Zufallsschwankungen und einer mittleren Wahrschein-lichkeit, dass der Zusammenhang kausal ist

x 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko von Confounding, Bias oder Zufallsschwankungen und einem signifikanten Risiko, dass der Zusammenhang nicht kausal ist

□ 3: Andere Studien wie Einzelfallberichte, Fallserien

□ 4: Expertenmeinung

5 Bezugsrahmen Prof. Gino Santini, Divisione di Ematologica, 16132 Genoa

6 Indikation Patienten mit rezidiviertem oder refraktärem low-grade NHL

7 Fragestellung / Zielsetzung Erfassung der Effizienz und Toxizität von zwei verschiedenen Fludarabin-Kombinationen: : Fludarabin/Cyclophosphamid (FC) sowie Fludarabin/Cyclophosphamid/Mitoxantron (FCM)

8 Relevante Ein- und Ausschlusskriterien

Typische Einschlusskriterien bzgl. der Hämatologie, Leber, Herz und Nierenfunktion, HIV negativ. Alter<=75 Jahre, ECOG Performance- Status 0-2 Kein Histologie-Review zentral Unvorbehandeltes low-grade Lymphom (gemäss Working Formulation Classification). Patienten mit Mantelzelllymphom wurden ausgeschlossen. Stage Ann-Arbor II-IV

9 Prüfintervention Fludarabin 25 mg/m2/d Tag 1-3 , Cyclophosphamid 300 mg i.v. d1-3 Fludarabin 25 mg/m2/d Tag 1-3 , Cyclophosphamid 300 mg i.v. d1-3, Mitoxantron 10 mg/m2 d1Wdh an Tag 28 , max. 6 Zyklen. Antibiotische Prophylaxe (Ciprofloxacin/Flucaonazol) Anpassung der Dosierung an hämatologische, Leber- und Nierentoxizität. Keine PCP-Prophylaxe

10 Vergleichsintervention 2 Zentren behandelten mit FC 3 Zentren behandelten mit FCM

11 Evtl. weitere Behandlungsgruppen

Entfällt

12 Studiendesign Offene, einarmige Phase II Studie

13 Zahl der Zentren 5

14 Randomisierung Keine, Therapiezuteilung nach Zentrum

Page 45: Fludara i.v. (2nd line NHL)

15 Concealment („Maskierung“ der Randomisierung)

Entfällt

16 Verblindung der Behandlung

Erfolgte eine Verblindung der Behandlung? x Nein, offene Behandlung □ Patienten verblindet □ Behandler verblindet □ Patienten und Behandler verblindet Wie wurde die Verblindung durchgeführt?

17 Beobachtungsdauer 3 Jahre

18 Primäre Zielkriterien Objektive Response-Rate, CR-, PR-Rate

19 Sekundäre Zielkriterien Overall Survival, FFS, Toxizität

20 Anzahl der zu behandelnden Patienten

53 Patienten

21 Zahl und Charakteristika der eingeschlossenen und ausgewerteten Patienten

53 Patienten eingeschlossen, Histologie: low grade Lymphom Medianes Alter 56 Jahre (35-75) 64% mit Stage IV Ann Arbor Tabelle über Patientencharakteristika in der Publikation angegeben: Alter, Histologie (64% Follikulläres Lymphom), Stage , KM-Befall, mittlere Zeit von Diagnosestellung, mittlere Zahl an Vortherapien (1-5), Status der Krankheit, Milzbefall, extranodaler Befall Alle Patienten vorbehandelt. Die Charakteristika in beiden Behandlungsgruppen seien gleich wird im Text erwähnt, die Tabelle gibt jedoch nur die Charakteristika gesamt aller 53 Patienten an. (Die Behandlungsgruppen wurde nach den 5 Zentren zugeteilt)

22 Vergleichbarkeit der Behandlungsgruppen

Keine, 2 parallele Behandlungsgruppen (2 parallele Phase II)

23 Ergebnisse Alle 53 Patienten ausgewertet Overall RR 88% (CR: 58%, PR: 30%) FC: CR/PR: 54%/41% FCM: CR/PR: 61%/21% Overall und failure-free survival für beide Gruppen graphisch dargestellt. OS nach 3 Jahren 71% versus 41% (FCM versus FC) FFS nach 3 Jahren 57% versus 42% (FCM versus FC)

24 Unerwünschte Therapiewirkungen

Toxizität: Grad III/IV Granulopenie 21% der Zyklen 11% Patienten mit neutropenem Fieber keine opportunistischen Infektionen

25 Fazit der Autoren FC und FCM zeigen eine hohe Effektivität und Sicherheit in der Behandlung des rezidivierten low grade Lymphoms

26 Abschließende Bewertung Fludarabin zeigt auch in dieser Studie eine hohe

Page 46: Fludara i.v. (2nd line NHL)

durch x den Bearbeiter □ die Expertengruppe

Effektivität bei guter Toleranz in der Behandlung des rezidivierten low grade NHL. Insbesondere die Fludarabin-basierte 3-fach Kombinationstherapie zeigt ein langes OS und FFS nach 3 Jahren.

Page 47: Fludara i.v. (2nd line NHL)

Bewertung und Extraktion von Therapiestudien Stand der Bearbeitung Bearbeiter Prof. Dr. med. J. T. Hartmann

Datum der Bearbeitung 15.02.2007

Datum der Diskussion mit der Expertengruppe

Nr. Feld Hinweise für die Bearbeitung

1 Quelle Tondini C, Balzarotti M, Rampinelli I, Valagussa P, Luoni M, De Paoli A, Santoro A, Bonadonna G. Fludarabine and cladribine in relapsed/refractory low-grade non-Hodgkin's lymphoma: a phase II randomized study. Ann Oncol 11: 231-3, 2000.

2 Studientyp vom Autor bezeichnet als

Phase II, unkontrolliert

3 Studientyp nach Durchsicht

Zuordnung zu einem der folgenden Studientypen: x Therapiestudie mit randomisierter Vergleichsgruppe □ Therapiestudie mit nicht-randomisierter

Vergleichsgruppe □ Therapiestudie mit Vergleichen über Zeit und Ort (z. B.

historische Kontrollen) □ Fallkontrollstudien □ Kohortenstudien □ Therapiestudie ohne Vergleichsgruppen (auch „Vorher-

Nachher-Studien“) □ Fallserie □ Fallbericht / Kasuistik (case report) □ Nicht eindeutig zuzuordnen

4 Formale Evidenzkriterien gemäß SIGN

Hier folgt eine formale Zuordnung zu den Evidenzstufen gemäß SIGN: □ 1++: Qualitativ hochwertige Metaanalyse bzw.

systematischer Review von RCTs oder RCT mit sehr geringem Risiko von Bias

□ 1+: Gut durchgeführte Metaanalyse bzw. systematischer Review von RCTs oder RCT mit geringem Risiko von Bias

□ 1-: Metaanalyse bzw. systematischer Review von RCTs oder RCT mit hohem Risiko von Bias

Page 48: Fludara i.v. (2nd line NHL)

□ 2++: Qualitativ hochwertiger systematischer Review von

Fallkontroll- oder Kohortenstudien

□ Qualitativ hochwertige Fallkontroll- oder Kohortenstudie mit sehr geringem Risiko von Confounding, Bias oder Zufallsschwankungen und hoher Wahrscheinlichkeit, dass der Zusammenhang kausal ist

x 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie mit einem niedrigen Risiko von Confounding, Bias oder Zufallsschwankungen und einer mittleren Wahrschein-lichkeit, dass der Zusammenhang kausal ist

□ 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko von Confounding, Bias oder Zufallsschwankungen und einem signifikanten Risiko, dass der Zusammenhang nicht kausal ist

□ 3: Andere Studien wie Einzelfallberichte, Fallserien

□ 4: Expertenmeinung

5 Bezugsrahmen Division of Medical Oncology,Instituto Clinico Humanitas, Rozzano, Milano, Italy

6 Indikation Erfassung der Effizienz, Verträglichkeit und Kreuzresistenz von Cladribine und Fludarabine bei Patienten mit refraktärem oder rezidiviertem indolenten B- Non-Hodgkin’s Lymphom

7 Fragestellung / Zielsetzung Es wird untersucht, ob eine Kreuzresistenz zwischen den Purinanaloga Cladribine und Fludarabin besteht. Es werden die Ansprechraten nach Switch der beiden Substanzen in einem vergleichbaren Patientengut bei Progress untersucht.

8 Relevante Ein- und Ausschlusskriterien

Typische Einschlusskriterien bzgl. der Hämatologie, Leber und Nierenfunktion. Alter bis 74 Jahre, ECOG 0-2.

9 Prüfintervention Randomisation in Fludarabin Phosphat 25 mg/m2/d Tag 1-5, Wdh an Tag 28 oder Cladribine 0,14 mg/m1 d1-5, Wdh. Tag 28 Anpassung der Dosierung an hämatologische, Leber- und Nierentoxizität. Therapieabbruch bei Grad III Neutropenie oder Grad II Thrombopenie über den d+42 hinaus. Behandlungsdauer bis CR, oder PR bis max, 10 Zyklen.

10 Vergleichsintervention Geplantes Crossover

11 Evtl. weitere Behandlungsgruppen

Entfällt

12 Studiendesign Randomisierte zweiarmige Phase II Studie

13 Zahl der Zentren 2 (?)

14 Randomisierung Ja.

15 Concealment („Maskierung“ der Randomisierung)

Keine Angabe.

Page 49: Fludara i.v. (2nd line NHL)

16 Verblindung der

Behandlung Erfolgte eine Verblindung der Behandlung? x Nein, offene Behandlung □ Patienten verblindet □ Behandler verblindet □ Patienten und Behandler verblindet Wie wurde die Verblindung durchgeführt?

17 Beobachtungsdauer Nicht angegeben

18 Primäre Zielkriterien Objektive Response-Rate, CR-, PR-Rate, Toxizitätsprofil, Response-Rate nach Cross-over

19 Sekundäre Zielkriterien Keine.

20 Anzahl der zu behandelnden Patienten

Keine Fallzahlkalkulation.

21 Zahl und Charakteristika der eingeschlossenen und ausgewerteten Patienten

60 eingeschlossene Patienten n=58 ausgewertet für Toxizität n=55 ausgewertet für Response im Mittel 2 Vortherapien zu etwa gleichen Anteilen refraktäre und Rezidiv-Situation Randomisation: 26 Patienten initial mit Fludarabin 32 Patienten mit Cladribine

22 Vergleichbarkeit der Behandlungsgruppen

Keine Darstellung.

23 Ergebnisse Ansprechraten: RR für Fludarabine: (CR+PR) 68%, CR: 48% RR für Cladribine 72%, CR 38% Patienten, die angesprochen haben: 3-Jahres PFS 58% nach Fludarabine, 52% nach Cladribine. Ein Switch in die andere Therapiegruppe war nur bei 16 Patienten möglich (überwiegend wegen Hämatotoxizität). Keiner der 7 Patienten mit Progredienz und switch erzielte ein Ansprechen. 8/9 Patienten mit switch nach Eintreten eines erneuten Rezidivs erzielten ein Ansprechen.

24 Unerwünschte Therapiewirkungen

Wegen hämatologischer Toxizität mussten 24% der Fludarabin-Zyklen und 37% der Cladribine-Zyklen dosisreduziert oder verschoben werden. Häufigste Nebenwirkungen waren hämatologischer Art, insbesondere Grad 3/4 Neutropenie (50%Fludarabine, 66% Cladribine). Die Nicht-Hämatologischen Toxizitäten waren gering ausgeprägt.

25 Fazit der Autoren Fludarabin und Cladribine sind beide sehr wirksame Substanzen beim rezidivierten und refraktären indolenten Lymphom. Es scheint eine Kreuzresistenz beider Substanzen vorzuliegen.

26 Abschließende Bewertung durch x den Bearbeiter

Mangelhaftes Studiendesign bzw. eingeschränkte Darstellung führen zu eingeschränkter Bewertbarkeit der Studie. Diese ist als doppelte, unkontrollierte Phase II zu werten, da kleine Fallzahl, keine statistische Hypothese,

Page 50: Fludara i.v. (2nd line NHL)

□ die Expertengruppe

und Fallzahlkalkulation ablesbar ist. Nachweis der Wirksamkeit von Fludarabin beim rez./refraktären low-grade Lymphom i.R. einer Fallkontrollstudie.

Page 51: Fludara i.v. (2nd line NHL)

Bewertung und Extraktion von Therapiestudien Stand der Bearbeitung Bearbeiter Prof. Dr. med. J. T. Hartmann

Datum der Bearbeitung 15.02.2007

Datum der Diskussion mit der Expertengruppe

Nr. Feld Hinweise für die Bearbeitung

1 Quelle Tsimberidou AM, McLaughlin P, Younes A, Rodriguez MA, Hagemeister FB, Sarris A, Romaguera J, Hess M, Smith TL, Yang Y, Ayala A, Preti A, Lee MS, Cabanillas F. Fludarabine, mitoxantrone, dexamethasone (FND) compared with an alternating triple therapy (ATT) regimen in patients with stage IV indolent lymphoma. Blood 100: 4351-7, 2002.

2 Studientyp vom Autor bezeichnet als

Phase III,, randomisiert

3 Studientyp nach Durchsicht

Zuordnung zu einem der folgenden Studientypen: x Therapiestudie mit randomisierter Vergleichsgruppe □ Therapiestudie mit nicht-randomisierter

Vergleichsgruppe □ Therapiestudie mit Vergleichen über Zeit und Ort (z. B.

historische Kontrollen) □ Fallkontrollstudien □ Kohortenstudien Therapiestudie ohne Vergleichsgruppen (auch „Vorher-

Nachher-Studien“) □ Fallserie □ Fallbericht / Kasuistik (case report) Nicht eindeutig zuzuordnen

4 Formale Evidenzkriterien gemäß SIGN

Hier folgt eine formale Zuordnung zu den Evidenzstufen gemäß SIGN: □ 1++: Qualitativ hochwertige Metaanalyse bzw.

systematischer Review von RCTs oder RCT mit sehr geringem Risiko von Bias

x 1+: Gut durchgeführte Metaanalyse bzw. systematischer Review von RCTs oder RCT mit geringem Risiko von Bias

□ 1-: Metaanalyse bzw. systematischer Review von RCTs oder RCT mit hohem Risiko von Bias

Page 52: Fludara i.v. (2nd line NHL)

□ 2++: Qualitativ hochwertiger systematischer Review von

Fallkontroll- oder Kohortenstudien Qualitativ hochwertige Fallkontroll- oder Kohortenstudie mit sehr geringem Risiko von Confounding, Bias oder Zufallsschwankungen und hoher Wahrscheinlichkeit, dass der Zusammenhang kausal ist

2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie mit einem niedrigen Risiko von Confounding, Bias oder Zufallsschwankungen und einer mittleren Wahrschein-lichkeit, dass der Zusammenhang kausal ist

2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko von Confounding, Bias oder Zufallsschwankungen und einem signifikanten Risiko, dass der Zusammenhang nicht kausal ist

□ 3: Andere Studien wie Einzelfallberichte, Fallserien

□ 4: Expertenmeinung

5 Bezugsrahmen Dep. of Lymphoma, M.D. Anderson Cancer Center, Houston, USA

6 Indikation Indolentes NHL. Phase I und II Studie mit Fludarabin und Mitoxantron zeigen hohe Remissionsraten. Die bisherigen Erfahrungen mit anderen Tripple-Therapien (DHAP, ESHAP, NOPP) sollten in einem randomisierten Vergleich geprüft werden.

7 Fragestellung / Zielsetzung Wirksamkeit und Verträglichkeit der Kombination von Fludarabin/Mitoxantron und Dexamethason im Vergleich zu anderen Kombinations-Chemotherapieschemata beim Stage IV indolenten Lymphom

8 Relevante Ein- und Ausschlusskriterien

indolenten Lymphom , Stage IV, unvorbehandelt Alter bis 75 Jahre Übliche Einschlusskriterien für Leber-,Knochenmark-, Nierenfunktion.

9 Prüfintervention FND : Fludarabin 25 mg/m2 Tag 1-3, Mitoxantron 10 mg/m2 Tag 1, Dexamethason 20 mg p.o. Tag 1-5 Wdh. d28. ATT (Alternating-Tripple Therapie (CHO-Bleo, ESHAP, NOPP-Schema) Geplant: 8 Zyklen PCP-Prophylaxe obligat im FMD-Schema Nach Erreichen einer CR/PR: IFN/Dexa-Erhaltungstherapie über 1 Jahr

10 Vergleichsintervention ATT versus FMD

11 Evtl. weitere Behandlungsgruppen

Entfällt

12 Studiendesign Randomisiert, Phase III

13 Zahl der Zentren Keine Angaben (aus dem Kontext 1 oder 2)

14 Randomisierung Keine genauen Angaben

15 Concealment Entfällt

Page 53: Fludara i.v. (2nd line NHL)

(„Maskierung“ der Randomisierung)

16 Verblindung der Behandlung

Erfolgte eine Verblindung der Behandlung? x Nein, offene Behandlung □ Patienten verblindet □ Behandler verblindet □ Patienten und Behandler verblindet keine genauen Angaben

17 Beobachtungsdauer 5,9 Jahre

18 Primäre Zielkriterien Objektive Response-Rate, CR-, PR-Rate

19 Sekundäre Zielkriterien Mittlere Response-Dauer, Toxizität

20 Anzahl der zu behandelnden Patienten

159 Patienten eingeschlossen , 142 Patienten ausgewertet.

21 Zahl und Charakteristika der eingeschlossenen und ausgewerteten Patienten

142 ausgewertete Patienten mit vergleichbaren Gruppen in überwiegend follikulläre und small lymphocytic Lymphome

22 Vergleichbarkeit der Behandlungsgruppen

Vergleichbar bezüglich Histologie und Risikofaktoren

23 Ergebnisse ATT 5-JÜLR: 82% cs. FMD 84%. 5-J-FFS: ATT 50%, FMD: 41% (p=0.02) Subgruppe follikuläre lymphome: 58% vs. 43% (p=0.04)

24 Unerwünschte Therapiewirkungen

In beiden Armen mehr Grad III/IV Neutro- und Thrombopenie unter ATT sowie mehr Infektionen bei ATT. Keine Veränderung gegenüber dem bisherigen Stand.

25 Fazit der Autoren Beide Therapieregime zeigen hohe Remissionsraten. In Bezug auf das Failure-free-survival ist ATT dem FMD-Regime überlegen, dies jedoch bei höherer Toxizität und komplizierterem Behandlungsregime.

26 Abschließende Bewertung durch x den Bearbeiter □ die Expertengruppe

FMD ist einer ATT (Alternating-Tripple Therapie mit CHO-Bleo, ESHAP, NOPP-Schemata) bzgl. FFS unterlegen. Om Überleben zeigen sich keine Unterschiede. Das FMD Regime besitzt eine niedrigere Toxizität.

Page 54: Fludara i.v. (2nd line NHL)

Zu Feld 22 Ergebnisdarstellung für quantitative Zielkriterien (mit Beispiel)

Verum Kontrolle

Zielkriterium n x SD* n x SD*

Maß für Gruppen- unterschied

Schätzer und 95% Konfidenzintervall für Gruppenunterschied

p-Wert (optional)

VAS Differenz**

* ggf. aus SE umrechnen: nSESD ⋅=

** Es kann u.U. notwendig sein, die Richtung des angegebenen Unterschieds deutlich zu machen (z.B. „negative Angaben kennzeichnen eine Überlegenheit von Verum“)

Ergebnisdarstellung für dichotome Zielkriterien (mit Beispiel)

Anzahl Patienten mit Ereignis / Anzahl aller Patienten Zielkriterium

Verum Kontrolle

Maß für Gruppen- unterschied

Schätzer und 95% Konfidenzintervall für Gruppenunterschied

p-Wert (optional)

Erfolg Odds Ratio

Abschließende Beurteilung Die vorliegende Publikation wird

x berücksichtigt □ nicht berücksichtigt ?? Gründe (Mehrfachnennungen möglich; ggf. näher zu erläutern):

□ Klinisch relevante Patientengruppen nicht berücksichtigt □ Klinisch relevante Alternativen zum Einsatz der Technologie nicht berücksichtigt □ Der in der Studie abgebildete Entwicklungsstatus der Technologie entspricht nicht mehr

heutigen Ansprüchen □ Keine (patienten-) relevanten Endpunkte □ Nicht auf den deutschen Versorgungskontext übertragbar □ Erheblich eingeschränkte Validität der Ergebnisse aufgrund schwerwiegender Mängel im

Studiendesign □ Es liegen aussagekräftigere Studien vor. □ Sonstige Gründe – und zwar:

Page 55: Fludara i.v. (2nd line NHL)

1

Bewertung und Extraktion von Therapiestudien Stand der Bearbeitung Bearbeiter Prof. Dr. med. J. T. Hartmann

Datum der Bearbeitung 15.02.2007

Datum der Diskussion mit der Expertengruppe

Nr. Feld Hinweise für die Bearbeitung

1 Quelle Zinzani PL, Magagnoli M, Moretti L, De Renzo A, Battista R, Zaccaria A, Guardigni L, Mazza P, Marra R, Ronconi F, Lauta VM, Bendandi M, Gherlinzoni F, Gentilini P, Ciccone F, Cellini C, Stefoni V, Ricciuti F, Gobbi M, Tura S. Randomized trial of fludarabine versus fludarabine and idarubicin as frontline treatment in patients with indolent or mantle-cell lymphoma. J Clin Oncol 18: 773-9, 2000.

2 Studientyp vom Autor bezeichnet als

Phase III Studie

3 Studientyp nach Durchsicht

Zuordnung zu einem der folgenden Studientypen: x Therapiestudie mit randomisierter Vergleichsgruppe □ Therapiestudie mit nicht-randomisierter

Vergleichsgruppe □ Therapiestudie mit Vergleichen über Zeit und Ort (z. B.

historische Kontrollen) □ Fallkontrollstudien □ Kohortenstudien □ Therapiestudie ohne Vergleichsgruppen (auch „Vorher-

Nachher-Studien“) □ Fallserie □ Fallbericht / Kasuistik (case report) □ Nicht eindeutig zuzuordnen

4 Formale Evidenzkriterien gemäß SIGN

Hier folgt eine formale Zuordnung zu den Evidenzstufen gemäß SIGN: □ 1++: Qualitativ hochwertige Metaanalyse bzw.

systematischer Review von RCTs oder RCT mit sehr geringem Risiko von Bias

x 1+: Gut durchgeführte Metaanalyse bzw. systematischer Review von RCTs oder RCT mit geringem Risiko von Bias

□ 1-: Metaanalyse bzw. systematischer Review von RCTs oder RCT mit hohem Risiko von Bias

Page 56: Fludara i.v. (2nd line NHL)

2

□ 2++: Qualitativ hochwertiger systematischer Review von

Fallkontroll- oder Kohortenstudien Qualitativ hochwertige Fallkontroll- oder Kohortenstudie mit sehr geringem Risiko von Confounding, Bias oder Zufallsschwankungen und hoher Wahrscheinlichkeit, dass der Zusammenhang kausal ist

□ 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie mit einem niedrigen Risiko von Confounding, Bias oder Zufallsschwankungen und einer mittleren Wahrschein-lichkeit, dass der Zusammenhang kausal ist

□ 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko von Confounding, Bias oder Zufallsschwankungen und einem signifikanten Risiko, dass der Zusammenhang nicht kausal ist

□ 3: Andere Studien wie Einzelfallberichte, Fallserien

□ 4: Expertenmeinung

5 Bezugsrahmen Instituto di Ematologica e Oncologica Bologna, Policlinico S. Orsola Italia

6 Indikation Vergleich einer Fludarabin mono-Therapie versus einer Kombination Fludarabin/Idarubicin beim indolenten- und Mantelzelllymphom

7 Fragestellung / Zielsetzung Die Kombination von Fludarabin und Mitoxantron oder Idarubicin hat zu sehr guten Ansprechraten : RR 70-90% und CR 25-45% gezeigt. Diese Studie evaluiert die Response-Rate einer Erstlinientherapie mit Fludarabine alleine versus der Kombination mit Idarubicin.

8 Relevante Ein- und Ausschlusskriterien

Patienten mit Alter 18-65 Jahre, unbehandelt, mit „low-grade“ Lymphom, Ann Arbor Stadium Std. II-IV oder Mantelzell-Lymphom, WHO PS 0-2, HIV negativ, normale Leber-Lungen- und Nierenfunktion. IPI bis intermediate-high risk (max. 3 Risikofaktoren nach IPI)

9 Prüfintervention Fludarabin Phosphat 25 mg/m2/d i.v. an Tag 1-5, versus Fludarabin 25 mg/m2 Tag 1-3 + Idarubicin 12 mg/m2 Tag 1 Wdh. des Zyklus Tag 28 6 Zyklen geplant. Keine G-CSF-Prophylaxe, keine PCP-Prophylaxe

10 Vergleichsintervention Fludarabin 25 mg/m2 Tag 1-3 + Idarubicin 12 mg/m2 Tag 1 Wdh. des Zyklus Tag 28 6 Zyklen geplant. Keine G-CSF-Prophylaxe, keine PCP-Prophylaxe

11 Evtl. weitere Behandlungsgruppen

Entfällt

12 Studiendesign 2-armig, randomisiert, keine Angaben zu möglichem

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Cross-over, aber anzunehmen.

13 Zahl der Zentren Multicenter, keine genauen Angaben (>10)

14 Randomisierung Keine genauen Angaben

15 Concealment („Maskierung“ der Randomisierung)

Keine Angaben

16 Verblindung der Behandlung

Erfolgte eine Verblindung der Behandlung? x Nein, offene Behandlung □ Patienten verblindet □ Behandler verblindet □ Patienten und Behandler verblindet Wie wurde die Verblindung durchgeführt?

17 Beobachtungsdauer 45 Monate

18 Primäre Zielkriterien CR, PR (Ziel CR-Rate Differenz antizipiert 15%)

19 Sekundäre Zielkriterien Overall survival, Relapse-free survival, Progression-free survival, Toxizität

20 Anzahl der zu behandelnden Patienten

208 Patienten eingeschlossen, 199 Patienten randomisiert

21 Zahl und Charakteristika der eingeschlossenen und ausgewerteten Patienten

Es wurden 208 Patienten eingeschlossen, 199 Patienten erfüllten die Kriterien Randomisiert wurden n= 101: Fludarabin-Gruppe n=98: Fludara/Idarubicin-Gruppe

22 Vergleichbarkeit der Behandlungsgruppen

Die Patientencharakteristika sind getrennt nach Studienarm dargestellt, betreffend Alter, Geschlecht, Ann-Arbor-Stadium, Histologie, LDH-Level, IPI, Histologie, B-Symptome, ES, bulky disease, PS, WHO-Performance-Status. Statistik: log-rank 2-seitig. Zu beachtende Unterschiede in den Gruppen: 11% Mantelzellymphom in der Fludarabin-Gruppe 18% Mantelzellymphom in der Fludara/Idarubicingruppe

23 Ergebnisse ResponseRate (CR/PR): 84% Fludarabin-Gruppe CR/PR 47/37% 81% Flu/Ida-Gruppe CR/PR: 39/42% Ansprechraten nach Histologie: Fludarabin / Flu/Ida -Gruppe: Follikuläres Lymphom CR 60%/40% Small lymphocytic Lymphom: 29% / 43% Immunozytom: 23% / 38% Mantelzellymphom: 27% / 33%

24 Unerwünschte Therapiewirkungen

Keine Toxizitätsdifferenz zwischen den beiden Gruppen >=III° hämatologische Tox <4% in bd. Gruppen Nur milde nicht-hämatologische Tox.

25 Fazit der Autoren Bei Patienten mit nur diagnostizierten Low-grade Non-Hodgkin-Lymphomen und Mantelzelllymphom wurden mit

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Fludarabin hohe Gesamtansprechraten mit hohen kompletten Remissionsraten beobachtet. Fludarabin ist eine hochaktive Mono-Therapie in dieser Patientengruppe. Die Kombination mit Idarubicin verbessert nicht die Ansprechraten, es wird jedoch vermutet, dass die Kombination eine länger andauernde RR erzielt als die Monotherapie, ohne höhere Toxizität. Möglicherweise ist die Kombination für eine Subgruppe (Small lymphozytic lymphoma und Immunozytom) von Vorteil.

26 Abschließende Bewertung durch x den Bearbeiter □ die Expertengruppe

Das primäre Studienziel wurde in dieser randomisierten Phase-III Studie nicht erreicht. Bzgl. der objektiven Remissionsrate sowie der kompletten Remission ist die Kombination mit Idarubicin nicht effektiver. Die hohe Wirksamkeit einer Mono-Therapie mit Fludarabin bei indolenten Lymphomen und Mantelzelllymphom wurde in der Erstlinientherapie belegt.

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Bewertung und Extraktion von Therapiestudien Stand der Bearbeitung Bearbeiter Prof. Dr. med. J. T. Hartmann

Datum der Bearbeitung 15.02.2007

Datum der Diskussion mit der Expertengruppe

Nr. Feld Hinweise für die Bearbeitung

1 Quelle Zinzani PL, Pulsoni A, Perrotti A, Soverini S, Zaja F, De Renzo A, Storti S, Lauta VM, Guardigni L, Gentilini P, Tucci A, Molinari AL, Gobbi M, Falini B, Fattori PP, Ciccone F, Alinari L, Martelli M, Pileri S, Tura S, Baccarani M. Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol 22: 2654-61, 2004.

2 Studientyp vom Autor bezeichnet als

Phase II, unkontrolliert

3 Studientyp nach Durchsicht

Zuordnung zu einem der folgenden Studientypen: X Therapiestudie mit randomisierter Vergleichsgruppe □ Therapiestudie mit nicht-randomisierter

Vergleichsgruppe □ Therapiestudie mit Vergleichen über Zeit und Ort (z. B.

historische Kontrollen) □ Fallkontrollstudien □ Kohortenstudien Therapiestudie ohne Vergleichsgruppen (auch „Vorher-

Nachher-Studien“) □ Fallserie □ Fallbericht / Kasuistik (case report) Nicht eindeutig zuzuordnen

4 Formale Evidenzkriterien gemäß SIGN

Hier folgt eine formale Zuordnung zu den Evidenzstufen gemäß SIGN: □ 1++: Qualitativ hochwertige Metaanalyse bzw.

systematischer Review von RCTs oder RCT mit sehr geringem Risiko von Bias

x 1+: Gut durchgeführte Metaanalyse bzw. systematischer Review von RCTs oder RCT mit geringem Risiko von Bias

□ 1-: Metaanalyse bzw. systematischer Review von RCTs oder RCT mit hohem Risiko von Bias

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□ 2++: Qualitativ hochwertiger systematischer Review von

Fallkontroll- oder Kohortenstudien Qualitativ hochwertige Fallkontroll- oder Kohortenstudie mit sehr geringem Risiko von Confounding, Bias oder Zufallsschwankungen und hoher Wahrscheinlichkeit, dass der Zusammenhang kausal ist

□ 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie mit einem niedrigen Risiko von Confounding, Bias oder Zufallsschwankungen und einer mittleren Wahrschein-lichkeit, dass der Zusammenhang kausal ist

□ 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko von Confounding, Bias oder Zufallsschwankungen und einem signifikanten Risiko, dass der Zusammenhang nicht kausal ist

□ 3: Andere Studien wie Einzelfallberichte, Fallserien

□ 4: Expertenmeinung

5 Bezugsrahmen P.L.Pinzani, Instituto di Ematologica e Onkologica, Bologna, Italy

6 Indikation Untersuchungen haben gezeigt, dass möglicherweise durch eine molekulare Response (bcl-2 neg) nach einer Chemotherapie mit CHOP auch eine verlängerte klinische Remission / ein verlängertes PFS impliziert. Da für Purinanaloga bisher auch eine hohe Effektivität bei indolenten Lymphomen gezeigt wurde, wurde eine Chemotherapie mit FM (Mitoxantron/Fludarabin) mit CHOP-Chemotherapie +- Rituximab-Erhaltung verglichen.

7 Fragestellung / Zielsetzung Vergleich der Effektivität und Toxizität in der Erstlinientherapie von CHOP und FM (+- Rituximab-Erhaltung bei CR mit persistierendem bcl-2 (CR-) sowie PR)

8 Relevante Ein- und Ausschlusskriterien

Unvorbehandeltes follikulläres B-NHL Grad I/II, CD-20 pos., Alter von 18-70 Jahre Übliche Einschlusskriterien für Leber-,KM-, Nierenfunktion.

9 Prüfintervention Fludarabin 25 mg/m2 d1-3, Mitoxantron 10 mg/m2 d1, Wdh. d28 +/- R-Erhaltung bei eingeschränkten Respondern (CR-, PR) Geplant: 6 Zyklen

10 Vergleichsintervention CHOP +/- R-Erhaltung bei eingeschränkten Respondern (CR-, PR)

11 Evtl. weitere Behandlungsgruppen

Entfällt

12 Studiendesign Open label, randomisiert , Phase III

13 Zahl der Zentren 15

14 Randomisierung Zentral in Bologna

15 Concealment („Maskierung“ der

Keine Angaben

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Randomisierung)

16 Verblindung der Behandlung

Erfolgte eine Verblindung der Behandlung? x Nein, offene Behandlung □ Patienten verblindet □ Behandler verblindet □ Patienten und Behandler verblindet

17 Beobachtungsdauer Keine genauen Angaben

18 Primäre Zielkriterien Objektive Response-Rate, CR-, PR-Rate, Molecular response: Bcl-2/IgH-Status (pos./neg.) Toxizität

19 Sekundäre Zielkriterien

20 Anzahl der zu behandelnden Patienten

151 Patienten eingeschlossen, 140 Patienten ausgewertet (FM-Arm n=72, CHOP-Arm: n=68)

21 Zahl und Charakteristika der eingeschlossenen und ausgewerteten Patienten

Ausgeglichene Patientenverteilung in beiden Gruppen nach Alter, Sex, Stage, B-Symptomen, Extranodal, Bulky und LDH.

22 Vergleichbarkeit der Behandlungsgruppen

Ist gegeben

23 Ergebnisse Overall-RR-Rate in beiden Gruppen gleich: FM vs CHOP: 96 vs. 98% CR-Rate in FM höher (68 vs. 62%) Molecular Response (bcl-2/IgH neg.) in FM höher (47 vs. 29%) In FM höher: CR und bcl-2 neg. 39 vs. 19% 3-Jahres Rezidivfreies Überleben bei CR und Bcl-2 neg. nach FM: 71% versus 58% nach CHOP. PFS und OS gleich.

24 Unerwünschte Therapiewirkungen

Keine Veränderung gegenüber dem bisherigen Stand.

25 Fazit der Autoren Nach diesen Daten ist FM bezüglich der Ansprechraten klinisch und molekulargenetisch wirksamer als CHOP in der Erstlinientherapie beim follikullären Lymphom.. Rituximab kann die längerfristigen Remissionsraten verbessern und zu einem verlängertem rezidivfreien Überleben.

26 Abschließende Bewertung durch x den Bearbeiter □ die Expertengruppe

Aufwendige und gut durchgeführte Studie mit vergleichbaren Gruppen. Wirksamkeit einer Kombination von Fludarabin und Mitoxantron bei der Behandlung des follikullären Lymphoms gegenüber CHOP bzgl. Induktion von klinischen und molekulargenetischen Remissionen. Diese Subgruppe profitiert bzgl. Des PFS. Für die Gesamtgruppe kein Unterschied im PFS und OS.

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1

Bewertung und Extraktion von Therapiestudien Stand der Bearbeitung Bearbeiter Axel Heyll

Stand der Bearbeitung 08.01.2009 Nr. Feld Hinweise für die Bearbeitung

1 Quelle Coiffier B et al, Ann Oncol 10: 1191-1197, 1999

2 Studientyp vom Autor bezeichnet als

Prospektive randomisierte Studie

3 Studientyp nach Durchsicht

Zuordnung zu einem der folgenden Studientypen: X Therapiestudie mit randomisierter Gruppenzuteilung □ Therapiestudie mit nicht-randomisierter

Gruppenzuteilung □ Therapiestudie mit Vergleichen über Zeit und Ort (z. B.

historische Kontrollen) □ Therapiestudie ohne Vergleichsgruppen (auch

Beobachtungsstudien und Anwendungsbeobachtungen) □ Fall-Kontrollstudien □ Fallserie □ Fallbericht / Kasuistik (case report) □ Nicht eindeutig zuzuordnen Falls Therapiestudie: □ mit Placebokontrolle(n) X mit Aktivkontrolle(n) □ mit Dosisgruppen □ sonstige Kontrollgruppe(n): Nennen

4 Formale Evidenzkriterien gemäß SIGN

□ 1++: Qualitativ hochwertige Metaanalyse bzw. systematischer Review von RCTs oder RCT mit sehr geringem Risiko von Bias

X 1+: Gut durchgeführte Metaanalyse bzw. systematischer Review von RCTs oder RCT mit geringem Risiko von Bias

□ 1-: Metaanalyse bzw. systematischer Review von RCTs oder RCT mit hohem Risiko von Bias

□ 2++: Qualitativ hochwertiger systematischer Review von Fallkontroll- oder Kohortenstudien oder Qualitativ hochwertige Fallkontroll- oder Kohortenstudie mit sehr geringem Risiko von Confounding, Bias oder Zufallsschwankungen und hoher Wahrscheinlichkeit, so dass der Zusammenhang kausal ist

□ 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie mit niedrigem Risiko von Confounding, Bias oder Zufallsschwankungen und einer mittleren Wahrschein-lichkeit, so dass der Zusammenhang kausal ist

□ 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko

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2

Nr. Feld Hinweise für die Bearbeitung von Confounding, Bias oder Zufallsschwankungen und einem signifikanten Risiko, so dass der Zusammenhang nicht kausal ist

□ 3: Andere Studien wie Einzelfallberichte, Fallserien

□ 4: Expertenmeinung

5 Bezugsrahmen Therapieoptimierungsstudie einer französischen Studiengruppe (GELA), IIT, kein Hinweis auf Interessenkonflikte

6 Indikation Follikuläre NHL

7 Primäre Fragestellung / primäre Zielsetzung(en)

Führt Fludarabin im Vergleich zum Kontrollarm mit CHVP und Interferon zu einer Verlängerung der medianen TTF (Zeit bis zum Therapieversagen) um 1 Jahr?

8 Relevante Ein- und Ausschlusskriterien

Histologie eines follikulären NHL, außer bei gleichzeitigem Vorliegen von > 50 % großzellig und > 50 % diffuse Infiltration

Alter 60 bis 75 Jahre und zusätzlich mindestens eines der folgenden Kriterien für eine ungünstige Prognose:

o B-Symptomatik o AZ nach WHO > 1 o LDH > Norm o Beta-2-MG > 3 mg/l o Große Tumormasse definiert durch mindestens

einen der folgenden Parameter: Durchmesser > 7 cm Ausgeprägte Splenomegalie Ergüsse Lokale Kompression durch

Tumorwachstum Keine Vortherapie Kein Zweittumor Nicht HIV-positiv Keine Kontraindikation für protokollgemäße

Chemotherapie

9 Prüfintervention Fludarabin 25 mg/m2 Tag 1-5, monatlich, 6 x dann Dosisreduktion auf 20 mg/m2 Tag 1-5 alle 2 Monate 6 x (12 Zyklen, Therapiedauer 18 Monate)

10 Vergleichsintervention Cyclophosphamid 600 mg/m2 Tag 1, Doxorubicin 25 mg/m2 Tag 1, Teniposid 60 mg/m2 Tag 1, Prednison 40 mg/m2 Tag 1 – 4, monatlich 6 x, dann alle 2 Monate (12 Zyklen, Therapiedauer 18 Monate), zusätzlich Interferon alpha 5 Mio U 2 x / Woche für 18 Monate

11 Evtl. weitere Behandlungsgruppen

Keine

12 Subgruppen Enthält die Studie Subgruppen, die für die Fragestellung an die Kommission relevant sind? X keine relevanten Subgruppen □ prospektiv geplante Subgruppenauswertung □ post hoc definierte oder in Auswertung gefundene

Subgruppen Subgruppen ggf. benennen

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13 Studiendesign Anzahl der Behandlungsarme 2 Typus: X Parallelgruppendesign □ Cross-Over Design □ Prae-Post-Vergleich □ Sonstige:......................... Geplante Fallzahl (falls angegeben) 400 Wurde eine Fallzahlplanung (Power-Kalkulation) durchgeführt? Ja Waren Interimanalysen geplant? Ja

14 Zentren Anzahl der Zentren 50 Vergleichbarkeit der Studiendurchführung in den einzelnen Zentren beurteilen: keine Angaben

15 Randomisierung Ausreichend beschrieben? Nein Erfolgte die Randomisierung maskiert, d.h. wurde sicher gestellt, dass die Randomisierungssequenz vor Behandlern und den Studienteilnehmern verborgen blieb (Concealment; z.B. durch zentrale telefonische Randomisierung)? Keine Angaben

16 Verblindung der Behandlung

X Keine Verblindung (offene Behandlung) □ Patienten verblindet □ Behandler verblindet □ Beurteiler verblindet ( z.B. bei Bildgebung)

17 Beobachtungsdauer Bezogen auf den einzelnen Patienten; und auf das Hauptzielkriterium Median 29 Monate

18 Primäre Zielkriterien Zielkriterien (outcomes) nennen, die von den Autoren als die primären bzw. Haupt-Zielkriterien genannt wurden. TTF, Zeit bei Behandlungsversagen, als Ereignis gewertet: Progression (PD), Rezidiv, Behandlungswechsel, Tod Wurden relevante patientennahe Zielkriterien verwendet? Ja, sekundäres Zielkriterium war Überlebenszeit Mit welchen Instrumenten und in welcher Form erfolgte die Erfassung der Zielkriterien (z. B. Interview, Untersuchung, standardisierte Fragebögen, Referenzbeurteilung)? Keine Angaben

19 Sekundäre Zielkriterien Beschränkung auf eine Auswahl von sekundären Zielkriterien möglich. Anpassung an das Beratungsthema Ansprechrate nach 6 Monaten Überlebenszeit Rezidivrate Rate an Transformation in hoch maligne NHL Toxizität

20 Statistische Methoden für die Analyse der primären Endpunkte

Bezeichnung der verwendeten Test- bzw. Schätzprozeduren Log-Rang-Test Signifikanz-/Konfidenzniveau Keine Angaben

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4

21 Anzahl der behandelten Patienten

Erreichte Fallzahl. 131 Wurde die Studie vorzeitig beendet? (Gründe) Rekrutierung seit September 1994, Abbruch der Rekrutierung nach geplanter Zwischenanalyse im Januar 1998 auf Empfehlung des Überwachungs-Komitees, keine Begründung, vermutlich war absehbar, dass Hypothese falsch war (Fludrarabin nicht über-, sondern unterlegen) und/oder geplante Fallzahl in angemessener Zeit nicht erreicht werden konnte

22 Zahl und Charakteristika der eingeschlossenen und ausgewerteten Patienten

Differenzierte Darstellung nach Behandlungsgruppen vorhanden? Ja Darstellung des Patientenflusses nach CONSORT Nein Sind die Ausfälle von Studienteilnehmern (Drop-outs) dokumentiert und begründet? Kein Ausschluss nach Randomisation trotz falscher Histologie in 11 Fällen (andere Unterformen des NHL) Erfolgte eine Intention-to-treat- (ITT-) Analyse? Ja Erfolgte eine Per Protocol- (PP-) Analyse? Nein Gibt es Hinweise auf systematische und relevante Unterschiede zwischen den Drop-outs und den gemäß Studienprotokoll behandelten Patienten. Nein

23 Vergleichbarkeit der Behandlungsgruppen

Gibt es relevante Unterschiede zwischen den Behandlungsgruppen □ bei Studienbeginn (Baseline)? Nein □ in der Durchführung der Intervention? Nein

24 Ergebnisse und ihre Darstellung

Therapiearm Fludarabine CHVP+I Patientenzahl n=61 n=70 Endpunkt TTF nach 2 Jahren 49 % 63 % 95%-KI 43 – 56 % 58 – 70 % p-Wert < 0,05 Endpunkt Überleben nach 2 Jahren 62 % 77 % 95%-KI 56 – 68 % 71 – 82 % p-Wert < 0,05

25 Unerwünschte Therapiewirkung

Sind unerwünschte Ereignisse (UEs/AEs) berichtet? Ja, Tabelle 4 der Publikation Sind schwerwiegende UEs (SUEs/SAEs) berichtet? Ja, Tabelle 4 der Publikation Wurde der Bezug zur Behandlung beurteilt? Ja

26 Fazit der Autoren Das Behandlungsergebnis der Patienten im Kontrollarm mit

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5

CHVP+Interferon war überlegen im Hinblick auf Überleben und TTP, allerdings war diese Therapie auch toxischer als Fludarabin

27 Abschließende Bewertung durch den Bearbeiter

Die Schlussfolgerung der Autoren einer überlegenen Wirksamkeit von CHVP+Interferon im Vergleich zu Fludarabin ist zutreffend, deshalb kann Fludarabin nicht als Alternative für die Erstlinientherapie empfohlen werden. Die Auswertung der Toxizität ergab keine signifikanten Differenzen und auch CHVP war mit akzeptabler Toxizität verbunden, so dass die Toxizität kein Argument gegen die Gabe von CHVP sein kann. Die Zugabe von Interferon, deren Nutzen ohnehin nicht gesichert ist, scheint eher ein relevantes Toxizitätsproblem darzustellen. Bei CHVP handelt es sich im Wesentlichen um ein dosisreduziertes CHOP-Protokoll, so dass diese Studie für eine Überlegenheit von CHOP im Vergleich zu einer Fludarabin-Monotherapie in der Erstlinienbehandlung von Patienten mit follikulären NHL und Risikofaktoren in der Altersgruppe von 60 bis 75 Jahren spricht.

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Zu Feld 24 Ergebnisdarstellung für quantitative Zielkriterien (mit Beispiel)

Prüftherapie Kontrolle Zielkriterium

n x SD* n x SD*

Maß für Gruppen- unterschied

Schätzer und 95% Konfidenzintervall für Gruppenunterschied

p-Wert (optional)

VAS 117 20.4 7.4 123 15.6 4.5 Differenz** 4.8 (3.25 ; 6.35)

* ggf. aus SE umrechnen: nSESD ⋅= ** Es kann u.U. notwendig sein, die Richtung des angegebenen Unterschieds deutlich zu machen (z.B. „negative Angaben kennzeichnen eine Überlegenheit von Verum“) Ergebnisdarstellung für dichotome Zielkriterien (mit Beispiel)

Anzahl Patienten mit Ereignis / Anzahl aller Patienten Zielkriterium Verum Kontrolle

Maß für Gruppen- unterschied

Schätzer und 95% Konfidenzintervall für Gruppenunterschied

p-Wert (optional)

Erfolg 12 / 120 (10%) 8 / 127 (6.3%) Odds Ratio 1.65 (0.65 ; 4.2)

6

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Bewertung und Extraktion von Therapiestudien Stand der Bearbeitung Bearbeiter Prof. Dr. med. J. T. Hartmann

Datum der Bearbeitung 15.02.2007

Datum der Diskussion mit der Expertengruppe

Nr. Feld Hinweise für die Bearbeitung

1 Quelle Crawley CR, Foran JM, Gupta RK, Rohatiner AZ, Summers K, Matthews J, Micallef IN, Radford JA, Johnson SA, Johnson PW, Sweetenham JW, Lister TA. A phase II study to evaluate the combination of fludarabine, mitoxantrone and dexamethasone (FMD) in patients with follicular lymphoma. Ann Oncol 11: 861-5, 2000.

2 Studientyp vom Autor bezeichnet als

Offene, Phase II Studie

3 Studientyp nach Durchsicht

Zuordnung zu einem der folgenden Studientypen: □ Therapiestudie mit randomisierter Vergleichsgruppe □ Therapiestudie mit nicht-randomisierter

Vergleichsgruppe □ Therapiestudie mit Vergleichen über Zeit und Ort (z. B.

historische Kontrollen) □ Fallkontrollstudien □ Kohortenstudien x Therapiestudie ohne Vergleichsgruppen (auch „Vorher-

Nachher-Studien“) □ Fallserie □ Fallbericht / Kasuistik (case report) □ Nicht eindeutig zuzuordnen

4 Formale Evidenzkriterien gemäß SIGN

Hier folgt eine formale Zuordnung zu den Evidenzstufen gemäß SIGN: □ 1++: Qualitativ hochwertige Metaanalyse bzw.

systematischer Review von RCTs oder RCT mit sehr geringem Risiko von Bias

□ 1+: Gut durchgeführte Metaanalyse bzw. systematischer Review von RCTs oder RCT mit geringem Risiko von Bias

□ 1-: Metaanalyse bzw. systematischer Review von RCTs oder RCT mit hohem Risiko von Bias

Page 69: Fludara i.v. (2nd line NHL)

□ 2++: Qualitativ hochwertiger systematischer Review von

Fallkontroll- oder Kohortenstudien Qualitativ hochwertige Fallkontroll- oder Kohortenstudie mit sehr geringem Risiko von Confounding, Bias oder Zufallsschwankungen und hoher Wahrscheinlichkeit, dass der Zusammenhang kausal ist

x 2+: Gut durchgeführte Fallkontroll- oder Kohortenstudie mit einem niedrigen Risiko von Confounding, Bias oder Zufallsschwankungen und einer mittleren Wahrschein-lichkeit, dass der Zusammenhang kausal ist

□ 2-: Fallkontroll- oder Kohortenstudie mit hohem Risiko von Confounding, Bias oder Zufallsschwankungen und einem signifikanten Risiko, dass der Zusammenhang nicht kausal ist

□ 3: Andere Studien wie Einzelfallberichte, Fallserien

□ 4: Expertenmeinung

5 Bezugsrahmen Instituto of Hematologica e Oncologica University of Bologna, Italy

6 Indikation Unvorbehandeltes, indolentes Non-Hodgkin-Lymphom.

7 Fragestellung / Zielsetzung Erfassung der Effizienz und Toxitzität einer Fludarabin-Kombination mit Mitoxantron (FM)

8 Relevante Ein- und Ausschlusskriterien

Unvorbehandeltes low-grade non-Hodgkin-Lymphom ECOG-PS <=2 Alter 18-70 Jahre Übliche Nieren-, Leber- und hämatologische Parameter, HIV negativ.

9 Prüfintervention Fludarabin 25 mg/m2/d Tag 1-3, Mitoxantron 10 mg/m2 d1, PCP-Prophylaxe Wdh an Tag 28 für max. Zyklen. Anpassung der Dosierung an hämatologische, Leber- und Nierentoxizität.

10 Vergleichsintervention Entfällt

11 Evtl. weitere Behandlungsgruppen

Entfällt

12 Studiendesign Offen, Phase II

13 Zahl der Zentren Ohne Angaben

14 Randomisierung Entfällt

15 Concealment („Maskierung“ der Randomisierung)

Entfällt

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16 Verblindung der

Behandlung Erfolgte eine Verblindung der Behandlung? x Nein, offene Behandlung □ Patienten verblindet □ Behandler verblindet □ Patienten und Behandler verblindet Wie wurde die Verblindung durchgeführt?

17 Beobachtungsdauer 26 Monate

18 Primäre Zielkriterien Response-Rate, CR-, PR-Rate, Toxizität, molecular response, Ereignisfreies- und Gesamtüberleben

19 Sekundäre Zielkriterien

20 Anzahl der zu behandelnden Patienten

Keine Angaben

21 Zahl und Charakteristika der eingeschlossenen und ausgewerteten Patienten

27 Patienten mit low grade Lymphom (62% foll. Lymphom), vorbehandelt nur 18 % high-intermediate IPI

22 Vergleichbarkeit der Behandlungsgruppen

Entfällt

23 Ergebnisse Remissionsrate: 89% (67% CR, 22% PR) Mediane Remissionsdauer bei CR : 18 Monaten

24 Unerwünschte Therapiewirkungen

Keine Veränderung gegenüber dem bisherigen Stand.

25 Fazit der Autoren FM ist ein hoch-effektives Regime beim unvorbehandelten low grade Lymphom bei geringer Toxizität

26 Abschließende Bewertung durch x den Bearbeiter □ die Expertengruppe

Gute Wirksamkeitsdaten für eine Therapie mit Fludarabin/Mitoxantron in Erstlinienbehandlung des low-grade Lymphoms. Einschränkend muss die gute Remissionsdauer in den Zusammenhang mit dem überwiegend geringen IPI gesetzt werden.

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Anlage 3 (zu Punkt 4) Für das zu beurteilende Anwendungsgebiet zugelassene Wirkstoffe (Anwendungsgebiet gemäß aktueller Fachinformation; Recherche vom 22.04.2008; Wirkstoffe in alphabetischer Reihenfolge) Asparaginase Asparaginase 5000 (10 000) E medac ist als Bestandteil einer antineoplastischen Kombinationstherapie der akuten lymphatischen Leukämie (ALL) im Kindes- und Erwachsenenalter sowie bei Non-Hodgkin-Lymphomen im Kindesalter angezeigt. (Fachinformation für Asparaginase® medac, medac, Stand September 2005) Bendamustin Primärtherapie fortgeschrittener indolenter Non-Hodgkin-Lymphome im Kombinationsprotokoll. Fortgeschrittenes multiples Myelom Stadium II mit Progress oder Stadium III (nach Salmon und Durie) im Kombinationsprotokoll mit Prednison. Chronisch lymphatische Leukämie. (Fachinformation für Ribomustin®, Munipharma, Stand März 2007) Bleomycin – Hodentumoren (Nicht-Seminom und Seminom) – Frühstadium des Hodgkin-Lymphoms (Stadium I – II) bei schlechter Prognose, fortgeschrittenes Hodgkin-Lymphom (Stadium III – IV) – Non-Hodgkin-Lymphome von intermediärem oder hohem Malignitätsgrad im Erwachsenenalter – Palliative intrapleurale Therapie maligner Pleuraergüsse Bleomycinsulfat wird bei diesen Erkrankungen üblicherweise in Kombination mit anderen Zytostatika verwendet. (Fachinformation für Bleomedac®, Medac, Stand Oktober 2007) Chlorambucil Chronisch lymphatische Leukämie (CLL), niedrig maligne Non-Hodgkin-Lymphome, Waldenström Makroglobulinämie. (Fachinformation für Leukeran® 2mg Filmtabletten, GlaxoSmith Kline, Stand September 2006) Cyclophosphamid Endoxan ist in Kombination mit weiteren antineoplastisch wirksamen Arzneimitteln bei der Chemotherapie folgender Tumoren angezeigt: Endoxan-Pulver zur Herstellung einer Injektionslösung: – Remissionsinduktion und Konsolidierungstherapie bei akuter lymphatischer Leukämie – Remissionsinduktion bei Morbus Hodgkin – Non-Hodgkin-Lymphome (in Abhängigkeit vom histologischen Typ und vom Krankheitsstadium auch als Monotherapie) – Chronisch lymphatische Leukämie (CLL) nach Versagen der Standardtherapie (Chlorambucil/Prednison) – Remissionsinduktion bei Plasmozytom (auch in Kombination mit Prednison) – Adjuvante Therapie des Mammakarzinoms nach Resektion des Tumors beziehungsweise Mastektomie – Palliative Therapie des fortgeschrittenen Mammakarzinoms – Fortgeschrittenes Ovarialkarzinom – Kleinzelliges Bronchialkarzinom

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– Ewing-Sarkom – Neuroblastom – Rhabdomyosarkom bei Kindern – Osteosarkom Konditionierung vor allogener Knochenmarkstransplantation bei: – schwerer aplastischer Anämie als Monotherapie oder in Kombination mit Anti- Thrombozyten-Globulin – akuter myeloischer und akuter lymphoblastischer Leukämie in Kombination mit Ganzkörperbestrahlung oder Busulfan – chronischer myeloischer Leukämie in Kombination mit Ganzkörperbestrahlung oder Busulfan Hinweise zur Konditionierung vor allogener Knochenmarkstransplantation: Die Indikationsstellung zur Knochenmarkstransplantation und damit zur vorausgehenden Konditionierungstherapie mit Endoxan ist von einer komplexen Faktorenkonstellation abhängig und individuell zu treffen. Als wesentliche Faktoren können hier Krankheitsstadium, Prognose (Risikogruppe), Art sowie Erfolg vorausgegangener Behandlungen der Grunderkrankung, Patientenalter bzw. -allgemeinzustand sowie Verfügbarkeit eines geeigneten Knochenmarkspenders genannt werden. – Bedrohlich verlaufende ,,Autoimmunkrankheiten‘‘ wie schwere, progrediente Formen von Lupus Nephritis, Wegener-Granulomatose Eine Behandlung von Lupus Nephritis und Wegener-Granulomatose mit Endoxan sollte nur durch Ärzte erfolgen, die über spezielle Erfahrungen zu den Krankheitsbildern und zu Endoxan verfügen. (Fachinformation für Endoxan® Pulver zur Herstellung einer Injektion, Baxter, Stand Januar 2005) Cytarabin Alexan _ 50 mg/ml-Infusionslösung wird eingesetzt zur Hochdosistherapie bei: – refraktären (anderweitig therapieresistenten) Non-Hodgkin-Lymphomen – refraktärer akuter nicht lymphatischer Leukämie – refraktärer akuter lymphoblastischer Leukämie – Rezidiven akuter Leukämien – Leukämien mit besonderem Risiko – sekundären Leukämien nach vorausgegangener Chemotherapie und/oder Bestrahlung – manifester Leukämie nach Transformation von Präleukämien – Konsolidierung der Remission akuter, nicht lymphatischer Leukämien bei Patienten unter 60 Jahren (Fachinformation für Alexan® 50mg/ml, Neocorp, Stand Januar 2006) Doxorubicin (Adriamycin) – kleinzelliges Bronchialkarzinom (SCLC) – Mammakarzinom – fortgeschrittenes Ovarialkarzinom – zur intravesikalen Rezidivprophylaxe oberflächlicher Harnblasenkarzinome nach TUR bei Patienten mit hohem Rezidivrisiko – zur systemischen Behandlung lokal fortgeschrittener oder metastasierter Harnblasenkarzinome – neoadjuvante und adjuvante Therapie des Osteosarkoms – fortgeschrittenes Weichteilsarkom des Erwachsenenalters – Ewing-Sarkom – Frühstadium des Hodgkin-Lymphoms (Stadium I – II) bei schlechter Prognose – fortgeschrittenes (Stadium III – IV) Hodgkin-Lymphom – hochmaligne Non-Hodgkin-Lymphome – Remissionsinduktion bei akuter lymphatischer Leukämie – Remissionsinduktion bei akuter myeloischer Leukämie – fortgeschrittenes multiples Myelom

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– fortgeschrittenes oder rezidiviertes Endometriumkarzinom – Wilms-Tumor (im Stadium II bei hochmalignen Varianten, alle fortgeschrittenen Stadien [III – IV]) – fortgeschrittenes papilläres/follikuläres Schilddrüsenkarzinom – anaplastisches Schilddrüsenkarzinom – fortgeschrittenes Neuroblastom – fortgeschrittenes Magenkarzinom (Fachinformation für Adriblasin®, Pfizer, Stand August 2006) Etoposid Vepesid J 500 mg ist in Kombination mit anderen antineoplastisch wirksamen Präparaten bei der Behandlung folgender bösartiger Neubildungen angezeigt: – Kleinzelliges Bronchialkarzinom; – Palliative Therapie des fortgeschrittenen, nicht-kleinzelligen Bronchialkarzinoms bei Patienten in gutem Allgemeinzustand (Karnofsky-Index_80 %); – Reinduktionstherapie bei Morbus Hodgkin nach Versagen (nicht vollständiges Ansprechen auf die Therapie bzw. Wiederauftreten der Erkrankung) von Standardtherapien; – Non-Hodgkin-Lymphome von intermediärem und hohem Malignitätsgrad; – Remissionsinduktion bei akuter myeloischer Leukämie im Kindesalter; – Reinduktionstherapie nach Versagen (nicht vollständiges Ansprechen bzw. Wiederauftreten der Erkrankung) von Standardtherapien bei akuter myeloischer Leukämie im Erwachsenenalter; – Hodentumoren; – Chorionkarzinom der Frau mit mittlerem und hohem Risiko nach Prognoseschema der WHO. In der Monotherapie ist Vepesid J 500 mg zur palliativen systemischen Behandlung fortgeschrittener Ovarialkarzinome nach Versagen von platinhaltigen Standardtherapien angezeigt. (Fachinformation für Vepesid® J 500mg, Bristol-Myers-Squibb, Stand Februar 2005) Epirubicin Mammakarzinom Ovarialkarzinom Magenkarzinom Pankreaskarzinom Hormonrefraktaeres Prostatakarzinom Rektumkarzinom Kleinzellige Bronchialkarzinome Non-Hodgkin-Lymphome Weichteilsarkome lt. AMIS Stand 2001 (Fachinformation für Farmorubicin® 50 HL, Pfizer, Stand März 2005 weist Non-Hodgkin-Lymphom nicht als Anwendungsgebiet aus,) Ifosfamid …… Non-Hodgkin-Lymphome Zur Kombinationschemotherapie bei Patienten mit hochmalignen Non-Hodgkin-Lymphomen, welche nicht oder nur unzureichend auf die Initialtherapie ansprechen. Zur Kombinationstherapie von Patienten mit rezidiviertenTumoren. …… (Fachinformation für Holoxan®, Baxter, Stand November 2005)

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Ibritumomab-Tiuxetan [90Y]-radiomarkiertes Zevalin ist indiziert zur Behandlung von erwachsenen Patienten mit einem nach einer Behandlung mit Rituximab rezidivierenden oder refraktären CD20-positiven follikulären Non-Hodgkin-Lymphom (NHL) vom B-Zell-Typ. (Fachinformation für Zevalin®, Stand Oktober 2007) Interferon α2a Roferon-A wird für die Behandlung der folgenden Erkrankungen angewendet: – Haarzell-Leukämie. – Progressives, asymptomatisches Kaposi-Sarkom bei AIDS-Patienten, die eine CD4-Zellzahl _250/mm3 aufweisen. – Philadelphia-Chromosom-positive, chronisch-myeloische Leukämie (CML) in der chronischen Phase. Für CML-Patienten, die einen HLA-identischen Verwandten haben und für die eine allogene Knochenmarktransplantation in der näheren Zukunft geplant ist oder möglich erscheint, stellt die Therapie mit Roferon-A keine Alternative dar. Es ist noch unbekannt, ob eine Behandlung mit Roferon-A als Therapie mit kurativem Potenzial für diese Indikation angesehen werden kann. – Kutanes T-Zell-Lymphom. Interferon alfa-2a (Roferon-A) könnte in der Behandlung von Patienten wirksam sein, die an einer fortschreitenden Erkrankung leiden und auf eine konventionelle Behandlung nicht ansprechen oder für eine solche ungeeignet sind. – Chronische, histologisch nachgewiesene Hepatitis B bei erwachsenen Patienten, bei denen Marker für die Virusreplikation, z. B. positive Nachweise von HBV-DNS oder HBe-Antigen, vorliegen. – Chronische, histologisch nachgewiesene Hepatitis C bei erwachsenen Patienten, bei denen HCV-Antikörper oder HCVRNA und erhöhte Serumspiegel der Alaninaminotransferase (ALT) ohne Leberdekompensation vorliegen. Die Wirksamkeit von Interferon alfa-2a bei der Behandlung der Hepatitis C wird durch die Kombination mit Ribavirin erhöht. Roferon-A sollte als Monotherapie nur bei Intoleranz oder Kontraindikationen gegen Ribavirin angewendet werden. – Follikuläres Non-Hodgkin-Lymphom. – Fortgeschrittenes Nierenzell-Karzinom. – Malignes Melanom des AJCC-Stadiums II (Breslow-Tumordicke -1,5 mm, ohne Lymphknotenbeteiligung oder Hautausbreitung) bei Patienten, die nach einer Tumorresektion krankheitsfrei sind. (Fachinformation für Roferon®, Roche, Stand April 2007) Methotrexat Onkologie: Methotrexat in niedriger (Einzeldosis -100 mg/m2 Körperoberfläche [KOF]) und mittelhoher Dosierung (Einzeldosis100 –1000 mg/m2 KOF) ist angezeigt bei folgenden onkologischen Erkrankungen: – MaligneTrophoblasttumore – als Monochemotherapie bei Patientinnenmit guter Prognose (,,low risk‘‘). – in Kombination mit anderen zytostatischen Arzneimitteln bei Patientinnen mit schlechter Prognose (,,high risk‘‘). – Mammakarzinome in Kombination mit anderen zytostatischen Arzneimitteln zur adjuvanten Therapie nach Resektion des Tumors oder Mastektomie sowie zur palliativen Therapie im fortgeschrittenen Stadium. – Karzinome im Kopf-Hals-Bereich zur palliativen Monotherapie im metastasierten Stadium oder bei Rezidiven. – Non-Hodgkin-Lymphome – im Erwachsenenalter:

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Zur Behandlung von Non-Hodgkin- Lymphomen von intermediärem oder hohem Malignitätsgrad in Kombination mit anderen zytostatischen Arzneimitteln. – im Kindesalter: in Kombination mit anderen zytostatischen Arzneimitteln. – Akute lymphatische Leukämien (ALL) Methotrexat in niedriger Dosierung wird angewendet zur Behandlung akuter lymphatischer Leukämien im Kindes- und Erwachsenenalter im Rahmen komplexer Therapieprotokolle in Kombination mit anderen zytostatischen Arzneimitteln zur remissionserhaltenden Therapie (bei systemischer Anwendung) und zur Prophylaxe und Therapie der Meningeosis leucaemica bei intrathekaler Anwendung mit einer Verdünnung auf eine maximale Methotrexat-Konzentration von 5 mg/ml. Bei der intrathekalen Anwendung von Methotrexat zur Prophylaxe und Therapie der Meningeosis leucaemica darf nach Verdünnung des methotrexathaltigen Arzneimittels eine maximale Methotrexat-Konzentration von 5 mg/ml nicht überschritten werden. Methotrexat in hoher Dosierung (Einzeldosis -1000 mg/m2 KOF) ist angezeigt bei folgenden onkologischen Erkrankungen: – Primär im Zentralnervensystem lokalisierte Non-Hodgkin-Lymphome vor einer Radiotherapie – Akute lymphatische Leukämien (ALL) Methotrexat in hoher Dosierung wird angewendet zur Behandlung der akuten lymphatischen Leukämie im Kindes- und Erwachsenenalter jeweils in Kombination mit anderen zytostatischen Arzneimitteln. Methotrexat in hoher Dosierung hat sich im Rahmen unterschiedlicher Therapieprotokolle insbesondere zur systemischen Vorbeugung und Behandlung der Meningeosis leucaemica als wirksam erwiesen. (Fachinformation Methotrexat Lederle Lösung, Wyeth, Stand Juni 2007)

Mitoxantron – Metastasierendes Mamma-Carcinom – Non-Hodgkin-Lymphome – Akute myeloische Leukämie des Erwachsenen,akute lymphoblastische Leukämie des Erwachsenen, Blastenschub der chronischen myeloischen Leukämie – Therapie des fortgeschrittenen und hormonresistenten Prostata-Carcinoms in Kombination mit niedrig dosierten oralen Glucocorticoiden, einschließlich Prednison und Hydrocortison, zur Schmerzlinderung bei Patienten, die auf Analgetika nicht mehr ansprechen und bei denen eine Strahlentherapie nicht indiziert ist. (Fachinformation für Novantron®, Wyeth, Stand März 2007) Prednisolon Erkrankungen, die einer systemischen Therapie mit Glucocorticoiden bedürfen. Hierzu gehören je nach Erscheinungsform und Schweregrad: ……. Blutkrankheiten/Tumortherapie: • Autoimmunhämolytische Anämie (DS: c bis a). • Thrombozytopenische Purpura (DS: a). • Thrombozytopenie (DS: b bis a). • Akute lymphoblastische Leukämie, Morbus Hodgkin, Non-Hodgkin-Lymphome, chronische lymphatische Leukämie, Morbus Waldenström, multiples Myelom (DS:b bis a, Anwendung im Rahmen von Polychemotherapien). • Hyperkalzämie bei malignen Lymphomen, multiplen Myelomen, Leukämien und Mammakarzinomen (DS: c bis a). • Palliativtherapie maligner Erkrankungen (DS: c bis a). ….. (Fachinformation für Decortin® H, Merck, Stand Februar 2006)

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Prednison Erkrankungen, die einer systemischen Therapie mit Glucocorticoiden bedürfen. Hierzu gehören je nach Erscheinungsform und Schweregrad: ……. Blutkrankheiten/Tumortherapie: - Autoimmunhämolytische Anämie (DS: c bis a). - Thrombozytopenische Purpura (DS: a). - Thrombozytopenie (DS: b bis a). - Akute lymphoblastische Leukämie, Morbus Hodgkin, Non-Hodgkin-Lymphome, chronische lymphatische Leukämie, Morbus Waldenström, multiples Myelom (DS: b bis a, Anwendung im Rahmen von Polychemotherapien). - Hyperkalzämie bei malignen Lymphomen, multiplen Myelomen, Leukämien und Mammakarzinomen (DS: c bis a). - Palliativtherapie maligner Erkrankungen (DS: c bis a). …… (Fachinformation für Decortin®, Merck, Stand Februar 2002) Rituximab Non-Hodgkin-Lymphom MabThera ist in Kombination mit einer Chemotherapie für die Erstbehandlung von Patienten mit follikulärem Lymphom im Stadium III – IV angezeigt. MabThera ist für die Erhaltungstherapie bei Patienten mit rezidivierendem/refraktärem follikulärem Lymphom angezeigt, die auf eine Induktionstherapie, bestehend aus einer Chemotherapie mit oder ohne MabThera, angesprochen haben. MabThera ist als Monotherapie für die Behandlung von Patienten mit follikulärem Lymphom im Stadium III – IV angezeigt, die gegen eine Chemotherapie resistent sind oder nach einer solchen einen zweiten oder neuerlichen Rückfall haben. MabThera ist für die Behandlung von Patienten mit CD20-positivem, diffusem großzelligen B-Zell-Non-Hodgkin-Lymphom in Kombination mit einer CHOP-Chemotherapie angezeigt. (Fachinformation für MabThera®, Roche, Stand Januar 2006)

Trofosfamid Therapie von Non-Hodgkin-Lymphomen nach Versagen von Standardtherapie. (Fachinformation für Ixoten®, Baxter, Stand Februar 2005)

Vinblastin Vinblastinsulfat-GRY10 mg wird überwiegend in Kombinationstherapie bei folgenden Tumoren angewandt: – Malignen Hodentumoren (nur bei metastasierendem Hodenkarzinom, dort nicht als Therapeutikum der I. Wahl) – Morbus Hodgkin – Non-Hodgkin-Lymphomen (nicht als Therapeutikum der I. Wahl) – Histiocytosis X (nur bei Letterer-Siwe-Krankheit) – Kaposi-Sarkom (nicht als Therapeutikum der I. Wahl) – Metastasierendem Mammakarzinom (Palliativtherapie bei ansonsten therapieresistenten Fällen) Vinblastinsulfat-GRY10 mg wird ferner zurMonotherapie angewandt bei: – Therapierefraktärem Morbus Werlhof (nicht als Therapeutikum der I. Wahl) (Fachinformation für Vinblastinsulfat-GRY 10mg, Teva, Stand Januar 2007)

Vincristinsulfat Vincristinsulfat ist in Kombination mit anderen onkologisch wirkenden Substanzen und/oder Strahlentherapie angezeigt bei: - akuter lymphatischer Leukämie (ALL)

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- akuter nicht lymphatischer Leukämie (ANLL) - Morbus Hodgkin - kleinzelligem Bronchialkarzinom - Mammakarzinom-Palliativtherapie bei ansonsten therapieresistenten Fällen - Wilms-Tumor - Rhabdomyosarkom - Ewing-Sarkom - Neuroblastom (Fachinformation für Vincristin 1mg/ml, medac, Stand: April 2005)

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Fachinformation (Zusammenfassung der Merkmale des Arzneimittels)

Fludara�

1. BEZEICHNUNG DES ARZNEIMITTELS

Fludara � 50 mg Pulver zur Herstellung einer Injektions- oder Infusionslösung

2. QUALITATIVE UND QUANTITATIVE ZUSAMMENSETZUNG

Jede Durchstechflasche enthält 50 mg Flu­darabinphosphat.

Sonstige Bestandteile siehe unter 6.1.

3. DARREICHUNGSFORM

Pulver zur Herstellung einer Injektions- oder Infusionslösung.

Weißes Lyophilisat.

4. KLINISCHE ANGABEN

4.1 Anwendungsgebiete Therapie der chronischen lymphatischen Leukämie (CLL) vom B-Zell-Typ bei Patienten mit ausreichender Knochenmarkreserve.

Die First-line-Therapie mit Fludara sollte nur bei Patienten mit fortgeschrittener Erkran­kung begonnen werden, d. h. im Rai-Stadi­um III/IV (Binet-Stadium C) oder im Rai-Sta­dium I/II (Binet-Stadium A/B) einhergehend mit krankheitsbedingten Symptomen oder dem Nachweis der fortschreitenden Erkran­kung.

4.2 Dosierung, Art und Dauer der Anwendung Fludara soll nur unter Aufsicht eines in der Onkologie erfahrenen Arztes angewendet werden.

Es wird dringend empfohlen, Fludara aus­schließlich intravenös zu applizieren. Bislang wurden keine Fälle berichtet, bei denen es nach paravenöser Gabe zu schweren loka­len Reaktionen kam. Dennoch muss die ver­sehentliche paravenöse Gabe von Fludara vermieden werden.

� Erwachsene Die empfohlene Dosis von 25 mg Fludara­binphosphat pro m2 Körperoberfläche soll täglich intravenös an 5 aufeinander folgen­den Tagen in Abständen von 28 Tagen ver­abreicht werden. Der Inhalt einer Durch­stechflasche wird mit 2 ml Wasser für Injek­tionszwecke aufgelöst. Die entstandene re­konstituierte Lösung enthält 25 mg Fludara­binphosphat pro Milliliter.

Die erforderliche, auf Basis der Körperober­fläche des Patienten errechnete Dosis der rekonstituierten Lösung wird in eine Spritze aufgezogen. Für die intravenöse Bolusinjek­tion wird diese Dosis mit 10 ml 0,9%iger Kochsalzlösung weiter verdünnt. Alternativ, für die Infusion, kann die erforderliche Dosis auch in 100 ml 0,9 %iger Kochsalzlösung verdünnt und über eine Dauer von etwa 30 Minuten intravenös infundiert werden (siehe auch Abschnitt 6.6).

Eine optimale Therapiedauer ist bisher nicht eindeutig etabliert. Die Dauer der Behand­lung hängt sowohl vom Behandlungserfolg als auch von der Verträglichkeit des Wirk­stoffes ab.

000698-Z914 -- Fludara -- n

Es wird empfohlen, Fludara anzuwenden bis ein Ansprechen erreicht ist (in der Regel 6 Behandlungszyklen) und das Präparat da­nach abzusetzen.

� Patienten mit Leberfunktionsstörung Es liegen keine Erkenntnisse über die An­wendung von Fludara bei Patienten mit Le­berfunktionsstörung vor. In dieser Patienten­gruppe sollte Fludara mit Vorsicht und nur dann verabreicht werden, wenn der zu er­wartende Nutzen das mögliche Risiko über­steigt.

� Patienten mit eingeschränkter Nierenfunktion

Die Gesamtclearance des Hauptmetaboliten 2F-Ara-A im Plasma korreliert mit der Kreati­nin-Clearance, was auf die Bedeutung der renalen Ausscheidung für die Elimination der Substanz hinweist. Patienten mit einge­schränkter Nierenfunktion zeigten eine er­höhte Wirkstoffexposition (AUC von 2F-Ara-A). Begrenzte klinische Daten bei Patienten mit eingeschränkter Nierenfunktion (Kreati­nin-Clearance unter 70 ml/min) sind verfüg­bar. Deshalb sollte bei Patienten mit klini­schem Verdacht auf eine eingeschränkte Nierenfunktion und bei Patienten über 70 Jahren die Kreatinin-Clearance bestimmt werden. Bei einem Wert zwischen 30 und 70 ml/min muss die Dosis um bis zu 50 % reduziert werden und eine engmaschige hä­matologische Überwachung erfolgen, um die Toxizität zu beurteilen. Fludara ist kon­traindiziert, wenn die Kreatinin-Clearance un­ter 30 ml/min beträgt.

� Kinder Die Unbedenklichkeit und Wirksamkeit von Fludara bei der Behandlung von Kindern wurden noch nicht nachgewiesen.

4.3 Gegenanzeigen Fludara ist kontraindiziert • bei Patienten, die überempfindlich gegen­

über dem Wirkstoff oder einem der sonsti­gen Bestandteilen des Präparates sind,

• bei Patienten mit eingeschränkter Nieren­funktion und einer Kreatinin-Clearance unter 30 ml/min,

• bei Patienten mit dekompensierter hämo­lytischer Anämie,

• bei Schwangerschaft und in der Stillzeit.

4.4 Warnhinweise und Vorsichtsmaß­nahmen für die Anwendung Bei Dosisfindungsstudien mit Patienten mit akuter Leukämie wurde Fludara in hohen Dosen gegeben. Dabei traten schwere neu­rologische Effekte bis hin zu Blindheit, Koma und Tod auf. Diese starke toxische Wirkung auf das zentrale Nervensystem trat bei 36 % der Patienten auf, die intravenös mit etwa der vierfachen für die Therapie der CLL empfoh­lenen Dosis behandelt wurden (96 mg/m2/ Tag über 5 – 7 Tage). Bei Patienten, die mit der für die Therapie der CLL empfohlenen Dosis behandelt wurden, kam es selten (Koma, Krampfanfälle und Erregung) oder gelegentlich (Verwirrung) zu schwerer ZNS-Toxizität. Patienten sind engmaschig auf An­zeichen neurologischer Nebenwirkungen zu überwachen.

Die Auswirkungen einer langfristigen An­wendung von Fludara auf das zentrale Ner­vensystem sind nicht bekannt. Jedoch wird die empfohlene Dosis von den Patienten vertragen, in einigen Studien über eine relativ lange Behandlungsdauer von bis zu 26 The­rapiezyklen.

Bei Patienten mit schlechtem Allgemeinzu­stand sollte Fludara nur mit Vorsicht und nach sorgfältiger Abwägung des Nutzen-Risiko-Verhältnisses angewendet werden. Dies gilt besonders für Patienten mit einer schweren Einschränkung der Knochen­markfunktion (Thrombozytopenie, Anämie und/oder Granulozytopenie), mit Immunde­fekt oder mit opportunistischen Infektionen in der Vorgeschichte.

Über schwere Knochenmarksuppression, insbesondere Anämie, Thrombozytopenie und Neutropenie, wurde bei mit Fludara be­handelten Patienten berichtet. Während einer Phase-I-Studie bei Patienten mit soli­den Tumoren betrug die mediane Zeit bis zum Nadir der Granulozyten 13 Tage (Streu­breite: 3 – 25 Tage), der Thrombozyten-Nadir wurde nach median 16 Tagen (Streubreite: 2 – 32 Tage) erreicht. Bei den meisten Patien­ten bestand bereits initial eine hämatologi­sche Störung entweder infolge der Grund­krankheit oder einer vorausgegangenen myelosuppressiven Therapie. Das Auftreten einer kumulativen Myelosuppression ist möglich. Obwohl eine Chemotherapie-be­dingte Myelosuppression oft reversibel ist, erfordert die Behandlung mit Fludarabin­phosphat eine sorgfältige hämatologische Überwachung.

Fludara ist ein potentes antineoplastisches Arzneimittel, welches ausgeprägte toxische Nebenwirkungen haben kann. Patienten sollten während der Behandlung engma­schig auf Anzeichen hämatologischer und nicht-hämatologischer Toxizität untersucht werden. Es wird empfohlen, regelmäßige Kontrollen des peripheren Blutbildes durch­zuführen, um eine sich entwickelnde An­ämie, Neutropenie und Thrombozytopenie zu erkennen.

Wie andere Zytostatika sollte auch Fludara­binphosphat vorsichtig angewandt werden, wenn bei Patienten im weiteren Krankheits­verlauf eine Stammzellsam mlung in Be­tracht gezogen wird.

Eine durch Transfusion von nicht-bestrahl­tem Blut ausgelöste Graft-versus-Host-Re­aktion (Reaktion der transfundierten immun­kompetenten Lymphozyten gegen den Empfängerorganismus) wurde bei mit Fluda­ra behandelten Patienten beobachtet. Sehr häufig wurde über einen tödlichen Ausgang als Folge dieser Krankheit berichtet. Deshalb sollten Patienten, die während oder nach einer Behandlung mit Fludara eine Bluttrans­fusion benötigen, nur bestrahltes Blut erhal­ten.

Während oder nach einer Therapie mit Flu­dara wurde bei einigen Patienten über eine reversible Verschlechterung oder ein Wie­deraufflammen einer vorbestehenden Haut­krebserkrankung berichtet. A

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Bei CLL-Patienten, bei denen große Tumor­zellmassen vorhanden waren, wurden in Verbindung mit einer Fludara-Behandlung ein Tumor-Lyse-Syndrom beobachtet. Da es unter Fludara bereits in der ersten Behand­lungswoche zu einem Ansprechen kommen kann, müssen entsprechende Vorsichts­maßnahmen bei Patienten getroffen werden, bei denen das Risiko einer solchen Kompli­kation besteht.

Unabhängig von autoimmunen Vorkomm­nissen oder dem Ergebnis eines Coombs-Testes in der Anamnese kam es während oder nach der Behandlung mit Fludara zu lebensbedrohlichen und manchmal tödli­chen Autoimmunphänomenen (z. B. autoim­munhämolytische Anämie, Autoimmun-Thrombozytopenie, thrombozytopenische Purpura, Pemphigus, Evans-Syndrom). Die meisten Patienten, die eine hämolytische Anämie unter der Behandlung mit Fludara entwickelt hatten, reagierten bei Reexposi­tion erneut mit einer Hämolyse. Daher müs­sen mit Fludara behandelte Patienten eng­maschig auf Anzeichen einer Hämolyse überwacht werden.

Bei Patienten, die mit Fludara therapiert wer­den, müssen engmaschige Kontrollen auf Zeichen einer autoimmunhämolytischen An­ämie erfolgen (Abfall des Hämoglobins in Verbindung mit einer Hämolyse und einem positiven Coombs-Test). Es wird empfohlen die Therapie mit Fludara abzubrechen, wenn eine Hämolyse auftritt. Bluttransfusionen (bestrahlt, siehe oben) und die Behandlung mit Adrenokortikoiden sind die üblichen Therapiemaßnahmen bei autoimmunhämo­lytischer Anämie.

Da für die Anwendung von Fludara bei älte­ren Personen (�75 Jahre) nur begrenzte Daten vorliegen, sollte Fludara bei diesen Patienten mit Vorsicht gegeben werden.

Da es zu einer Behandlung von Kindern mit Fludara keine klinischen Daten gibt, wird die­se nicht empfohlen.

Frauen im gebärfähigen Alter oder Männer müssen während und für mindestens 6 Mo­nate nach Beendigung der Therapie emp­fängnisverhütende Maßnahmen anwenden. Während und nach der Behandlung mit Flu­dara muss eine Impfung mit Lebendvakzinen vermieden werden.

Patienten, die initial mit Fludara behandelt wurden und darauf nicht ansprachen, sollten nicht mit Chlorambucil weiter behandelt wer­den, da die meisten Patienten, die resistent gegenüber Fludara waren, ebenfalls eine Resistenz gegenüber Chlorambucil zeigten.

4.5 Wechselwirkungen mit anderen Arzneimitteln und sonstige Wechselwirkungen Bei einer klinischen Untersuchung, in der Fludara in Kombination mit Pentostatin (De­oxycoformycin) zur Behandlung therapiere­fraktärer chronischer lymphatischer Leuk­ämien (CLL) angewendet wurde, kam es zu einer nicht akzeptablen Häufung toxischer Wirkungen auf die Lunge mit letalem Aus­gang. Die Anwendung von Fludara in Kombi­nation mit Pentostatin ist daher nicht zu emp­fehlen.

Die therapeutische Wirkung von Fludara kann durch Dipyridamol und andere Inhibi­toren der Adenosinaufnahme reduziert wer­den.

Eine pharmakokinetische Wechselwirkung wurde bei Patienten mit CLL und akuter mye­loischer Leukämie (AML) während der Kom­binationstherapie mit Fludarabinphosphat und Ara-C beobachtet. In klinischen Studien und In-vitro-Untersuchungen an Krebszell­linien waren nach Fludara-Gabe und an­schließender Ara-C-Behandlung in leukämi­schen Zellen die intrazellulären Ara-CTP-Spiegel erhöht. Dies betraf sowohl die intra­zellulären Spitzenkonzentrationen als auch die intrazelluläre Gesamtbelastung (AUC). Die Plasmakonzentrationen von Ara-C und die Eliminationsrate von Ara-CTP wurden nicht beeinflusst.

4.6 Schwangerschaft und Stillzeit � Schwangerschaft Fludara darf nicht während der Schwanger­schaft angewendet werden.

Frauen im gebärfähigen Alter müssen dazu angehalten werden, eine Schwangerschaft zu vermeiden und den behandelnden Arzt sofort zu informieren, falls dennoch eine Schwangerschaft eintreten sollte.

Es liegen nur sehr wenige Erfahrungen beim Menschen vor, die die Ergebnisse tierexperi­menteller Embryotoxizitätsstudien bestäti­gen, nach denen ein embryotoxisches und/ oder teratogenes Potenzial bei der therapeu­tischen Dosis besteht. Präklinische Daten bei der Ratte zeigten, dass Fludarabinphos­phat und/oder dessen Metabolite die feto­plazentare Schranke passieren.

� Stillzeit Während der Therapie mit Fludara darf nicht gestillt werden.

Es ist nicht bekannt, ob Fludara in die Mut­termilch übertritt.

Jedoch deuten präklinische Daten darauf hin, dass Fludarabinphosphat und/oder dessen Metabolite vom Blut in die Mutter­milch übertreten.

4.7 Auswirkungen auf die Verkehrs­tüchtigkeit und das Bedienen von Maschinen Die Auswirkungen einer Therapie mit Fluda­ra auf die Fahrtüchtigkeit oder auf die Fähig­keit zum Bedienen von Maschinen wurden nicht untersucht.

4.8 Nebenwirkungen Zu den häufigsten Nebenwirkungen gehö­ren Myelosuppression (Neutropenie, Throm­bozytopenie und Anämie), Infektionen inkl. Pneumonie, Fieber, Übelkeit, Erbrechen und Diarrhoe. Weitere häufig beobachtete Ne­benwirkungen sind Müdigkeit, Schwäche, Stomatitis, Unwohlsein, Anorexie, Ödeme, Schüttelfrost, periphere Neuropathie, Seh­störungen und Hautausschläge. Schwere opportunistische Infektionen traten während der Therapie mit Fludara auf. Es wurde über Todesfälle als Folge schwerer Nebenwirkun­gen berichtet.

Die am häufigsten berichteten unerwünsch­ten Ereignisse und die Reaktionen, bei de­nen ein Zusammenhang mit der Anwendung des Präparates wahrscheinlicher ist, werden, nach Organsystemen geordnet, ungeachtet der Schwere im Folgenden aufgeführt. Dabei beziehen sich die aufgeführten Häufigkeits­angaben (häufig �1 %; gelegentlich �0,1 und �1 %) auf die Ergebnisse klinischer Prüfungen, unabhängig vom kausalen Zu­sammenhang mit der Fludara-Therapie. Sel­tene Nebenwirkungen (�0,1 %) stammen überwiegend aus der Spontanerfassung.

� Allgemeinsymptome Über Infektionen, Fieber, Ermüdung, Schwä­che, Unwohlsein und Schüttelfrost wurde häufig berichtet.

� Blut und lymphatisches System Hämatologische Nebenwirkungen (Neutro­penie, Thrombozytopenie und Anämie) wur­den bei der Mehrzahl der mit Fludara behan­delten Patienten beobachtet. Eine auftreten-de Myelosuppression kann schwerwiegend und kumulativ sein. Eine länger dauernde Reduktion der Anzahl von T-Lymphozyten durch Fludara kann zu einem erhöhten Risi­ko opportunistischer Infektionen führen. Dies gilt auch für solche, die durch latente virale Reaktivierung bedingt sind, beispielsweise Herpes zoster, Epstein-Barr-Virus (EBV) oder die progressive multifokale Leukenze­phalopathie (siehe Abschnitt 4.4). Der Über­gang einer EBV-Infektion/-Reaktivierung in eine EBV-assoziierte lymphoproliferative Er­krankung wurde bei Patienten mit beein­trächtigtem Immunsystem beobachtet.

Selten wurde das Auftreten eines myelodys­plastischen Syndroms (MDS) bei mit Fluda­ra behandelten Patienten beschrieben. Die Mehrheit dieser Patienten hatte vorher, gleichzeitig oder nachfolgend auch eine Be­handlung mit Alkylanzien oder eine Bestrah­lung erhalten. Eine Monotherapie mit Fludara wurde nicht mit einem erhöhten Risiko für die Entwicklung eines MDS in Zusammenhang gebracht.

Gelegentlich wurde über klinisch ausge­prägte Autoimmunphänomene berichtet (siehe Abschnitt 4.4).

� Stoffwechsel- und Ernährungsstörungen Unter der Fludara-Therapie wurde bei Pa­tienten das Auftreten eines Tumor-Lyse-Syn­droms gelegentlich beobachtet. Diese Kom­plikation kann mit Hyperurikämie, Hyper­phosphatämie, Hypokalzämie, metaboli­scher Azidose, Hyperkaliämie, Hämaturie, Ausscheidung von Harnsäurekristallen und Nierenversagen einhergehen. Erste Anzei­chen dieses Syndroms können Schmerzen in der Hüft- und Nierengegend und Hämat­urie sein.

Häufig wurde über das Auftreten von Öde­men berichtet.

Gelegentlich kommt es zu Veränderungen der Enzymwerte von Leber und Pankreas.

� Nervensystem Eine periphere Neuropathie wurde häufig beobachtet. Verwirrung kann gelegentlich auftreten. Koma, Erregung und Krampfanfälle treten selten auf.

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� Sinnesorgane Häufig wurde über Sehstörungen bei mit Fludara behandelten Patienten berichtet. In seltenen Fällen kam es zu optischer Neuritis, optischer Neuropathie und Blindheit.

� Respirationstrakt Im Zusammenhang mit der Fludara-Be­handlung kommt es häufig zu Pneumonien. Überempfindlichkeitsreaktionen der Lunge auf Fludara (Lungeninfiltrate, Pneumonitis, Fi­brose), die mit Dyspnoe und Husten einher­gehen, wurden gelegentlich beobachtet.

� Verdauungstrakt Gastrointestinale Störungen wie Übelkeit und Erbrechen, Diarrhoe, Stomatitis und Ap­petitlosigkeit sind häufige Nebenwirkungen. Über gastrointestinale Blutungen, vorwie­gend in Zusammenhang mit einer Thrombo­zytopenie, wurde gelegentlich bei mit Fluda­ra behandelten Patienten berichtet.

� Herz, Kreislauf Selten wurde von Patienten berichtet, die un­ter Fludara-Therapie Herzinsuffizienz und Herzrhythmusstörungen entwickelten.

� Urogenitaltrakt Es wurde über seltene Fälle von hämorrha­gischer Zystitis berichtet.

� Haut und Hautanhangsgebilde Über Hautausschläge bei mit Fludara be­handelten Patienten wurde häufig berichtet.

In seltenen Fällen können ein Stevens-John­son-Syndrom oder eine toxisch-epidermale Nekrolyse (Lyell-Syndrom) auftreten.

4.9 Überdosierung Hohen Dosen von Fludara wird eine irrever­sible toxische Wirkung auf das ZNS zuge­schrieben, die sich in verzögert auftretender Blindheit, Koma und Tod äußern kann. Hohe Dosen können auch zu Thrombozytopenie und Neutropenie, bedingt durch Myelosup­pression, führen. Ein spezifisches Antidot bei einer Überdosierung von Fludara ist nicht bekannt. Die Behandlung muss in einem solchen Fall abgesetzt und unterstützende Maßnahmen eingeleitet werden.

5. PHARMAKOLOGISCHE EIGEN­SCHAFTEN

5.1 Pharmakodynamische Eigenschaften Pharmakotherapeutische Gruppe: Antineo­plastische Wirkstoffe ATC-Code: L01B B05

Fludara enthält Fludarabinphosphat (2F-Ara-AMP), ein wasserlösliches fluoriertes Nu­kleotid-Analogon des Virostatikums Vidara­bin (Ara-A, 9-β-D-Arabinofuranosyladenin), das relativ stabil gegenüber der Desaminie­rung durch Adenosin-Desaminase ist.

Fludarabinphosphat wird rasch zu 2F-Ara-A dephosphoryliert. Dieses wird in die Zellen aufgenommen und dann intrazellulär durch Deoxycytidin-Kinase zum aktiven Triphos­phat, 2F-Ara-ATP, phosphoryliert. Dieser Metabolit verhindert die DNA-Synthese durch Hemmung der Ribonukleotid-Reduk­tase, DNA-Polymerase α/β und ε sowie der DNA-Primase und DNA-Ligase. Die Aktivität der RNA-Polymerase II wird ebenfalls partiell gehemmt und dadurch die Proteinsynthese reduziert.

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Obwohl der Wirkungsmechanismus von 2F-Ara-ATP noch nicht vollständig geklärt ist, kann davon ausgegangen werden, dass die Wirkungen auf die DNA, RNA und Protein­synthese zur Hemmung des Zellwachstums beitragen, wobei die DNA-Synthesehem­mung als dominierender Faktor hervorzuhe­ben ist. In-vitro-Untersuchungen haben außerdem gezeigt, dass die Einwirkung von 2F-Ara-A auf CLL-Lymphozyten eine ausge­prägte DNA-Fragmentierung und Zelltod auslöst, die charakteristisch für Apoptose sind.

In einer Phase-III-Studie bei nicht vorbehan­delten Patienten mit chronischer lymphati­scher Leukämie vom B-Zell-Typ wurden 195 Patienten mit Fludara und 199 Patienten mit Chlorambucil (40 mg/m2, Wiederholung alle 4 Wochen) behandelt. Folgende Ergebnisse konnten gezeigt werden: Statistisch signifi­kant höhere Gesamtansprechrate und Rate kompletter Remissionen nach First-Line-Therapie mit Fludara im Vergleich zu Chlo­rambucil (61,1 % gegenüber 37,6 % bzw. 14,9 % gegenüber 3,4 %); statistisch signi­fikant längere Ansprechdauer (19 gegenüber 12,2 Monate) und längere Zeit bis zur Pro­gression (17 gegenüber 13,2 Monate) bei Patienten im Fludara-Arm. Das mediane Überleben lag im Fludara-Arm bei 56,1 Mo­naten, im Chlorambucil-Arm bei 55,1 Mona­ten; der Allgemeinzustand der Patienten un­terschied sich ebenfalls nicht signifikant.

Der Anteil von Patienten mit berichteten Toxi­zitäten war zwischen den mit Fludara (89,7 %) bzw. Chlorambucil (89,9 %) be­handelten Patienten vergleichbar. Während der Unterschied in der Gesamtinzidenz hä­matologischer Toxizität zwischen beiden Be­handlungsarmen nicht signifikant war, traten im Fludara-Arm Toxizitäten auf Leukozyten (p=0,0054) und auf Lymphozyten (p= 0,0240) signifikant häufiger auf als bei mit Chlorambucil behandelten Patienten. Übel­keit, Erbrechen und Diarrhoe traten bei mit Fludara behandelten Patienten signifikant seltener auf als im Chlorambucil-Arm (p�0,0001, p�0,0001 bzw. p=0,0489). Le­bertoxizitäten wurden ebenfalls im Fludara-Arm signifikant seltener berichtet als im Chlorambucil-Arm (p=0,0487).

Patienten, die initial auf Fludara ansprechen, haben eine gute Chance, erneut auf eine Fludara-Monotherapie anzusprechen.

Eine randomisierte Studie mit Fludara einer­seits und Cyclophosphamid, Adriamycin und Prednisolon (CAP) andererseits an 208 CLL-Patienten des Binet-Stadiums B bzw. C ergab in einer Untergruppe von 103 vorbe­handelten Patienten die folgenden Ergebnis-se: Die Gesamtansprechrate sowie die An­zahl kompletter Remissionen waren unter der Behandlung mit Fludara höher als bei der CAP-Behandlung (45 % gegenüber 26 % bzw. 13 % gegenüber 6 %). Die Dau­er des Ansprechens sowie das Gesamt­überleben waren für Fludara und CAP ähn­lich. Während der vorgegebenen Behand­lungsdauer von 6 Monaten lag die Anzahl der Todesfälle bei 9 (Fludara) bzw. 4 (CAP).

Nachträgliche Analysen der Daten bis zu 6 Monaten nach Behandlungsbeginn zeig­ten in der Untergruppe der vorbehandelten

Patienten mit Binet-Stadium C einen Unter­schied zwischen den Überlebenszeit-Kurven bei Fludara- bzw. CAP-Behandlung, der zu Gunsten von CAP ausfiel.

5.2 Pharmakokinetische Eigenschaften � Plasma- und Urinpharmakokinetik

von Fludarabin (2F-Ara-A) Das pharmakokinetische Verhalten von Flu­darabin (2F-Ara-A) wurde nach intravenöser Bolusinjektion, nach Kurzzeitinfusion sowie nach längerdauernder Infusion von Fludara­binphosphat (Fludara, 2F-Ara-AMP) an Tu­morpatienten untersucht.

2F-Ara-AMP ist ein wasserlösliches Pro­drug, das im menschlichen Organismus rasch und quantitativ zum Nukleosid Fluda­rabin (2F-Ara-A) dephosphoryliert wird. Nachdem Krebspatienten eine einmalige In­fusion von 25 mg 2F-Ara-AMP pro m2 Kör­peroberfläche über 30 Minuten erhielten, wurden mittlere Höchstkonzentrationen im Plasma von 3,5 – 3,7 µM unmittelbar am En­de der Infusion gemessen. Die entsprechen­den Spiegel von 2F-Ara-A nach der fünften Applikation zeigten eine mäßige Akkumula­tion mit mittleren Höchstkonzentrationen von 4,4 – 4,8 µM am Ende der Infusion. Während einer fünftägigen Behandlungsperiode stie­gen die Plasmaspiegelminima von 2F-Ara-A um einen Faktor von etwa 2 an. Eine Akku­mulation von 2F-Ara-A über mehrere Be­handlungszyklen kann ausgeschlossen werden. Die postmaximalen 2F-Ara-A-Plas­maspiegel fielen in drei Dispositionsphasen ab, mit einer initialen Halbwertszeit von ca. 5 Minuten, einer intermediären Halbwertszeit von 1 – 2 Stunden sowie einer terminalen Halbwertszeit von ca. 20 Stunden.

Eine vergleichende Untersuchung von Stu­dien zur Pharmakokinetik von 2F-Ara-A zeig­te eine mittlere Gesamtplasmaclearance (CL) von 79�40 ml/min/m2 (2,2�1,2 ml/ min/kg) und ein mittleres Verteilungsvolu­men (Vss) von 83�55 l/m2 (2,4�1,6 l/kg). Die Daten zeigten eine ausgeprägte interin­dividuelle Variabilität. Die 2F-Ara-A-Plasma­spiegel und die Flächen unter den Plasma­spiegelverläufen nahmen linear mit der Do­sis zu; dagegen waren die Halbwertszeiten, die Plasmaclearance und die Verteilungsvo­lumina unabhängig von der Dosis gleichblei­bend, was auf ein dosislineares pharmakoki­netisches Verhalten hinweist.

Das Auftreten von Neutropenie und Hämato­kritveränderungen zeigten, dass die zytotoxi­sche Wirkung von Fludarabinphosphat zu einer dosisabhängigen Hemmung der Hä­matopoese führt.

2F-Ara-A wird im Wesentlichen über die Nie­ren eliminiert, wobei 40 – 60 % einer appli­zierten i.v.-Dosis mit dem Urin ausgeschie­den werden. Studien zur Massenbilanz an Labortieren mit 3H-2F-Ara-AMP ergaben eine vollständige Ausscheidung der radio­aktiv markierten Substanzen mit dem Urin. 2F-Ara-Hypoxanthin, der Hauptmetabolit von 2F-Ara-AMP beim Hund, wurde beim Menschen nur sehr geringfügig nachgewie­sen. Da Patienten mit Nierenfunktionsstörun­gen eine verminderte Clearance für 2F-Ara-A aufweisen, ist in diesen Fällen eine Dosisre­duktion angezeigt. In-vitro-Untersuchungen mit menschlichen Plasmaproteinen zeigten A

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keine ausgeprägte Eiweißbindung von 2F-Ara-A.

� Zelluläre Pharmakokinetik von Fludarabintriphosphat

2F-Ara-A wird nach aktiver Aufnahme in leu­kämischen Zellen zum Mono-, Di- und schließlich zum Triphosphat rephosphory­liert. Das Fludarabintriphosphat, 2F-Ara-ATP, ist der wichtigste intrazelluläre Metabolit von Fludarabin und der einzige Metabolit, der zytotoxische Aktivität aufweist. Maximale 2F­Ara-ATP-Spiegel in leukämischen Lympho­zyten von CLL-Patienten wurden etwa 4 Stunden nach der Applikation gemessen, wobei die Höchstkonzentration mit beträcht­lichen Abweichungen etwa 20 µM (Median-Werte) betrug. Die 2F-Ara-ATP-Spiegel in den leukämischen Zellen lagen beträchtlich über den maximalen 2F-Ara-A-Spiegeln im Plasma, was für eine Anreicherung in den Zielzellen spricht. Die In-vitro-Inkubation von leukämischen Lymphozyten zeigte eine li­neare Beziehung zwischen der extrazellulä­ren Exposition mit 2F-Ara-A (Produkt der 2F­Ara-A-Konzentration und der Inkubations­dauer) und der intrazellulären Anreicherung von 2F-Ara-ATP. Die Halbwertszeiten für die Elimination von 2F-Ara-ATP aus den Zielzel­len betrugen 15 und 23 Stunden (Median-Werte).

Eine eindeutige Korrelation zwischen der Pharmakokinetik von 2F-Ara-A und der Wirk­samkeit der Behandlung bei Krebspatienten wurde nicht gefunden.

5.3 Präklinische Daten zur Sicherheit In akuten Toxizitätsprüfungen mit einmaliger Verabreichung von Fludarabinphosphat wurden schwere Vergiftungssymptome oder Todesfälle erst in einem Dosisbereich beob­achtet, der zwei Größenordnungen über der therapeutischen Dosis liegt. Wie für eine zy­totoxische Substanz zu erwarten, zeigten sich die toxischen Wirkungen vor allem im Knochenmark, den lymphatischen Organen, der Schleimhaut des Magen-Darm-Traktes, den Nieren und den männlichen Gonaden. Bei Patienten wurden schwerwiegende Ne­benwirkungen bereits unter Dosierungen beobachtet, die wesentlich näher an der empfohlenen therapeutischen Dosis liegen (Faktor 3 bis 4). Hier sind insbesondere neu­rotoxische Wirkungen mit fallweise letalem Ausgang zu nennen (siehe Abschnitt 4.9).

Systemische Verträglichkeitsprüfungen mit wiederholter Verabreichung von Fludarabin­phosphat zeigten oberhalb einer Schwellen­dosis ebenfalls die erwarteten Effekte auf Gewebe mit hoher Zellteilungsrate. Die mor­phologischen Veränderungen waren mit zu­nehmender Dosis und Behandlungsdauer stärker ausgeprägt, und die beobachteten Veränderungen wurden generell als reversi­bel betrachtet. Grundsätzlich weisen die bis­herigen Erfahrungen aus der therapeuti­schen Anwendung von Fludara auf ein ver­gleichbares toxikologisches Wirkungsprofil beim Menschen hin, obwohl bei Patienten zusätzliche unerwünschte Wirkungen wie Neurotoxizität beobachtet wurden (siehe Ab­schnitt 4.8).

Aus den Ergebnissen der tierexperimentel­len Embryotoxizitätsstudien lässt sich ein te­ratogenes Potenzial von Fludarabinphos­phat ableiten. Angesichts des geringen Si­cherheitsabstandes zwischen den teratoge­nen Dosierungen im Tierexperiment und der therapeutischen Dosis sowie in Analogie zu anderen Antimetaboliten, für die eine Wech­selwirkung mit der embryonalen Zelldifferen­zierung vermutet wird, ist davon auszuge­hen, dass die therapeutische Anwendung von Fludara mit einem bedeutsamen Risiko für teratogene Wirkungen beim Menschen behaftet ist (siehe Abschnitt 4.6).

Fludarabinphosphat induzierte Chromoso­menaberrationen in einem zytogenetischen Test in vitro, erzeugte DNA-Schäden im Schwesterchromatidaustauschtest und er­höhte die Mikrokernrate im Mausmikrokern­test in vivo. Dagegen verliefen die Untersu­chungen zur mutagenen Wirkung sowie der Dominant-letal-Test an männlichen Mäusen negativ. Folglich konnte ein mutagenes Po­tenzial zwar in somatischen, nicht aber in Keimzellen nachgewiesen werden.

Zusammen mit den Ergebnissen der Muta­genitätsprüfungen stellt der Wirkungsme­chanismus von Fludarabinphosphat auf DNA-Ebene die Grundlage für den Verdacht auf ein tumorigenes Potenzial dar. Spezielle tierexperimentelle Tumorigenitätsstudien wurden nicht durchgeführt, da die bestehen­den Verdachtsmomente hinsichtlich des Ri­sikos für die Entstehung von Sekundärtumo­ren als Folge der zytotoxischen Therapie mit Fludara nur mit Hilfe epidemiologischer Da­ten abgeklärt werden können.

Gemäß den tierexperimentellen Ergebnis­sen aus Versuchen mit intravenöser Verab­reichung von Fludarabinphosphat sind bei Anwendung des Präparates keine bedeut­samen lokalen Reizwirkungen an der Injek­tionsstelle zu erwarten. Sogar bei einer Fehl­injektion wurden nach paravenöser, intraar­terieller und intramuskulärer Verabreichung einer wässrigen Lösung mit 7,5 mg/ ml Flu­darabinphosphat keine bedeutsamen loka­len Reizerscheinungen beobachtet.

6. PHARMAZEUTISCHE ANGABEN

6.1 Sonstige Bestandteile Mannitol Natriumhydroxid (zur Einstellung des pH-Wertes auf 7,7).

6.2 Inkompatibilitäten Darf nicht mit anderen Arzneimitteln ge­mischt werden.

6.3 Dauer der Haltbarkeit Im unversehrten Behältnis: 3 Jahre

Die chemische und physikalische Stabilität nach Rekonstitution wurde für 7 Tage bei 4 �C nachgewiesen. Aus mikrobiologischer Sicht, muss das Produkt sofort verwendet werden. Wird es nicht sofort verwendet, liegt die Verantwortung für die Lagerungszeiten und -bedingungen für das gebrauchsfertige Produkt beim Anwender. Eine 24-stündige Lagerung bei 2 bis 8 �C oder eine 8-stündi­ge Lagerung bei Raumtemperatur sollte nicht überschritten werden.

6.4 Besondere Lagerungshinweise Dieses Arzneimittel erfordert keine besonde­ren Lagerungsbedingungen.

Für die Lagerung nach Rekonstitution oder Verdünnung siehe Abschnitt 6.3.

6.5 Art und Inhalt des Behältnisses Farblose Durchstechflaschen zu 10 ml, Glas-Typ I, mit 50 mg Fludarabinphosphat.

Eine Packung enthält 5 Durchstechflaschen.

6.6 Hinweise für die Handhabung und Entsorgung � Rekonstitution Für die parenterale Verabreichung ist Fluda­ra unter aseptischen Bedingungen durch Zugabe von sterilem Wasser zur Injektion zuzubereiten. Nach Rekonstitution mit 2 ml sterilem Wasser für Injektionszwecke sollte sich das Pulver innerhalb von höchstens 15 Sekunden vollständig auflösen.

Die so erhaltene Lösung enthält je Milliliter 25 mg Fludarabinphosphat, 25 mg Mannitol sowie Natriumhydroxid zur Einstellung des pH-Wertes auf 7,7. Der zulässige pH-Wert des Endproduktes liegt zwischen 7,2 und 8,2.

� Verdünnung Die erforderliche Dosis (errechnet auf Basis der Körperoberfläche des Patienten) wird in eine Spritze aufgezogen.

Für eine intravenöse Bolus-Injektion wird diese Dosis in 10 ml einer 0,9%igen Natri­umchloridlösung weiter verdünnt.

Alternativ, für die Infusion, kann die erforderli­che Dosis in 100 ml einer 0,9%igen Natri­umchloridlösung verdünnt und über etwa 30 Minuten infundiert werden.

In klinischen Untersuchungen wurde das Präparat in 100 ml oder 125 ml 5%iger Glu­koselösung oder 0,9 %iger Natriumchlorid­lösung verdünnt.

� Prüfung vor der Anwendung Die rekonstituierte Lösung ist klar und farb­los. Sie muss vor der Anwendung visuell überprüft werden.

Nur klare und farblose Lösungen ohne Parti­kel dürfen angewendet werden. Falls das Behältnis defekt ist, darf Fludara darf nicht verwendet werden.

� Handhabung und Entsorgung Schwangeres Personal muss vom Umgang mit Fludara ausgeschlossen werden.

Die Vorschriften für eine ordnungsgemäße Handhabung gemäß der nationalen Anfor­derungen für zytotoxische Arzneimittel müs­sen beachtet werden. Bei der Zubereitung und dem Umgang mit der Fludara-Lösung ist Vorsicht geboten. Es wird empfohlen, Schutzhandschuhe und -brille zu tragen, um einen Kontakt mit der Substanz beim Zerbre­chen der Flasche oder anderweitigem verse­hentlichen Verschütten zu vermeiden. Soll­ten Haut oder Schleimhaut mit der Lösung in Berührung kommen, so muss der betroffene Bereich sorgfältig mit Wasser und Seife ge­reinigt werden. Bei Kontakt mit den Augen sind diese gründlich mit reichlich Wasser auszuspülen. Das Einatmen von Trocken­substanzstaub muss vermieden werden.

000698-Z914 -- Fludara -- n 4

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Fachinformation (Zusammenfassung der Merkmale des Arzneimittels)

Fludara�

Das Arzneimittel ist für den einmaligen Ge­brauch bestimmt. Sämtliche nicht verbrauch­ten Reste des Produktes oder Abfälle müs­sen in Übereinstimmung mit den nationalen Vorschriften entsorgt werden.

7. NAME ODER FIRMA UND ANSCHRIFT DES PHARMAZEUTISCHEN UNTER­NEHMERS

Pharmazeutischer Unternehmer: Bayer Vital GmbH D-51368 Leverkusen Telefon: (0214) 30-5 13 48 Telefax: (0214) 30-5 15 98 E-Mail-Adresse: bayer-vital�bayerhealthcare.com

Zulassungsnummer30590.00.00

8. DATUM DER ZULASSUNG/VERLÄNGERUNG DER ZULASSUNG

27.4.2001/13.12.2006

9. STAND DER INFORMATION

April 2007

10. VERSCHREIBUNGSSTATUS/ APOTHEKENPFLICHT

Verschreibungspflichtig

Dieses Arzneimittel enthält einen Wirkstoff, dessen antineoplastische Wirkung in Ver­bindung mit der Art der Anwendung in der medizinischen Wissenschaft noch nicht all­gemein bekannt ist. Für dieses Arzneimittel hat der pharmazeutische Unternehmer der zuständigen Bundesoberbehörde einen Er­fahrungsbericht nach § 49 Abs. 6 AMG vor­zulegen.

Zentrale Anforderung an:

Rote Liste Service GmbH

FachInfo-Service

Postfach 11 01 71 10831 Berlin

000698-Z914 -- Fludara -- n

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Anlage 5 Anmerkungen zur Auswahl der Literatur

Ausgewählt und in die Bewertung eingeschlossen wurden nur Literaturbeiträge, die alle folgenden Kriterien erfüllten: 1. Auswertungen klinischer Studien der Phase 2 mit Einschluss von mindestens 20 Patienten in

der Rezidivtherapie bzw. Therapie primär refraktärer NHL (bei Einschluss vorbehandelter und nicht vorbehandelter Patienten getrennte Auswertung für vorbehandelte Patienten und mindestens 20 Patienten in dieser Untergruppe) oder klinische Studie der Phase 3 / Metaanalyse unabhängig von der Therapielinie, in der Auswertung als Endpunkt(e) Ansprechrate und / oder progessionsfreies bzw. ereignisfreies Überleben und / oder Gesamtüberleben und / oder krankheitsbezogene Lebensqualität, und

2. intravenöses Fludarabin als Prüfmedikament und

3. geprüfte Indikation niedrig- oder intermediär malignes B-NHL außer CLL oder multiples Myelom, bei verschiedenen Unterformen getrennte Auswertung für CLL, andere niedrig und intermediär maligne B-NHL (mindestens 20 Patienten) und hoch maligne B-NHL und

4. geprüftes Therapiekonzept ist konventionell dosierte Chemotherapie ohne Hochdosistherapie und / oder Stammzelltransplantation und

5. Publikationstyp: Auswertung einer Studie, keine Übersichtsarbeit, kein „letter“, kein „editorial“

Fett gedruckte Titel wurden eingeschlossen Bei den übrigen Publikationen wurde in der letzten Zeile mindestens eines der Auswahlkriterien genannt, weshalb diese Arbeit nicht berücksichtigt wurde (siehe auch Abschnitt 8 des Gutachtens), ggf. Erläuterung in Klammern, sofern der Ausschlussgrund nicht schon aufgrund von Überschrift oder Abstract erkennbar war: Tue Jul 8 11:10:57 2008 Search fludarabine AND Clinical Trial AND (lymphoma OR lymphoplasmacytic OR lymphoplasmocytic OR immunocytoma OR waldenström OR follicular OR mantle OR marginal zone) Limits: Publication Date from 1999/01/01 to 2008/06/30 Sort by: Author Entrez PubMed Results Items 1 -193 of 193 1: Abbasi MR, Sparano JA, Sarta C, Wiernik PH. Phase I trial of fludarabine and paclitaxel in non-Hodgkin's lymphoma. Med Oncol. 2003;20(1):53-8. PMID: 12665685 [PubMed - indexed for MEDLINE] 1 2: Akpek G, Koh HK, Bogen S, O'Hara C, Foss FM. Chemotherapy with etoposide, vincristine, doxorubicin, bolus cyclophosphamide,

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and oral prednisone in patients with refractory cutaneous T-cell lymphoma. Cancer. 1999 Oct 1;86(7):1368-76. PMID: 10506727 [PubMed - indexed for MEDLINE] 2 3: Al-toma A, Visser OJ, van Roessel HM, von Blomberg BM, Verbeek WH, Scholten PE, Ossenkoppele GJ, Huijgens PC, Mulder CJ. Autologous hematopoietic stem cell transplantation in refractory celiac disease with aberrant T cells. Blood. 2007 Mar 1;109(5):2243-9. Epub 2006 Oct 26. PMID: 17068146 [PubMed - indexed for MEDLINE] 4 4: Alessandrino EP, Bernasconi P, Colombo AA, Caldera D, Malcovati L, Troletti D, Vanelli L, Varettoni M, Montanari F, Lazzarino M. Reduced-intensity conditioning regimen with thiotepa and fludarabine followed by allogeneic blood stem cell transplantation in haematological malignancies. Bone Marrow Transplant. 2004 Dec;34(12):1039-45. PMID: 15516936 [PubMed - indexed for MEDLINE] 4 5: Alliot C. Fludarabine versus cyclophosphamide, vincristine, and prednisone in recurrent low-grade lymphomas. J Clin Oncol. 2003 Jul 1;21(13):2626; author reply 2626-7. No abstract available. PMID: 12829689 [PubMed - indexed for MEDLINE] 5 6: Alvarez I, Sureda A, Caballero MD, Urbano-Ispizua A, Ribera JM, Canales M, García-Conde J, Sanz G, Arranz R, Bernal MT, de la Serna J, Díez JL, Moraleda JM, Rubió-Félix D, Xicoy B, Martínez C, Mateos MV, Sierra J. Nonmyeloablative stem cell transplantation is an effective therapy for refractory or relapsed hodgkin lymphoma: results of a spanish prospective cooperative protocol. Biol Blood Marrow Transplant. 2006 Feb;12(2):172-83. PMID: 16443515 [PubMed - indexed for MEDLINE] 4 7: Anderlini P, Saliba R, Acholonu S, Giralt SA, Andersson B, Ueno NT, Hosing C, Khouri IF, Couriel D, de Lima M, Qazilbash MH, Pro B, Romaguera J, Fayad L, Hagemeister F, Younes A, Munsell MF, Champlin RE. Fludarabine-melphalan as a preparative regimen for reduced-intensity conditioning allogeneic stem cell transplantation in relapsed and refractory Hodgkin's lymphoma: the updated M.D. Anderson Cancer Center experience. Haematologica. 2008 Feb;93(2):257-64. Epub 2008 Jan 26. PMID: 18223284 [PubMed - indexed for MEDLINE] 4 8: Anderlini P, Giralt S, Andersson B, Ueno NT, Khouri I, Acholonu S, Cohen A, Körbling MJ, Manning J, Romaguera J, Sarris A, Rodriguez, Hagemeister F, Mclaughlin P, Cabanillas F, Champlin RE. Allogeneic stem cell transplantation with fludarabine-based, less intensive

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conditioning regimens as adoptive immunotherapy in advanced Hodgkin's disease. Bone Marrow Transplant. 2000 Sep;26(6):615-20. PMID: 11041566 [PubMed - indexed for MEDLINE] 4 9: Arima N, Mizoguchi H, Shirakawa S, Tomonaga M, Takatsuki K, Ohno R. [Phase I clinical study of SH L573 (fludarabine phosphate) in patients with chronic lymphocytic leukemia and adult T-cell leukemia/lymphoma] Gan To Kagaku Ryoho. 1999 Apr;26(5):619-29. Japanese. PMID: 10234292 [PubMed - indexed for MEDLINE] 1 10: Armitage JO. The role of mitoxantrone in non-Hodgkin's lymphoma. Oncology (Williston Park). 2002 Apr;16(4):490-502, 507-8; discussion 511-2, 514. Review. PMID: 12017536 [PubMed - indexed for MEDLINE] 5 11: Bacigalupo A, Locatelli F, Lanino E, Marsh J, Socié G, Maury S, Prete A, Locasciulli A, Cesaro S, Passweg J; Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation. Fludarabine, cyclophosphamide and anti-thymocyte globulin for alternative donor transplants in acquired severe aplastic anemia: a report from the EBMT-SAA Working Party. Bone Marrow Transplant. 2005 Dec;36(11):947-50. PMID: 16205733 [PubMed - indexed for MEDLINE] 4 12: Bertz H, Illerhaus G, Veelken H, Finke J. Allogeneic hematopoetic stem-cell transplantation for patients with relapsed or refractory lymphomas: comparison of high-dose conventional conditioning versus fludarabine-based reduced-intensity regimens. Ann Oncol. 2002 Jan;13(1):135-9. PMID: 11863095 [PubMed - indexed for MEDLINE] 4 13: Bethge WA, Hegenbart U, Stuart MJ, Storer BE, Maris MB, Flowers ME, Maloney DG, Chauncey T, Bruno B, Agura E, Forman SJ, Blume KG, Niederwieser D, Storb R, Sandmaier BM. Adoptive immunotherapy with donor lymphocyte infusions after allogeneic hematopoietic cell transplantation following nonmyeloablative conditioning. Blood. 2004 Feb 1;103(3):790-5. Epub 2003 Oct 2. PMID: 14525766 [PubMed - indexed for MEDLINE] 4 14: Bishop MR, Hou JW, Wilson WH, Steinberg SM, Odom J, Castro K, Kasten-Sportes C, Gea-Banacloche J, Marchigiani D, Gress R, Fowler DH. Establishment of early donor engraftment after reduced-intensity allogeneic hematopoietic stem cell transplantation to potentiate the graft-versus-lymphoma effect against refractory lymphomas. Biol Blood Marrow Transplant. 2003 Mar;9(3):162-9.

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PMID: 12652466 [PubMed - indexed for MEDLINE] 4 15: Bordonaro R, Petralia G, Restuccia N, Todaro AM, Serraino D, Giuffrida D, Cordio S, Giannitto-Giorgio C, Salice P, Ursino M, Novello G, Marletta F, Manusia M. Fludarabine, mitoxantrone and dexamethasone as front-line therapy in elderly patients affected by newly-diagnosed, low-grade non-Hodgkin's lymphomas with unfavorable prognostic factors: results of a phase II study. Leuk Lymphoma. 2004 Jan;45(1):93-100. PMID: 15061203 [PubMed - indexed for MEDLINE] 1 16: Buser AS, Stern M, Bucher C, Arber C, Heim D, Halter J, Meyer-Monard S, Stussi G, Lohri A, Ghielmini M, Tichelli A, Passweg JR, Gratwohl A. High-dose chemotherapy using BEAM without autologous rescue followed by reduced-intensity conditioning allogeneic stem-cell transplantation for refractory or relapsing lymphomas: a comparison of delayed versus immediate transplantation. Bone Marrow Transplant. 2007 Mar;39(6):335-40. PMID: 17342158 [PubMed - indexed for MEDLINE] 4 17: Buser AS, Heim D, Bucher C, Tichelli A, Gratwohl A, Passweg JR. High-dose chemotherapy using BEAM for tumor debulking without stem cell support followed by early allogeneic reduced intensity conditioning transplantation to induce a graft-versus-lymphoma effect in patients with high risk or refractory lymphoma. Bone Marrow Transplant. 2004 May;33(10):1011-4. PMID: 15064693 [PubMed - indexed for MEDLINE] 4 18: Byrd JC, Kitada S, Flinn IW, Aron JL, Pearson M, Lucas D, Reed JC. The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction. Blood. 2002 Feb 1;99(3):1038-43. PMID: 11807010 [PubMed - indexed for MEDLINE] 3 19: Carella AM, Cavaliere M, Lerma E, Ferrara R, Tedeschi L, Romanelli A, Vinci M, Pinotti G, Lambelet P, Loni C, Verdiani S, De Stefano F, Valbonesi M, Corsetti MT. Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin's disease and non-Hodgkin's lymphoma. J Clin Oncol. 2000 Dec 1;18(23):3918-24. PMID: 11099321 [PubMed - indexed for MEDLINE] 4 20: Casper J, Knauf W, Kiefer T, Wolff D, Steiner B, Hammer U, Wegener R, Kleine HD, Wilhelm S, Knopp A, Hartung G, Dölken G, Freund M.

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Treosulfan and fludarabine: a new toxicity-reduced conditioning regimen for allogeneic hematopoietic stem cell transplantation. Blood. 2004 Jan 15;103(2):725-31. Epub 2003 Aug 28. PMID: 12947008 [PubMed - indexed for MEDLINE] 4 21: Casper J, Knauf W, Blau I, Ruutu T, Volin L, Wandt H, Schafer-Eckart K, Holowiecki J, Giebel S, Aschan J, Zander A, Kroger N, Doelken G, Freund M. Treosulfan/fludarabine: a new conditioning regimen in allogeneic transplantation. Ann Hematol. 2004;83 Suppl 1:S70-1. PMID: 15124679 [PubMed - indexed for MEDLINE] 4 22: Castagna L, Bertuzzi A, Nozza A, Siracusano L, Balzarotti M, Magagnoli M, Sarina B, Timofeeva I, Sinnone M, Grimoldi MG, Farè M, Santoro A. Reduced intensity conditioning regimen followed by glycosylated G-CSF mobilized PBSCT in patients with solid tumors and malignant lymphomas. Bone Marrow Transplant. 2002 Aug;30(4):207-14. PMID: 12203136 [PubMed - indexed for MEDLINE] 4 23: Child JA, Johnson SA, Rule S, Smith GM, Morgan GJ, Johnson PW, Prentice AG, Tollerfield SM, Wareham E. FLUDAP: salvage chemotherapy for relapsed/refractory aggressive non-Hodgkin's lymphoma. Leuk Lymphoma. 2000 Apr;37(3-4):309-17. PMID: 10752982 [PubMed - indexed for MEDLINE] 3 24: Clavio M, Pierri I, Venturino C, Garrone A, Canepa L, Miglino M, Varaldo R, Ballerini F, Michelis GL, Balocco M, Abdall N, Gatto S, Gobbi M. Role of liposomal daunorubicin, fludarabine and cytarabine (FLAD) in the salvage therapy of adult acute lymphoblastic leukemia. Leuk Lymphoma. 2004 Dec;45(12):2527-30. No abstract available. PMID: 15621773 [PubMed - indexed for MEDLINE] 3 25: Clavio M, Venturino C, Pierri I, Garrone A, Miglino M, Canepa L, Balleari E, Balocco M, Michelis GL, Ballerini F, Gobbi M. Combination of liposomal daunorubicin (DaunoXome), fludarabine, and cytarabine (FLAD) in patients with poor-risk acute leukemia. Ann Hematol. 2004 Nov;83(11):696-703. Epub 2004 Aug 18. PMID: 15322763 [PubMed - indexed for MEDLINE] 3 26: Cohen BJ, Moskowitz C, Straus D, Noy A, Hedrick E, Zelenetz A. Cyclophosphamide/fludarabine (CF) is active in the treatment of mantle cell lymphoma. Leuk Lymphoma. 2001 Sep-Oct;42(5):1015-22. PMID: 11697618 [PubMed - indexed for MEDLINE] 1 (Erstlinientherapie, Phase 2 Studie))

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27: Coiffier B, Neidhardt-Bérard EM, Tilly H, Belanger C, Bouabdallah R, Haioun C, Brice P, Péaud PY, Pico JL, Janvier M, Solal-Celigny P, Brousse N. Fludarabine alone compared to CHVP plus interferon in elderly patients with follicular lymphoma and adverse prognostic parameters: a GELA study. Groupe d'Etudes des Lymphomes de l'Adulte. Ann Oncol. 1999 Oct;10(10):1191-7. PMID: 10586336 [PubMed - indexed for MEDLINE] 28: Cooper BW, Veal GJ, Radivoyevitch T, Tilby MJ, Meyerson HJ, Lazarus HM, Koc ON, Creger RJ, Pearson G, Nowell GM, Gosky D, Ingalls ST, Hoppel CL, Gerson SL. A phase I and pharmacodynamic study of fludarabine, carboplatin, and topotecan in patients with relapsed, refractory, or high-risk acute leukemia. Clin Cancer Res. 2004 Oct 15;10(20):6830-9. PMID: 15501959 [PubMed - indexed for MEDLINE] 1 29: Cooper T, Kantarjian H, Plunkett W, Gandhi V. Clofarabine in adult acute leukemias: clinical success and pharmacokinetics. Nucleosides Nucleotides Nucleic Acids. 2004 Oct;23(8-9):1417-23. PMID: 15571270 [PubMed - indexed for MEDLINE] 2 30: Corradini P, Dodero A, Zallio F, Caracciolo D, Casini M, Bregni M, Narni F, Patriarca F, Boccadoro M, Benedetti F, Rambaldi A, Gianni AM, Tarella C. Graft-versus-lymphoma effect in relapsed peripheral T-cell non-Hodgkin's lymphomas after reduced-intensity conditioning followed by allogeneic transplantation of hematopoietic cells. J Clin Oncol. 2004 Jun 1;22(11):2172-6. PMID: 15169805 [PubMed - indexed for MEDLINE] 4 31: Crawley CR, Foran JM, Gupta RK, Rohatiner AZ, Summers K, Matthews J, Micallef IN, Radford JA, Johnson SA, Johnson PW, Sweetenham JW, Lister TA. A phase II study to evaluate the combination of fludarabine, mitoxantrone and dexamethasone (FMD) in patients with follicular lymphoma. Ann Oncol. 2000 Jul;11(7):861-5. PMID: 10997815 [PubMed - indexed for MEDLINE] 32: Curbo S, Karlsson A. Nelarabine: a new purine analog in the treatment of hematologic malignancies. Rev Recent Clin Trials. 2006 Sep;1(3):185-92. Review. PMID: 18473971 [PubMed - indexed for MEDLINE] 2 33: Czuczman MS, Grillo-López AJ, Alkuzweny B, Weaver R, Larocca A, McLaughlin P. Prognostic factors for non-Hodgkin's lymphoma patients treated with chemotherapy may not predict outcome in patients treated with rituximab. Leuk Lymphoma. 2006 Sep;47(9):1830-40. PMID: 17064996 [PubMed - indexed for MEDLINE] 4 34: Czuczman MS, Koryzna A, Mohr A, Stewart C, Donohue K, Blumenson L, Bernstein

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ZP, McCarthy P, Alam A, Hernandez-Ilizaliturri F, Skipper M, Brown K, Chanan-Khan A, Klippenstein D, Loud P, Rock MK, Benyunes M, Grillo-Lopez A, Bernstein SH. Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma. J Clin Oncol. 2005 Feb 1;23(4):694-704. PMID: 15681517 [PubMed - indexed for MEDLINE] 1 (40 Patienten, davon 68 % Erstlinientherapie, Phase 2 Studie) 35: Czuczman MS. Immunochemotherapy in indolent non-Hodgkin's lymphoma. Semin Oncol. 2002 Apr;29(2 Suppl 6):11-7. Review. PMID: 12040529 [PubMed - indexed for MEDLINE] 5 36: Czuczman MS, Fallon A, Mohr A, Stewart C, Bernstein ZP, McCarthy P, Skipper M, Brown K, Miller K, Wentling D, Klippenstein D, Loud P, Rock MK, Benyunes M, Grillo-López AJ, Bernstein SH. Rituximab in combination with CHOP or fludarabine in low-grade lymphoma. Semin Oncol. 2002 Feb;29(1 Suppl 2):36-40. Review. PMID: 11842387 [PubMed - indexed for MEDLINE] 5 37: Czuczman MS. Combination chemotherapy and rituximab. Anticancer Drugs. 2001 Jun;12 Suppl 2:S15-9. Review. PMID: 11508932 [PubMed - indexed for MEDLINE] 5 38: Dabaja BS, O'Brien SM, Kantarjian HM, Cortes JE, Thomas DA, Albitar M, Schlette ES, Faderl S, Sarris A, Keating MJ, Giles FJ. Fractionated cyclophosphamide, vincristine, liposomal daunorubicin (daunoXome), and dexamethasone (hyperCVXD) regimen in Richter's syndrome. Leuk Lymphoma. 2001 Jul;42(3):329-37. PMID: 11699397 [PubMed - indexed for MEDLINE] 2 39: de Romeuf C, Dutertre CA, Le Garff-Tavernier M, Fournier N, Gaucher C, Glacet A, Jorieux S, Bihoreau N, Behrens CK, Béliard R, Vieillard V, Cazin B, Bourel D, Prost JF, Teillaud JL, Merle-Béral H. Chronic lymphocytic leukaemia cells are efficiently killed by an anti-CD20 monoclonal antibody selected for improved engagement of FcgammaRIIIA/CD16. Br J Haematol. 2008 Mar;140(6):635-43. PMID: 18302712 [PubMed - indexed for MEDLINE] 3 40: Densmore JJ, Williams ME. Mantle cell lymphoma. Curr Treat Options Oncol. 2000 Aug;1(3):281-5. Review. PMID: 12057172 [PubMed - indexed for MEDLINE] 5 41: Desikan KR, Dhodapkar MV, Barlogie B.

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172: Tsimberidou AM, Keating MJ. Richter's transformation in chronic lymphocytic leukemia. Semin Oncol. 2006 Apr;33(2):250-6. Review. PMID: 16616072 [PubMed - indexed for MEDLINE] 5 173: Tsimberidou AM, McLaughlin P, Younes A, Rodriguez MA, Hagemeister FB, Sarris A, Romaguera J, Hess M, Smith TL, Yang Y, Ayala A, Preti A, Lee MS, Cabanillas F. Fludarabine, mitoxantrone, dexamethasone (FND) compared with an alternating triple therapy (ATT) regimen in patients with stage IV indolent lymphoma. Blood. 2002 Dec 15;100(13):4351-7. Epub 2002 Aug 8. PMID: 12393618 [PubMed - indexed for MEDLINE] 174: Tsimberidou AM, O'Brien SM, Cortes JE, Faderl S, Andreeff M, Kantarjian HM, Keating MJ, Giles FJ. Phase II study of fludarabine, cytarabine (Ara-C), cyclophosphamide, cisplatin and GM-CSF (FACPGM) in patients with Richter's syndrome or refractory lymphoproliferative disorders. Leuk Lymphoma. 2002 Apr;43(4):767-72. PMID: 12153163 [PubMed - indexed for MEDLINE] 1 (n=22 davon Richter-Syndrom n=15) 175: Velasquez WS, Lew D, Grogan TM, Spiridonidis CH, Balcerzak SP, Dakhil SR, Miller TP, Lanier KS, Chapman RA, Fisher RI; Southwest Oncology Group. Combination of fludarabine and mitoxantrone in untreated stages III and IV low-grade lymphoma: S9501. J Clin Oncol. 2003 May 15;21(10):1996-2003. PMID: 12743154 [PubMed - indexed for MEDLINE] 1 176: Vigouroux S, Michallet M, Porcher R, Attal M, Ades L, Bernard M, Blaise D, Tabrizi R, Garban F, Cassuto JP, Chevalier P, Facon T, Ifrah N, Renaud M, Tilly H, Vernant JP, Kuentz M, Bourhis JH, Bordigoni P, Deconinck E, Lioure B, Socié G, Milpied N; French Society of Bone Marrow Graft Transplantation and Cellular Therapy (SFGM-TC). Long-term outcomes after reduced-intensity conditioning allogeneic stem cell transplantation for low-grade lymphoma: a survey by the French Society of Bone Marrow Graft Transplantation and Cellular Therapy (SFGM-TC). Haematologica. 2007 May;92(5):627-34. PMID: 17488686 [PubMed - indexed for MEDLINE] 4 177: Voliotis D, Diehl V. Challenges in treating hematologic malignancies. Semin Oncol. 2002 Jun;29(3 Suppl 8):30-9. Review. PMID: 12082652 [PubMed - indexed for MEDLINE] 5 178: Waselenko JK, Burrows A, Nelson DA, Lucas M, Ekstrand J, Edenfield WJ, Myhand RC. Post-transplant interleukin-2 in patients with low-grade lymphoid neoplasms previously treated with fludarabine is limited by hematologic toxicity.

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Ann Hematol. 2003 Sep;82(9):552-7. Epub 2003 Aug 9. PMID: 12910372 [PubMed - indexed for MEDLINE] 4 179: Waselenko JK, Flynn JM, Byrd JC. Stem-cell transplantation in chronic lymphocytic leukemia: the time for designing randomized studies has arrived. Semin Oncol. 1999 Feb;26(1):48-61. Review. PMID: 10073561 [PubMed - indexed for MEDLINE] 4 180: Wilder DD, Ogden JL, Jain VK. Efficacy of fludarabine/mitoxantrone/dexamethasone alternating with CHOP in bulky follicular non-Hodgkin's lymphoma. Clin Lymphoma. 2002 Mar;2(4):229-37. PMID: 11970762 [PubMed - indexed for MEDLINE] 1 (Erstlinie, Phase 2) 181: Willis CR, Goodrich A, Park K, Waselenko JK, Lucas M, Reese A, Diehl LF, Grever MR, Byrd JC, Flinn IW. A phase I/II study examining pentostatin, chlorambucil, and theophylline in patients with relapsed chronic lymphocytic leukemia and non-Hodgkin's lymphoma. Ann Hematol. 2006 May;85(5):301-7. Epub 2006 Mar 4. PMID: 16518606 [PubMed - indexed for MEDLINE] 2 182: Winkler U, Jensen M, Manzke O, Schulz H, Diehl V, Engert A. Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8). Blood. 1999 Oct 1;94(7):2217-24. PMID: 10498591 [PubMed - indexed for MEDLINE] 3 183: Yalman N, Sarper N, Devecioglu O, Anak S, Eryilmaz E, Can M, Yenilmez H, Agaoglu L, Gedikoglu G. Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of relapsed or poor risk childhood acute leukemia. Turk J Pediatr. 2000 Jul-Sep;42(3):198-204. PMID: 11105617 [PubMed - indexed for MEDLINE] 3 184: Yung L, Cunningham D, Hancock B, Smith P, Maclennan K, Linch D, McMillan A. Fludarabine, adriamycin and dexamethasone (FAD) in newly diagnosed advanced follicular lymphoma: a phase II study by the British National Lymphoma Investigation (BNLI). Br J Cancer. 2004 Aug 16;91(4):695-8. PMID: 15280929 [PubMed - indexed for MEDLINE] 1 185: Zinzani PL, Tani M, Pulsoni A, Gobbi M, Perotti A, De Luca S, Fabbri A, Zaccaria A, Voso MT, Fattori P, Guardigni L, Ronconi S, Cabras MG, Rigacci L, De

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Renzo A, Marchi E, Stefoni V, Fina M, Pellegrini C, Musuraca G, Derenzini E, Pileri S, Fanti S, Piccaluga PP, Baccarani M. Fludarabine and mitoxantrone followed by yttrium-90 ibritumomab tiuxetan in previously untreated patients with follicular non-Hodgkin lymphoma trial: a phase II non-randomised trial (FLUMIZ). Lancet Oncol. 2008 Apr;9(4):352-8. Epub 2008 Mar 14. PMID: 18342572 [PubMed - indexed for MEDLINE] 1 186: Zinzani PL, Tani M, Fanti S, Stefoni V, Musuraca G, Vitolo U, Perrotti A, Fina M, Derenzini E, Baccarani M. A phase 2 trial of fludarabine and mitoxantrone chemotherapy followed by yttrium-90 ibritumomab tiuxetan for patients with previously untreated, indolent, nonfollicular, non-Hodgkin lymphoma. Cancer. 2008 Feb 15;112(4):856-62. PMID: 18189293 [PubMed - indexed for MEDLINE] 1 187: Zinzani PL, Pulsoni A, Gentilini P, Visani G, Perrotti A, Molinari AL, Guardigni L, Tani M, Villivà N, Stefoni V, Alinari L, Martelli M, Bonifazi F, Pileri S, Tura S, Baccarani M. Effectiveness of fludarabine, idarubicin and cyclophosphamide (FLUIC) combination regimen for young patients with untreated non-follicular low-grade non-Hodgkin's lymphoma. Leuk Lymphoma. 2004 Sep;45(9):1815-9. PMID: 15223641 [PubMed - indexed for MEDLINE] 1 188: Zinzani PL, Pulsoni A, Perrotti A, Soverini S, Zaja F, De Renzo A, Storti S, Lauta VM, Guardigni L, Gentilini P, Tucci A, Molinari AL, Gobbi M, Falini B, Fattori PP, Ciccone F, Alinari L, Martelli M, Pileri S, Tura S, Baccarani M. Fludarabine plus mitoxantrone with and without rituximab versus CHOP with and without rituximab as front-line treatment for patients with follicular lymphoma. J Clin Oncol. 2004 Jul 1;22(13):2654-61. Epub 2004 May 24. PMID: 15159414 [PubMed - indexed for MEDLINE] 189: Zinzani PL, Magagnoli M, Bendandi M, Gherlinzoni F, Orcioni GF, Cellini C, Stefoni V, Pileri SA, Tura S. Efficacy of fludarabine and mitoxantrone (FN) combination regimen in untreated indolent non-Hodgkin's lymphomas. Ann Oncol. 2000 Mar;11(3):363-5. PMID: 10811507 [PubMed - indexed for MEDLINE] 1 190: Zinzani PL, Magagnoli M, Moretti L, De Renzo A, Battista R, Zaccaria A, Guardigni L, Mazza P, Marra R, Ronconi F, Lauta VM, Bendandi M, Gherlinzoni F, Gentilini P, Ciccone F, Cellini C, Stefoni V, Ricciuti F, Gobbi M, Tura S. Randomized trial of fludarabine versus fludarabine and idarubicin as frontline treatment in patients with indolent or mantle-cell lymphoma. J Clin Oncol. 2000 Feb;18(4):773-9. PMID: 10673518 [PubMed - indexed for MEDLINE]

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191: Zinzani PL, Magagnoli M, Moretti L, Battista R, Ronconi F, De Renzo A, Zaccaria A, Gentilini P, Guardigni L, Gherlinzoni F, Cellini C, Fattori PP, Bendandi M, Bocchia M, Aitini E, Tura S. Fludarabine-based chemotherapy in untreated mantle cell lymphomas: an encouraging experience in 29 patients. Haematologica. 1999 Nov;84(11):1002-6. PMID: 10553160 [PubMed - indexed for MEDLINE] 1 192: [No authors listed] Oblimersen: Augmerosen, BCL-2 antisense oligonucleotide - Genta, G 3139, GC 3139, oblimersen sodium. Drugs R D. 2007;8(5):321-34. Review. PMID: 17767397 [PubMed - indexed for MEDLINE] 5 193: [No authors listed] 45th annual meeting of the American Society of Hematology. December 6-9, 2003, San Diego, California. Clin Lymphoma. 2003 Dec;4(3):141-8. No abstract available. PMID: 14715094 [PubMed - indexed for MEDLINE] 5

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Anlage 6

Fachinformation des Arzneimittel-Kompendium der Schweiz®

Fludara® SCHERING

AMZV 9.11.2001

Zusammensetzung

Wirkstoff: Fludarabinphosphat.

Hilfsstoffe: Mannitol.

Galenische Form und Wirkstoffmenge pro Einheit

Stechampullen mit Lyophilisat zu 50 mg.

Indikationen/Anwendungsmöglichkeiten

Therapie der chronisch-lymphatischen Leukämie (CLL) vom B-Zell-Typ. Die Firstline-Therapie mit Fludara sollte nur bei Patienten mit fortgeschrittener Erkrankung begonnen werden, d.h. im Binet-Stadium B oder C, einhergehend mit krankheitsbedingten Symptomen oder Zeichen einer Krankheitsprogression.

Behandlung des niedrig malignen Non-Hodgkin Lymphoms im Stadium 3 bis 4 bei Patienten, die auf eine Standardtherapie mit mindestens einer alkylierenden Substanz nicht angesprochen haben oder bei denen die Krankheit während oder nach der Standardtherapie fortgeschritten ist.

Dosierung/Anwendung

Fludara soll nur unter Aufsicht eines in der Onkologie erfahrenen Arztes angewendet werden.

Fludara wird als intravenöse Bolusinjektion oder als intravenöse Infusion über 30 Minuten verabreicht. Zubereitung der Lösungen: siehe «Sonstige Hinweise/Hinweise für die Handhabung».

Übliche Dosierung

Die empfohlene Dosis beträgt 25 mg Fludarabinphosphat pro Quadratmeter Körperoberfläche. Sie wird in Abständen von 28 Tagen jeweils 5 Tage hintereinander verabreicht.

Die Behandlungsdauer ist vom Behandlungserfolg und von der Verträglichkeit des Arzneimittels abhängig.

Bei CLL Patienten sollten nach Erreichen der maximalen Wirkung (komplette oder partielle Remission, normalerweise 6 Behandlungszyklen) 3 weitere Behandlungszyklen mit Fludara durchgeführt werden. Danach sollte das Präparat abgesetzt werden.

Bei Patienten mit niedrig malignem Non-Hodgkin Lymphom wird ebenfalls eine Behandlung mit Fludara bis zum Erreichen der besten Wirkung (komplette oder partielle Remission) empfohlen. Danach sollten zur Konsolidierung der Wirkung zwei Behandlungszyklen in Betracht gezogen werden. In klinischen Studien wurde die Mehrzahl der Patienten mit niedrig malignem Non-Hodgkin Lymphom nicht länger als über 8 Zyklen behandelt.

Spezielle Dosierungsanweisungen

Bei Patienten über 70 Jahren sollte besonders vorsichtig dosiert werden.

Über Patienten mit eingeschränkter Nierenfunktion (Kreatinin-Clearance unter 70 ml/min) sind begrenzte Daten verfügbar. Deshalb muss bei Patienten mit klinischem Verdacht auf eingeschränkte Nierenfunktion und bei Patienten über 70

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Jahren die Kreatinin-Clearance bestimmt werden. Bei einem Wert zwischen 30 und 70 ml/min muss die Dosis um bis zu 50% reduziert werden und eine strenge hämatologische Überwachung erfolgen, um die Toxizität der Therapie zu beurteilen. Fludara ist kontraindiziert, wenn die Kreatinin-Clearance unter 30 ml/min liegt.

Über die Verwendung von Fludara bei Patienten mit einer beeinträchtigten Leberfunktion liegen keine Daten vor. Bei diesen Patienten sollte Fludara mit Vorsicht und nur angewendet werden, wenn der erwartete Nutzen das potentielle Risiko übersteigt.

Klinische Studien zur Wirksamkeit und Sicherheit bei Kindern und Jugendlichen wurden nicht durchgeführt.

Kontraindikationen

Überempfindlichkeit gegenüber einem Bestandteil des Präparates;

Niereninsuffizienz mit Kreatinin-Clearance unter 30 ml/min.;

dekompensierte hämolytische Anämie;

Schwangerschaft, Stillzeit.

Warnhinweise und Vorsichtsmassnahmen

Neurotoxizität

In Dosisfindungsstudien bei Patienten mit akuter Leukämie führte Fludara in hohen Dosen zu schweren neurologischen Wirkungen, bis hin zu Blindheit, Koma und Tod. Diese starke toxische Wirkung auf das zentrale Nervensystem trat bei 36% der Patienten auf, die mit etwa der vierfachen für die Therapie der CLL und des niedrig malignen Non-Hodgkin Lymphoms empfohlenen Dosis behandelt wurden (96 mg/m²/Tag über 5–7 Tage). Bei Patienten, die mit der für die Therapie der CLL und des niedrig malignen Non-Hodgkin Lymphoms empfohlenen Dosis behandelt wurden, kamen schwere Wirkungen auf das ZNS selten (Koma und Erregung) oder gelegentlich (Verwirrung) vor. Patienten sind sorgfältig auf Anzeichen neurologischer Nebenwirkungen zu überwachen.

Es ist nicht bekannt, welche Auswirkungen eine chronische Anwendung von Fludara auf das zentrale Nervensystem hat. Allerdings wurde die empfohlene Dosis von den Patienten in einigen Studien mit relativ langer Behandlungsdauer (bis zu 26 Zyklen) ertragen.

Beeinträchtigter Gesundheitszustand

An Patienten mit einem beeinträchtigten Gesundheitszustand sollte Fludara nur mit Vorsicht und nach sorgfältigem Abwägen des Risikos verabreicht werden. Dies gilt besonders für Patienten mit einer schweren Beeinträchtigung der Knochenmarkfunktion (Thrombozytopenie, Anämie und/oder Granulozytopenie), mit einem geschwächten Immunsystem oder mit vorausgegangenen opportunistischen Infektionen.

Knochenmarksuppression

Schwere Knochenmarksuppression, insbesondere Anämie, Thrombozytopenie und Neutropenie, wurde bei mit Fludara behandelten Patienten berichtet (Nadir der Granulozyten nach durchschnittlich 13 Tagen [Streubreite: 3–25 Tage] der Thrombozyten nach durchschnittlich 16 Tagen [Streubreite: 2–32 Tage]).

Es wird empfohlen, regelmässige Kontrollen des peripheren Blutbildes durchzuführen, um eine sich entwickelnde Anämie, Neutropenie und Thrombozytopenie zu entdecken.

Transfusion von Blutprodukten

Eine durch Transfusion von nicht-bestrahltem Blut ausgelöste Graft versus host Reaktion (Reaktion der transfundierten (immunkompetenten) Lymphozyten gegen den Empfängerorganismus) wurde bei mit Fludara behandelten Patienten beobachtet. Sehr häufig wurde über einen tödlichen Ausgang als Folge dieser

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Krankheit berichtet. Deshalb sollten Patienten, die während oder nach einer Behandlung mit Fludara Bluttransfusionen benötigen, nur bestrahltes Blut erhalten.

Hautkrebs

Während und nach einer Therapie mit Fludara wurde bei manchen Patienten über eine Verschlimmerung oder ein Rezidiv einer Hautkrebserkrankung berichtet.

Tumor-Zerfall-Syndrom

Bei Patienten mit grossen Tumorzellmassen wurde unter Fludara ein Tumor-Zerfall-Syndrom beobachtet.

Bei Patienten, bei denen das Risiko einer solchen Komplikation besteht, sind entsprechende Vorsichtsmassnahmen zu treffen.

Autoimmune Phänomene

Es wurde über lebensbedrohliche und manchmal tödliche autoimmune Ereignisse berichtet (z.B. autoimmunhämolytische Anämie, autoimmune Thrombozytopenie, thrombzytopenische Purpura, Pemphigus, Evans-Syndrom), die während und nach der Behandlung mit Fludara auftraten, unabhängig davon, ob der Patient in der Vorgeschichte eine autoimmune Erkrankung oder einen positiven Coombs-Test aufwies. Die meisten der behandelten Patienten, die bereits früher eine hämolytische Anämie entwickelt hatten, reagierten nach wiederholter Verabreichung von Fludara erneut mit einer Hämolyse.

Während der Therapie mit Fludara sollten daher engmaschige Kontrollen auf Zeichen einer autoimmunhämolytischen Anämie (Abfall des Hämoglobin in Verbindung mit einer Hämolyse und einem positiven Coombs-Test) erfolgen. Es wird empfohlen, bei Auftreten einer Hämolyse die Therapie mit Fludara zu unterbrechen. Bluttransfusionen (bestrahlt, siehe oben) und die Behandlung mit Kortikosteroiden sind die häufigsten Therapiemassnahmen bei autoimmunhämolytischer Anämie.

Impfungen

Aufgrund der immunsuppressiven Eigenschaften von Fludara ist der Impferfolg beeinträchtigt und die Aussagekraft von Kutantests reduziert. Wegen der Gefahr einer Infektion soll während und nach der Behandlung mit Fludara keine Impfung mit Lebendvakzinen durchgeführt werden.

Interaktionen

Bei einer klinischen Untersuchung, in der Fludara in Kombination mit Pentostatin (Deoxycoformycin) zur Behandlung therapierefraktärer CLL angewendet wurde, kam es zu einer nicht akzeptablen Häufung toxischer Wirkungen auf die Lunge mit letalem Ausgang. Die Anwendung von Fludara in Kombination mit Pentostatin ist daher nicht zu empfehlen.

Die therapeutische Wirkung von Fludara kann durch Dipyridamol und andere Inhibitoren der Adenosinaufnahme reduziert werden.

Schwangerschaft/Stillzeit

In tierexperimentellen Studien wirkte Fludara teratogen und/oder embryotoxisch. Präklinische Daten bei der Ratte zeigten, dass Fludarabinphosphat bzw. seine Metaboliten die fetoplazentare Schranke passieren.

Es wurde berichtet, dass in einem Fall die Behandlung mit Fludarabinphosphat während der frühen Schwangerschaft zu Missbildungen des Skelettes und des Herzens des Neugeborenen führte.

Fludara soll während der Schwangerschaft nicht verwendet werden.

Sowohl Frauen im gebärfähigen Alter als auch Männer müssen während und für mindestens 6 Monate nach Beendigung der Therapie kontrazeptive Massnahmen ergreifen. Falls dennoch eine Schwangerschaft eintritt, sollte sofort der behandelnde Arzt informiert werden.

Die präklinischen Daten deuten darauf hin, dass Fludarabinphosphat bzw. dessen

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Metabolite vom Blut in die Muttermilch übertreten.

Während der Therapie mit Fludara sollte sofort abgestillt werden.

Wirkung auf die Fahrtüchtigkeit und auf das Bedienen von Maschinen

Die Wirkung auf die Fahrtüchtigkeit und auf das Bedienen von Maschinen wurde nicht untersucht. Aufgrund der möglichen unerwünschten Wirkungen von Fludarabinphosphat ist jedoch Vorsicht geboten.

Unerwünschte Wirkungen

Zu den häufigsten Nebenwirkungen gehören Myelosuppression (Neutropenie, Thrombozytopenie und Anämie), Infektionen (einschliesslich Pneumonie), Fieber, Übelkeit, Erbrechen und Diarrhoe. Weitere oft beobachtete Nebenwirkungen sind Müdigkeit, Schwächegefühl, Stomatitis, Unwohlsein, Appetitlosigkeit, Oedeme, Schüttelfrost, periphere Neuropathie, Sehstörungen und Hautrötungen. Schwere opportunistische Infektionen traten während der Therapie mit Fludara auf. Es wurde über Todesfälle als Folge schwerer Nebenwirkungen berichtet.

Die am häufigsten berichteten unerwünschten Ereignisse und die Reaktionen, bei denen ein Zusammenhang mit der Anwendung des Präparates wahrscheinlich ist, werden unabhängig von ihrem Schweregrad, nach Organsystemen geordnet, im folgenden aufgeführt:

Infektionen

Sehr häufig: Pneumonien (bis zu 22%).

Häufig: Herpes Zoster, opportunistische Infektionen inkl. Reaktivierung von latenten viralen Infektionen, z.B. progressive multifokale Leukoenzephalopathie.

Blut- und Lymphsystem

Sehr häufig: Neutropenie, Thrombozytopenie und Anämie (bis zu 60%). Die Myelosuppression kann schwerwiegend und kumulativ sein.

Immunsystem

Selten: autoimmun hämolytische Anämie, autoimmune Thrombozytopenie, thrombozytopenische Purpura, Evans-Syndrom.

Stoffwechsel und Ernährungsstöungen

Selten: Tumor-Zerfall-Syndrom mit Hyperurikämie, Hyperphosphatämie, Hypokalzämie, metabolischer Azidose, Hyperkaliämie, Hämaturie, Ausscheidung von Harnsäurekristallen und Nierenversagen. Erste Anzeichen dieses Syndroms können Schmerzen in der Hüft- und Nierengegend und Hämaturie sein.

Psychiatrische Störungen

Gelegentlich: Verwirrung.

Selten: Erregung.

Nervensystem

Häufig: Periphere Neuropathie.

Selten: Koma.

Augen

Häufig: Sehstörungen.

Selten: Optikusneuritis, Optikusneuropathie, Blindheit.

Herz, Gefässe

Häufig: Ödeme.

Selten: Herzversagen, Arrhythmien.

Atmungsorgane

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Gelegentlich: Überempfindlichkeitsreaktionen der Lunge (Lungeninfiltrate, Pneumonitis und Lungenfibrose) begleitet von Dyspnoe und Husten.

Gastrointestinale Störungen

Häufig: Übelkeit, Erbrechen, Diarrhoe, Stomatitis, Appetitlosigkeit.

Gelegentlich: Veränderungen der Pankreasenzymwerte; Berichte über gastrointestinale Blutungen, hauptsächlich in Verbindung mit Thrombozytopenie.

Leber und Galle

Gelegentlich: Veränderungen der Leberenzymwerte.

Haut

Häufig: Hautausschläge.

Selten: toxischepidermale Nekrolyse (Lyell-Syndrom), Pemphigus.

Nieren und Harnwege

Selten: hämorrhagische Zystitis.

Allgemeine Störungen

Häufig: Allgemeine Störungen, Fieber, Müdigkeit, Schwächegefühl, Unwohlsein, Schüttelfrost.

Überdosierung

Hohen Dosen von Fludara wird eine irreversible toxische Wirkung auf das ZNS zugeschrieben, die sich in verzögert auftretender Blindheit, Koma und Tod äussern kann. Hohe Dosen können auch zu Thrombozytopenie und Neutropenie, bedingt durch Myelosuppression, führen.

Ein spezifisches Antidot bei einer Überdosierung von Fludara ist nicht bekannt. Die Behandlung sollte in einem solchen Fall abgesetzt und unterstützende Massnahmen eingeleitet werden.

Eigenschaften/Wirkungen

ATC-Code: L01BB05

Wirkmechanismus, Pharmakodynamik

Fludara enthält Fludarabinphosphat, ein fluoriertes Nukleotid-Analogon des Virostatikums Vidarabin (Ara-A, 9-β-D-Arabinofuranosyladenin), das relativ stabil gegenüber der Desaminierung durch Adenosin-Desaminase ist.

Fludarabinphosphat (2F-Ara-AMP) wird rasch zu Fludarabin (2F-Ara-A) dephosphoryliert. Dieses wird in die Zellen aufgenommen und dann intrazellulär durch Deoxycytidin-Kinase zum aktiven Triphosphat 2F-Ara-ATP phosphoryliert. Dieser Metabolit verhindert die DNA-Synthese durch Hemmung der Ribonukleotid-Reduktase, DNA-Polymerase α, δ und ε sowie der DNA-Primase und DNA-Ligase. Die Aktivität der RNA-Polymerase II wird ebenfalls partiell gehemmt und dadurch die Proteinsynthese reduziert.

Obwohl der Wirkungsmechanismus von 2F-Ara-ATP noch nicht vollständig geklärt ist, kann davon ausgegangen werden, dass die Wirkungen auf die DNA, RNA und Proteinsynthese zur Hemmung des Zellwachstums beitragen, wobei die DNA-Synthesehemmung als dominierender Faktor hervorzuheben ist. In-vitro Untersuchungen haben ausserdem gezeigt, dass die Einwirkung von 2F-Ara-A auf Lymphozyten eine Apoptose auslöst. Infolgedessen werden lymphatische Malignome und auch normale Lymphozyten zerstört.

Eine eindeutige Korrelation zwischen der Pharmakokinetik von 2F-Ara-A und der Wirksamkeit der Behandlung bei Krebspatienten wurde nicht gefunden. Das Auftreten von Neutropenie und Hämatokritveränderungen zeigte jedoch, dass die zytotoxische Wirkung von Fludarabinphosphat zu einer dosisabhängigen Hemmung der Hämatopoese führt.

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Klinische Wirksamkeit

In einer vergleichenden multizentrischen Studie bei 938 bisher unbehandelten Patienten mit fortgeschrittenem Stadium der CLL (Binet-Stadium B oder C) wurde entweder mit Fludara oder CAP (Cyclophosphamid, Adriamycin, Prednisolon) oder CHOP (Cyclophosphamid, Adriamycin, Vincristin, Prednisolon) über 6 Monate behandelt. Die Remissionsraten waren bei Fludara 71,1%, CAP 58,2% und CHOP 71,5%, das mediane Überleben war mit 69,67 und 70 Monaten nicht unterschiedlich.

Pharmakokinetik

Absorption

Nach Verabreichung von 2F-Ara-AMP verläuft die Pharmakokinetik des Metaboliten 2F-Ara-A dosislinear.

Nach einmaliger Infusion der Dosis von 25 mg 2F-Ara-AMP pro Quadratmeter Körperoberfläche an Patienten mit chronisch-lymphatischer Leukämie über 30 Minuten wurden mittlere Höchstkonzentrationen im Plasma von 3,5–3,7 µM am Ende der Infusion gemessen. Die entsprechenden maximalen 2F-Ara-A-Plasmaskonzentrationen am Ende der letzten Infusion bei einer fünftägigen Behandlung zeigten mit 4,4–4,8 µM eine mässige Kumulation. Während einer fünftägigen Behandlungsperiode stiegen die Plasmaspiegelminima von 2F-Ara-A im Plasma ca. um den Faktor 2 an. Eine Kumulation von 2F-Ara-A über mehrere Behandlungszyklen kann ausgeschlossen werden.

Distribution

Studien zur Pharmakokinetik von 2F-Ara-A zeigten ein mittleres Verteilungsvolumen (Vss) von 83 l/m² (2,4 l/kg). Es besteht eine ausgeprägte interindividuelle Variabilität.

In-vitro Untersuchungen mit menschlichen Plasmaproteinen zeigten keine ausgeprägte Eiweissbindung von 2F-Ara-A.

Metabolismus

Fludarabinphosphat (2F-Ara-AMP) wird im menschlichen Organismus innerhalb kürzester Zeit vollständig in seinen Hauptmetaboliten 2F-Ara-A umgewandelt. 2F-Ara-A wird aktiv in leukämische Zellen aufgenommen und dort zum cytotoxischen Metaboliten 2F-Ara-ATP umgewandelt.

2F-Ara-Hypoxanthin, ein Hauptmetabolit beim Hund, wurde im menschlichen Harn nur in kleinem Umfang nachgewiesen.

Elimination

Die 2F-Ara-A-Plasmaspiegel fielen in drei Phasen mit Dispositionshalbwertszeiten von ca. 5 Minuten, 1–2 Stunden sowie mit einer terminalen Halbwertszeit von ca. 20 Stunden. Die mittlere Gesamtplasmaclearance beträgt 79 ml/min/m² (2,2 ml/min/kg).

2F-Ara-A wird im wesentlichen über die Nieren ausgeschieden. 40–60% einer applizierten i.v.-Dosis werden mit dem Urin ausgeschieden. Über das Schicksal des verbleibenden Anteils ist nichts bekannt. Studien zur Massenbilanz an Labortieren mit ³H-2F-Ara-AMP ergaben eine vollständige Ausscheidung der radioaktiv markierten Substanzen mit dem Urin. 2F-Ara-Hypoxanthin, ein Hauptmetabolit beim Hund, wurde im menschlichen Harn nur in kleinem Umfang nachgewiesen.

Pharmakokinetik in besonderen klinischen Situationen

Niereninsuffizienz

Die Gesamtclearance des Hauptmetaboliten 2F-Ara-A im Plasma korreliert mit der Kreatinin-Clearance. Bei Patienten mit eingeschränkter Nierenfunktion wurde eine erhöhte Wirkstoffexposition mit 2F-Ara-A (AUC) und eine verminderte Clearance für 2F-Ara-A nachgewiesen. Daher ist eine Dosisreduktion angezeigt (siehe

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«Dosierung/Anwendung»).

Leberinsuffizienz

Es sind keine pharmakokinetischen Studien bei Patienten mit Leberinsuffizienz verfügbar.

Geriatrie

Pharmakokinetische Studien bei älteren Patienten liegen nicht vor.

Pädiatrie

Pharmakokinetische Studien bei pädiatrischen Patienten liegen nicht vor.

Präklinische Daten

Embryotoxitzität

Aus den Ergebnissen der tierexperimentellen Embryotoxizitätsstudien lässt sich ein teratogenes Potential von Fludarabinphosphat ableiten. Angesichts des geringen Sicherheitsabstandes zwischen den teratogenen Dosierungen im Tierexperiment und der therapeutischen Dosis sowie in Analogie zu anderen Substanzen der Gruppe der Antimetaboliten, für die eine Wechselwirkung mit dem Differenzierungsprozess vermutet wird, ist davon auszugehen, dass die therapeutische Anwendung von Fludara mit einem bedeutsamen Risiko für teratogene Wirkungen beim Menschen behaftet ist (vgl. «Schwangerschaft/Stillzeit»).

Genotoxizitäts-Potential, Tumorigenität

Fludarabinphosphat induzierte Chromosomenaberrationen in einem zytogenetischen Test in vitro, erzeugte DNA-Schäden im Schwesterchromatidaustauschtest und erhöhte die Mikrokernrate im Mausmikronukleustest in vivo, dagegen verliefen die Genmutationsuntersuchungen und die Dominanzletaluntersuchungen bei männlichen Mäusen negativ. Die mutagenen Eigenschaften wurden also in somatischen Zellen gezeigt, wurden aber in Keimzellen nicht gefunden.

Die Vermutung, dass die Substanz tumorinduzierende Eigenschaften hat, basiert auf der bekannten Aktivität von Fludarabinphosphat auf die DNA und den Ergebnissen der Mutagenitätsuntersuchungen. Spezielle tierexperimentelle Tumorigenitätsstudien wurden nicht durchgeführt, da die bestehenden Verdachtsmomente hinsichtlich des durch Fludarabinphosphat erhöhten Risikos für die sekundäre Entstehung von Tumoren nur mit Hilfe epidemiologischer Daten abgeklärt werden können.

Lokale Verträglichkeit

Gemäss den tierexperimentellen Ergebnissen aus Versuchen mit intravenöser Verabreichung von Fludarabinphosphat sind keine bedeutsamen lokalen Reizwirkungen an der Injektionsstelle zu erwarten. Sogar bei einer Fehlinjektion wurden nach paravenöser, intraarterieller und intramuskulärer Verabreichung einer wässrigen Lösung mit 7,5 mg/ml Fludarabinphosphat keine bedeutsamen lokalen Reizerscheinungen beobachtet.

Sonstige Hinweise

Inkompatibilitäten

Fludara darf nur mit den unter «Hinweise für die Handhabung» aufgeführten Arzneimitteln gemischt werden.

Haltbarkeit

Das Arzneimittel darf nur bis zu dem auf der Packung mit «EXP» bezeichneten Datum verwendet werden.

Die rekonstituierte Lösung (siehe unten, «Hinweise für die Handhabung») ist 7 Tage im Kühlschrank (2–8 °C) physikalisch und chemisch stabil. Die Lösung enthält kein Konservierungsmittel und sollte deshalb aus mikrobiologischer Sicht

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sofort nach Zubereitung verwendet werden; falls erforderlich kann sie maximal 24 Stunden im Kühlschrank (2–8 °C) aufbewahrt werden.

Die mit 5%iger Glucoselösung verdünnte Lösung für die Infusion (siehe unten, «Hinweise für die Handhabung») ist 8 Stunden im Kühlschrank (2–8 °C) resp. bei Raumtemperatur (15–25 °C), die mit 0,9%iger Kochsalzlösung verdünnte Lösung für die Bolusinjektion resp. für die Infusion (siehe unten, «Hinweise für die Handhabung») 24 Stunden bei Raumtemperatur (15–25 °C) und 48 Stunden im Kühlschrank (2–8 °C) physikalisch und chemisch stabil. Aus mikrobiologischer Sicht sollten die verdünnten Lösungen sofort nach Zubereitung verwendet werden; falls erforderlich kann die mit 5%iger Glucoselösung verdünnte Lösung maximal 8 Stunden im Kühlschrank (2–8 °C) und die mit 0,9%iger Kochsalzlösung verdünnte Lösung maximal 24 Stunden im Kühlschrank (2–8 °C) aufbewahrt werden.

Besondere Lagerungshinweise

Nicht über 30 °C lagern. Nicht im Kühlschrank aufbewahren und nicht einfrieren.

Hinweise für die Handhabung

Zubereitung der Lösung und Verabreichung

Das Lyophilisat wird mit 2 ml Wasser für Injektionszwecke rekonstituiert. Es sollte sich innerhalb von höchstens 15 Sekunden vollständig auflösen.

Das so erhaltene Konzentrat enthält 25 mg/ml Fludarabinphosphat.

Die Verabreichung von Fludara erfolgt als intravenöse Bolusinjektion oder als intravenöse Infusion über 30 Minuten.

Für die Bolusinjektion wird die erforderliche Menge des Konzentrates mit 10 ml 0,9%iger Kochsalzlösung verdünnt.

Für die Infusion wird die erforderliche Menge des Konzentrates mit 100 oder 125 ml 5%iger Glukoselösung oder 0,9%iger Kochsalzlösung verdünnt.

Fludara soll ausschliesslich intravenös verabreicht werden. Bislang wurden nach paravenöser Gabe keine schwerwiegenden lokalen Nebenwirkungen gemeldet. Dennoch ist die versehentliche paravenöse Gabe von Fludara strikt zu vermeiden.

Hinweis betreffend Zytostatika

Bei der Handhabung von Fludara, der Zubereitung der Lösungen und der Entsorgung sind die Vorschriften für Zytostatika zu befolgen.

Zulassungsvermerk

52795 (Swissmedic).

Zulassungsinhaberin

Schering (Schweiz) AG, Baar.

Stand der Information

Februar 2006.

Der Text wurde behördlich genehmigt und vom verantwortlichen Unternehmen zur Publikation durch die Documed AG freigegeben.© Copyright 2007 by Documed AG, Basel. Die unberechtigte Nutzung und Weitergabe ist untersagt. [27.10.2006]

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Anlage 7 Anmerkungen zur Auswahl der Literatur

Ausgewählt und in die Bewertung eingeschlossen wurden nur Literaturbeiträge, die alle folgenden Kriterien erfüllten: 1. Nicht in Medlinerecherche vom 08.07.2008 (siehe Anlage 1) enthalten und

2. Auswertungen klinischer Studien der Phase 2 mit Einschluss von mindestens 20 Patienten in der Rezidivtherapie bzw. Therapie primär refraktärer NHL (bei Einschluss vorbehandelter und nicht vorbehandelter Patienten getrennte Auswertung für vorbehandelte Patienten und mindestens 20 Patienten in dieser Untergruppe) oder klinische Studie der Phase 3 / Metaanalyse unabhängig von der Therapielinie, in der Auswertung als Endpunkt(e) Ansprechrate und / oder progessionsfreies Überleben o. ä. und / oder Gesamtüberleben und / oder krankheitsbezogene Lebensqualität und/oder nach anerkannter Skalierung erfasste Toxizität, und

3. intravenöses Fludarabin als Prüfmedikament und

4. geprüfte Indikation niedrig- oder intermediär malignes B-NHL außer CLL oder multiples Myelom, bei verschiedenen Unterformen getrennte Auswertung für CLL, andere niedrig und intermediär maligne B-NHL (mindestens 20 Patienten) und hoch maligne B-NHL und

5. geprüftes Therapiekonzept ist konventionell dosierte Chemotherapie ohne Hochdosistherapie und / oder Stammzelltransplantation und

6. Publikationstyp: Auswertung einer Studie, keine Übersichtsarbeit, kein „letter“, kein „editorial“

Fett gedruckte Titel wurden eingeschlossen Bei den übrigen Publikationen wurde in der letzten Zeile mindestens eines der Auswahlkriterien genannt, weshalb diese Arbeit nicht berücksichtigt wurde (siehe auch Abschnitt 8 des Gutachtens), ggf. Erläuterung in Klammern, sofern der Ausschlussgrund nicht schon aufgrund von Überschrift oder Abstract erkennbar war: Im Ergebnis erfüllte keine der unten aufgelisteten Publikationen sämtliche Einschlusskriterien 2.Recherche, 26.10.2007, EMBASE bei DIMDI, 79 Treffer Phase 2 Suchschritt : ((AU=PHASE ? OR (PHASE#)) AND FLUDARABINE# AND LYMPHOMA# AND NON# AND HODGKIN# AND FT=2) AND PY=1999 to 2007 1/2 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007484256 AU: Martin P; Furman RR; Coleman M; Leonard JP Titel: Phase I to III trials of anti-B cell therapy in non-Hodgkin's lymphoma Quelle: Clinical Cancer Research; VOL: 13 (18); p. 5636s-5642s /15 SEP 2007/

http://clincancerres.aacrjournals.org/cgi/reprint/13/18/5636sSprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1078-0432 CO: CCREF

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Corporate Source:

J.P. Leonard, Weill Medical College of Cornell University, New York Presbyterian Hospital, Starr Building, 520 East 70th Street, New York, NY 10021 United States [email protected]

COU: United States DT: Journal RN: 0077 DN: sgn 40 TE: allopurinol/315-30-0; apolizumab/267227-08-7; cyclophosphamide/50-18-0;

diphenhydramine/147-24-0; diphenhydramine/58-73-1; doxorubicin/23214-92-8; doxorubicin/25316-40-9; epratuzumab/205923-57-5; fludarabine/21679-14-1; galiximab/357613-77-5; ibritumomab tiuxetan/206181-63-7; paracetamol/103-90-2; prednisone/53-03-2; rasburicase/352311-12-7; rituximab/174722-31-7; tositumomab i 131/192391-48-3; tumor necrosis factor receptor/129203-93-6; tumor necrosis factor receptor/184595-01-5; vincristine/57-22-7

CR: 315-30-0; 267227-08-7; 50-18-0; 147-24-0; 58-73-1; 23214-92-8; 25316-40-9; 205923-57-5; 21679-14-1; 357613-77-5; 206181-63-7; 103-90-2; 53-03-2; 352311-12-7; 174722-31-7; 192391-48-3; 129203-93-6; 184595-01-5; 57-22-7

AB: Led by the anti-CD20 antibody rituximab, therapeutic monoclonal antibodies have dramatically altered the treatment of patients with non-Hodgkin's lymphoma. As the understanding of the biology of this novel therapy improves, so does the potential for further progress. There are currently four monoclonal antibodies approved by the Food and Drug Administration for the treatment of B-cell malignancies and dozens more are in various stages of development. The indications for the currently available antibodies, both labeled and unlabeled, are being expanded to include first-line treatment, maintenance strategies, and combinations with chemotherapy. Newer agents are being engineered to target novel antigens, and to interact more specifically with the host immune system. These promising therapeutics face a significant challenge in evaluation and integration in the post-rituximab world. © 2007 American Association for Cancer Research.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

» Volltext » 3, 6 2/2 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007342872 AU: Xiao Y; Jiang Z-J; Lin J-R; Xiao H-W; Li S-W; Xiao Z-F; Yan D-A Titel: Effective factors for quantity and quality of auto-peripheral blood stem cells in

hematopoietic system of patients with malignant tumor Quelle: Journal of Clinical Rehabilitative Tissue Engineering Research; VOL: 11 (20); p. 4052-

4056 /20 MAY 2007/ Sprache: ENGLISH AL: CHINESE CY: China ISSN: 1673-8225 Corporate Source:

Y. Xiao, Department of Hematology, Guangzhou General Hospital, Guangzhou Military Area Command of Chinese PLA, Guangzhou 510010 Guangdong Province China

Page 124: Fludara i.v. (2nd line NHL)

[email protected] COU: China DT: Journal RN: 0023 MN: Chugai TE: cyclophosphamide/50-18-0; cytarabine/147-94-4; cytarabine/69-74-9;

etoposide/33419-42-0; fludarabine/21679-14-1; trypan blue/72-57-1 CR: 50-18-0; 147-94-4; 69-74-9; 33419-42-0; 21679-14-1; 72-57-1 AB: Background: Hematopoietic reconstruction of malignant tumor in hematopoietic

system is related to disease itself, pretreatment program and therapeutic tool after transplantation; especially, mobilization, collection and cryopreservation of auto-peripheral blood stem cell play a key role in successful reconstruction of hematopoietic system after transplantation. Objective: To investigate the reconstruction of hematopoietic system through mobilization, collection and cryopreservation of auto-peripheral blood stem cell in patients with malignant tumor and analyze the effective factors on quantity and quality of auto-peripheral blood stem cell. Design: Case analysis based on malignant tumor in hematopoietic system. Setting: Department of Blood, Guangzhou General Hospital of Guangzhou Military Area Command of Chinese PLA; Department of Blood, Zhujiang Hospital, Nanfang Medical University. Participants: A total of 18 patients with malignant tumor in hematopoietic system were selected from Department of Blood, Guangzhou General Hospital of Guangzhou Military Area Command of Chinese PLA. Their ages ranged from 16 to 56 years. Among them, 2 patients had acute myelogenous leukemia (AML), 1 acute lymphoblastic leukemia (ALL), 2 lymphoblastic leukemia (LL), 2 chronic granulocytic leukemia (CGL), 4 multiple myeloma (MM), and 7 non-Hodgkin lymphoma. Granulocyte colony-stimulating factor (G-CSF) was made by Chugai Pharmaceutical Company Limited (batch number: N3G31). Methods: 1 All patients were mobilized with associated chemotherapy + G-CSF. Associate chemotherapy: Patients with leukemia were given 2 g/m² arabinosyl cytosine every 12 hours from the first to the third days and 200 mg/m² etoposide or 50 mg/m² fludarabine from the first to the fifth days. In addition, patients with MM were treated with arabinosyl cytosine as the same way mentioned above and with 1 g/m² cyclophosphamide from the first to the second days. And patients with lymphoma were given 2 g/m² cyclophosphamide from the first to the second days. When numbers of leucocyte of all patients decreased below 1.0×10(sup(9)) L(sup(-1)) after chemotherapy, G-CSF started mobilization and the collection was stopped with 5 µg/(kg·d) subcutaneous injection. 2 When numbers of leucocyte increased to (4.0-10.0)× 10(sup(9)) L(sup(-1)), hemopoietic stem cells of peripheral blood were collected till the amount of mononuclear cells (greater-than or equal to) 4.0×1(sup(8))/kg or numbers of CD34(sup(+)) cells (greater-than or equal to) 2.0×10(sup(6))/kg. And then, the samples were dealt with cooling device, maintained in liquid nitrogen at -196 °C and defrosted in water bath at 37-40 °C. 3 Focal sites of patients were pretreated with local irradiation with 200 cGy/time and 5 times/week for 4 successive weeks. The total dosage was 40 Gy. At 48 hours leter, (55.3±28.7) mL hemopoietic stem cells of peripheral blood were transfused back, and the duration from transfusion to collection was about (56.5±22.3) days. 300 µg/d G-CSF was subcutaneously injected into all patients at 1 day after transplantation and the reaction was stopped at the phase of neutrophil (greater-than or equal to) 0.5×10(sup(9)) L(sup(-1)). Finally, refusing-staining rate of trypan blue of peripheral blood stem cell, amount of mononuclear cells, number of granulation-monophyly progenitor cell colony and percentage of CD34(sup(+)) cells were detected before and after thaw. Main outcome measures: 1 Collection of auto-peripheral blood stem cell; 2 survival rate and related markers of auto-peripheral blood stem cell after cryopreservation; 3 hematopoietic reconstruction of auto-peripheral blood stem cell after transplantation. Results: All 18 patients with malignant tumor in hematopoietic system were involved in the final analysis. The

Page 125: Fludara i.v. (2nd line NHL)

mean collection time of auto-peripheral blood stem cell was 12.6 days after chemotherapy, the collection times were 1.9, total number of leucocyte was (8.93±1.27) × 10(sup(9)) L(sup(-1)) on the first day, and collection rate of mononuclear cell was (138.33± 28.61)%. 2 Refusing-staining rate of trypan blue of auto-peripheral blood stem cell was similar before and after cryopreservation [(96.26±1.33)%, (92.75±2.04)%, P>0.05]. In addition, after cryopreservation, recovery rates of mononuclear cells, CD34(sup(+)) cells and granulation-monophyly progenitor cell were (91.96±1.37)%, (85.94±0.64 and (87.69±4.53)%, respectively. Collection rate of mononuclear cells, number of granulation-monophyly progenitor cell colony and percentage of CD34(sup(+)) cells were lower in patients with myeloma than in those with leukemia and lymphoma (t = 2.524-3.268, P < 0.05). 3 At 15 days after transplantation, 15 patients had the neutrophil (greater-than or equal to) 0.5 × 10(sup(9)) L(sup(-1)); at 20 days after transplantation, blood platelet was (greater-than or equal to) 20 × 10(sup(9)) L(sup(-1)). granulation-monophyly progenitor cells [(18.67-26.82) × 10(sup(5))/kg] of 5 patients grew poorly if the course of chemotherapy was more than 10 times. Among them, 3 patients had delayed hematopoietic reconstruction after transplantation of auto-peripheral blood stem cell. Conclusion: 1 High-dose chemotherapy combined with G-CSF can shorten collection time of peripheral blood stem cell and improve collection rate of mononuclear cells. 2 Increase of chemotherapy times before transplantation can affect quantity and quality of auto-peripheral blood stem cell and cause delayed hematopoietic reconstruction.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Radiology

Cancer Hematology Clinical Biochemistry Drug Literature Index

5 2/3 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007346439 AU: Korycka A; Blonski JZ; Robak T Titel: FORODEZYNA (BCX-1777, IMMUCYLINA H). MECHANIZM DZIAlANIA I

PERSPEKTYWY KLINICZNEGO ZASTOSOWANIA NOWEGO INHIBITORA FOSFORYLAZY NUKLEOZYDOW PURYNOWYCH Forodesine (BCX-1777, Immucillin H) - Mechanism of action and potential clinical application of a new purine nucleoside phosphorylase inhibitor

Quelle: Acta Haematologica Polonica; VOL: 38 (1); p. 15-26 /2007/ Sprache: POLISH AL: POLISH CY: Poland ISSN: 0001-5814 CO: AHPLB Corporate Source:

A. Korycka, Z Katedry I Kliniki Hematologii Uniwersytetu Medycznego W Lodzi

DT: Journal RN: 0040 DN: bcx 1777 TE: cladribine/4291-63-8; clofarabine/123318-82-1; deoxycytidine kinase/9039-45-6;

deoxyguanosine phosphate/902-04-5; deoxyguanosine triphosphate/2564-35-4; deoxyguanosine/961-07-9; deoxyribose/533-67-5; fludarabine/21679-14-1;

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guanine/69257-39-2; guanine/73-40-5; interleukin 2/85898-30-2; nelarabine/121032-29-9; pentostatin/53910-25-1; phytohemagglutinin/9008-97-3; purine nucleoside phosphorylase/9030-21-1; purine nucleoside phosphorylase/9075-52-9

CR: 4291-63-8; 123318-82-1; 9039-45-6; 902-04-5; 2564-35-4; 961-07-9; 533-67-5; 21679-14-1; 69257-39-2; 73-40-5; 85898-30-2; 121032-29-9; 53910-25-1; 9008-97-3; 9030-21-1; 9075-52-9

AB: Recently, a few new purine nucleoside analogues (PNA) have been synthesized and introduced into preclinical and clinical trials. Clofarabine (CAFdA), nelarabine (ara-G) and forodesine (BCX-1777, Immucillin H), similarly to cladribine (2-CdA), fludarabine (FA) and pantostatin (deoxycoformycin, DCF) seem to be efficient in the treatment of hematological disorders. The transition-state theory has led to the design of 9-deazanucleotide analogues which belong to purine nucleoside phosphorylase (PNP) inhibitors, termed immucillins. Among them the most promising results have been obtained with forodesine which in the presence of 2'-deoxyguanosine (dGuo) forodesine inhibits human lymphocyte proliferation activated by various agents such as interleukin-2 (IL-2) or phytohemagglutinin. In the mechanism of forodesine action mainly two enzymes are involved: PNP which catalyzes the phosphorolysis of dGuo to guanine (Gu) and 2'-deoxyribose-alpha-D-1-phosphate, and deoxycytidine kinase (dCK) converting dGuo to deoxyguanosino-5'- monophosphate (dGMP) and finally to deoxyguanosino-5'-triphosphate (dGTP). The affinity of dGuo is higher for PNP than for dCK. Nevertheless, if PNP is blocked by forodesine, plasma dGuo is not cleaved to Gu, but instead it is intracellularly converted to dGTP which eventually results in apoptosis. Forodesine is active in some experimental tumors in mice, however it could be used for the treatment of human T-cell proliferative disorders. It is undergoing phase I and II of clinical trials for the treatment of T-cell non-Hodgkin's lymphoma, including cutaneous T-cell lymphoma (CTCL), T- and B-cell acute lymphoblastic leukemia (T- and B-ALL).

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index

3 2/4 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007289667 AU: Wang Y; Serradell N; Bolós J; Rosa E Titel: Obatoclax mesilate: Bcl-2 inhibitor apoptosis inducer oncolytic Quelle: Drugs of the Future; VOL: 32 (3); p. 228-233 /2007/ Sprache: ENGLISH AL: ENGLISH CY: Spain ISSN: 0377-8282 CO: DRFUD Corporate Source:

Y. Wang, 8106 Runnymeade Dr., Frederick, MD 21702 United States

COU: United States DT: Journal RN: 0046 DN: abt 737; bh 311; bh 312; gw 2974; gx 015070; gx 15070 ms; gx 15070; ha 14 1; npi

0052

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TE: bortezomib/179324-69-7; bortezomib/197730-97-5; chlorambucil/305-03-3; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; cytarabine/147-94-4; cytarabine/69-74-9; dexamethasone/50-02-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; fludarabine/21679-14-1; gefitinib/184475-35-2; gefitinib/184475-55-6; gefitinib/184475-56-7; gossypol/303-45-7; melphalan/148-82-3; protein bcl 2/219306-68-0; protein bcl xl/151033-38-4; rituximab/174722-31-7; somatomedin C/67763-96-6; vincristine/57-22-7

CR: 179324-69-7; 197730-97-5; 305-03-3; 15663-27-1; 26035-31-4; 96081-74-2; 147-94-4; 69-74-9; 50-02-2; 23214-92-8; 25316-40-9; 21679-14-1; 184475-35-2; 184475-55-6; 184475-56-7; 303-45-7; 148-82-3; 219306-68-0; 151033-38-4; 174722-31-7; 67763-96-6; 57-22-7

AB: Obatoclax mesilate (GX15-070, GX15-070MS) is a small molecule specifically designed to inhibit all relevant members of the Bcl-2 protein family, which play critical roles in regulating apoptosis. Preclinical studies demonstrated that obatoclax alone or in combination with other drugs induces apoptosis in many human cancer cell lines. Obatoclax has entered clinical development for the treatment of a variety of cancers, and early results have confirmed potential antitumor activity. Obatoclax is currently in phase II clinical development for the treatment of Hodgkin's lymphoma, myelodysplastic/myeloproliferative disorders and follicular lymphoma, as well as earlier clinical development for several other cancers. Copyright © 2007 Prous Science.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3 2/5 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007253221 AU: Dragovich T; Gordon M; Mendelson D; Wong L; Modiano M; Chow H-HS; Samulitis B;

O'Day S; Grenier K; Hersh E; Dorr R Titel: Phase I trial of imexon in patients with advanced malignancy Quelle: Journal of Clinical Oncology; VOL: 25 (13); p. 1779-1784 /01 MAY 2007/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND Corporate Source:

Dr. R. Dorr, Arizona Cancer Center, University of Arizona, 1515 N Campbell Ave, Tucson, AZ 85724 United States [email protected]

COU: United States DT: Journal RN: 0025 DN: nsc 714597/Ben Venue,United States MN: Ben Venue,United States; Ben Venue TE: cyclophosphamide/50-18-0; cystine/24645-67-8; cystine/56-89-3; cystine/6020-39-9;

docusate sodium/577-11-7; doxorubicin/23214-92-8; doxorubicin/25316-40-9; elsamicin A/97068-30-9; fludarabine/21679-14-1; granisetron/107007-99-8;

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granisetron/109889-09-0; ibritumomab tiuxetan/206181-63-7; imexon/59643-91-3; ondansetron/103639-04-9; ondansetron/116002-70-1; ondansetron/99614-01-4; prednisone/53-03-2; rituximab/174722-31-7; sodium dihydrogen phosphate/7558-80-7; sodium dihydrogen phosphate/7632-05-5; vincristine/57-22-7

CR: 50-18-0; 24645-67-8; 56-89-3; 6020-39-9; 577-11-7; 23214-92-8; 25316-40-9; 97068-30-9; 21679-14-1; 107007-99-8; 109889-09-0; 206181-63-7; 59643-91-3; 103639-04-9; 116002-70-1; 99614-01-4; 53-03-2; 174722-31-7; 7558-80-7; 7632-05-5; 57-22-7

AB: Purpose: Imexon, a pro-oxidant small molecule, has antitumor activity in preclinical models. The drug induces apoptosis through accumulation of reactive oxygen species. The purpose of this trial was to define the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and pharmacodynamics of imexon in patients with advanced cancers. Patients and Methods: Forty-nine patients with metastatic cancer received intravenous imexon over 30 to 45 minutes for 5 consecutive days (one course) every other week (days 1 through 5 and 15 through 19) monthly. Doses were initially escalated using an accelerated trial design and then a modified Fibonacci method. Plasma imexon levels and six different thiols were measured by high-performance liquid chromatography assays. Results: There were 13 dose levels evaluated, from 20 mg/m²/d to 1,000 mg/m²/d. The MTD recommended for phase II studies was 875 mg/m ²/d for 5 days every 2 weeks (n = 9 patients). The two dose-limiting toxicities at 1,000 mg/m²/d involved grade 3 abdominal pain and fatigue and grade 4 neutropenia, which occurred in one patient each. Other common toxicities included nausea and vomiting (58%) and constipation (63%); both were managed well with prophylactic medications. One partial response was obtained in a heavily pretreated patient with non-Hodgkin's lymphoma. Pharmacokinetic studies showed dose-independent clearance, with a 95-minute mean half-life. Plasma thiol studies showed a dose- and area under the curve-dependent decrease in cystine levels 8 hours after dosing at (greater-than or equal to) 750 mg/m²/d. Conclusion: The phase II recommended dose of imexon is 875 mg/m²/d for 5 days every other week. A decrease in plasma thiols did correlate with imexon exposure. © 2007 by American Society of Clinical Oncology.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Pharmacology Drug Literature Index Adverse Reactions Titles

3 2/6 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007207282 AU: Kaminski MS; Radford JA; Gregory SA; Leonard JP; Knox SJ; Kroll S; Wahl RL Titel: Re-treatment with I-131 tositumomab in patients with non-Hodgkin's lymphoma who

had previously responded to I-131 tositumomab Quelle: Journal of Clinical Oncology; VOL: 23 (31); p. 7985-7993 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND Corporate Source:

Dr. M.S. Kaminski, University of Michigan Comprehensive Cancer Center, Cancer Center, 1500 E Medical Center Drive, Ann Arbor, MI United States [email protected]

COU: United States DT: Journal

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RN: 0018 TE: cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9;

fludarabine/21679-14-1; rituximab/174722-31-7; topotecan/119413-54-6; topotecan/123948-87-8; tositumomab i 131/192391-48-3

CR: 50-18-0; 23214-92-8; 25316-40-9; 21679-14-1; 174722-31-7; 119413-54-6; 123948-87-8; 192391-48-3

AB: Purpose: To study efficacy and safety of re-treatment with I-131 tositumomab in patients with low-grade, follicular, or transformed low-grade B-cell lymphoma who relapsed following a response to I-131 tositumomab. Patients and Methods: A prior response (greater-than or equal to) 3 months to I-131 tositumomab was required. The single therapeutic dose following a dosimetric dose was adjusted to give the same total body dose (in Gy) as that used for the original dose, or was attenuated if the platelet count was less than 150,000 per mm³ or if the prior treatment resulted in grade 4 cytopenias lasting longer than 7 days. Results: Of 32 patients enrolled, 28 completed the therapeutic dose. A median of four therapies were given before re-treatment. Eighteen (56%) of 32 patients had a complete or partial response (median duration, 15.2 months); eight (25%) had a complete response (median duration, 35 months). Five continue in response from 1.8 to 5.7 years, with a median follow-up of 35 months. The overall median response duration was not significantly different for the two treatments, with no clinical factors predicting response or its duration. Ten of 18 re-responders had longer responses with re-treatment, with five having responses (greater-than or equal to) 1.5 years longer. Grade 3/4 neutropenia and thrombocytopenia occurred in 50% and 43% of patients, respectively, similar to initial treatment. Antimouse antibodies developed in 10% of patients, and 12% developed elevated serum thyroid-stimulating hormone. Six patients were diagnosed with second malignancies, including four patients who developed myelodysplastic syndrome (one who had not received the therapeutic dose) and one with acute myelogenous leukemia. Conclusion: Re-treatment with I-131 tositumomab following a previous response can produce second responses that can be durable. © 2005 by American Society of Clinical Oncology.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Nuclear Medicine Hematology Drug Literature Index Adverse Reactions Titles

3 2/7 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007190074 AU: Leonard JP; Coleman M; Ketas JC; Chadburn A; Ely S; Furman RR; Wegener WA;

Hansen HJ; Ziccardi H; Eschenberg M; Gayko U; Cesano A; Goldenberg DM Titel: Phase I/II trial of epratuzumab (humanized anti-CD22 antibody) in indolent non-

Hodgkin's lymphoma Quelle: Journal of Clinical Oncology; VOL: 21 (16); p. 3051-3059 /15 AUG 2003/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND Corporate

Dr. J.P. Leonard, Division of Hematology and Oncology, Weill Medical College of Cornell University, New York Presbyterian Hospital, 520 East 70th Street, New York,

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Source: NY 10021 United States [email protected]

COU: United States DT: Journal RN: 0031 TE: bleomycin/11056-06-7; carmustine/154-93-8; cisplatin/15663-27-1; cisplatin/26035-31-

4; cisplatin/96081-74-2; cladribine/4291-63-8; cyclophosphamide/50-18-0; cytarabine/147-94-4; cytarabine/69-74-9; dexamethasone/50-02-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; epratuzumab/205923-57-5; etoposide/33419-42-0; fludarabine/21679-14-1; ifosfamide/3778-73-2; mesna/19767-45-4; mesna/3375-50-6; methylprednisolone/6923-42-8; methylprednisolone/83-43-2; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; prednisone/53-03-2; rituximab/174722-31-7; thiotepa/52-24-4; tositumomab i 131/192391-48-3; vincristine/57-22-7

CR: 11056-06-7; 154-93-8; 15663-27-1; 26035-31-4; 96081-74-2; 4291-63-8; 50-18-0; 147-94-4; 69-74-9; 50-02-2; 23214-92-8; 25316-40-9; 205923-57-5; 33419-42-0; 21679-14-1; 3778-73-2; 19767-45-4; 3375-50-6; 6923-42-8; 83-43-2; 65271-80-9; 70476-82-3; 53-03-2; 174722-31-7; 52-24-4; 192391-48-3; 57-22-7

AB: Purpose: This single-center, dose-escalation study examines the safety, efficacy, and pharmacokinetics of epratuzumab (anti-CD22 humanized monoclonal antibody) in patients with recurrent indolent non-Hodgkin's lymphoma (NHL). Patients and Methods: Patients had indolent NHL and recurrent disease after at least one chemotherapy regimen. Epratuzumab was administered intravenously at 120 to 1,000 mg/m² over 30 to 60 minutes weekly for four treatments. Results: Fifty-five patients received epratuzumab and were assessable for safety; 51 patients were assessable for response. Patients were heavily pretreated (50% had at least four prior regimens) and 49% had bulky disease ((greater-than or equal to) 5 cm). Epratuzumab was well tolerated, with no dose-limiting toxicity. Circulating B cells transiently decreased without significant effects on T cells or immunoglobulin levels. More than 95% of infusions were completed in approximately 1 hour. Mean serum half-life was 23 days. Across all dose levels and histologies, nine patients (18%; 95% confidence interval, 8% to 31%) achieved objective response, including three complete responses (CRs). All responses were in patients with follicular NHL: 24% of these patients responded, including 43% in the 360 mg/m² dose group and 27% in the 480 mg/m² dose group. No responses were observed in other indolent histologies. Median duration of objective response was 79.3 weeks (range, 11.1 to 143.3 weeks), with median time to progression for responders of 86.6 weeks by Kaplan-Meier estimate. Conclusion: Epratuzumab was well tolerated at up to 1,000 mg/m²/wk (for 4 weeks) and had clinical activity. One third of responding patients achieved CR. A 43% objective response rate in follicular NHL patients treated at 360 mg/m²/wk indicates that this dose should be explored in additional studies. © 2003 by American Society of Clinical Oncology.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3 2/8 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007189679

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AU: Vose JM; Bierman PJ; Loberiza FR; Bociek RG; Matso D; Armitage JO Titel: Phase I trial of (sup(90))Y-ibritumomab tiuxetan i patients with relapsed B-cell non-

Hodgkin's lymphoma following high-dose chemotherapy and autologous stem cell transplantation

Quelle: Leukemia and Lymphoma; VOL: 48 (4); p. 683-690 /2007/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 EISSN: 1029-2403 CO: LELYE PII: 777232254 Corporate Source:

J.M. Vose, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE United States

COU: United States DT: Journal RN: 0040 TE: diphenhydramine/147-24-0; diphenhydramine/58-73-1; fludarabine/21679-14-1;

ibritumomab tiuxetan/206181-63-7; paracetamol/103-90-2; rituximab/174722-31-7 CR: 147-24-0; 58-73-1; 21679-14-1; 206181-63-7; 103-90-2; 174722-31-7 AB: Between January 2001 and September 2005, 19 patients with progressive B-cell non-

Hodgkin's lymphoma were treated with a cohort-specific dose of yttrium-90 ibritumomab tiuxetan (0.10-0.20 mCi/kg) to determine appropriate dosing in patients who had previously received high-dose chemotherapy and autologous stem cell transplantation (ASCT). Patients were required to have adequate end organ function and bone marrow status. Patients had been treated with a median of three prior therapies (range, 1-9). The median time from ASCT to radioimmunotherapy was 28 months. Hematologic toxicities were dose-limiting and included grade 3-4 thrombocytopenia (53%), neutropenia (32%), and anemia (21%). The majority of grade 3-4 events occurred at the 0.2mCi/kg dose level. Nine patients responded (complete response, complete response unconfirmed, or partial response) to the therapy. At a median follow-up of 37 months, the 1-year event-free and overall survival rates were 26% and 57%, respectively. A dose of 0.2 mCi/kg ibritumomab tiuxetan is safe and effective for patients with progressive disease after high-dose chemotherapy and ASCT.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

3 2/9 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007102076 AU: Leonard JP; Coleman M; Kostakoglu L; Chadburn A; Cesarman E; Furman RR;

Schuster MW; Niesvizky R; Muss D; Fiore J; Kroll S; Tidmarsh G; Vallabhajosula S; Goldsmith SJ

Titel: Abbreviated chemotherapy with fludarabine followed by tositumomab and iodine I 131 tositumomab for untreated follicular lymphoma

Quelle: Journal of Clinical Oncology; VOL: 23 (24); p. 5696-5704 /2005/ Sprache: ENGLISH

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AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND Corporate Source:

Dr. J.P. Leonard, Starr Bldg, Weill Medical College of Cornell University, New York Presbyterian Hospital, 520 E 70th St, New York, NY 10021 United States [email protected]

COU: United States DT: Journal RN: 0041 TE: fludarabine/21679-14-1; protein bcl 2/219306-68-0; tositumomab i 131/192391-48-3;

tositumomab/208921-02-2 CR: 21679-14-1; 219306-68-0; 192391-48-3; 208921-02-2 AB: Purpose: To evaluate the safety and efficacy of a sequential chemotherapy plus

radioimmunotherapy (RIT) regimen in previously untreated follicular non-Hodgkin's lymphoma. Patients and Methods: Thirty-five patients received an abbreviated course (three cycles) of fludarabine followed 6 to 8 weeks later by tositumomab and iodine I 131 tositumomab. Results: After fludarabine, 31 (89%) of 35 patients responded, with three (9%) of 31 patients achieving a complete response (CR). After the full regimen of fludarabine and iodine I 131 tositumomab, all 35 patients responded; 30 (86%) of 35 patients achieved CR, and five (14%) of 35 achieved partial response. After a median follow-up of 58 months, the median progression-free survival (PFS) had not been reached (95% CI, 27 months to not reached), but it will be at least 48 months. The 5-year estimated PFS rate is 60%. Baseline Follicular Lymphoma International Prognostic Index (FLIPI) was significantly associated (P = .003) with PFS. Five of six patients with more than 25% bone marrow involvement at baseline achieved adequate bone marrow cytoreduction to receive standard-dose iodine I 131 tositumomab. Ten (77%) of 13 patients with baseline bone marrow Bcl-2 positivity demonstrated molecular remissions at month 12. Toxicities were manageable and principally hematologic. Two (6%) of 35 patients developed human antimurine antibodies (HAMA) after RIT. Conclusion: Use of abbreviated fludarabine before iodine I 131 tositumomab can reduce bone marrow involvement, when needed, to allow the use of RIT and can suppress HAMA responses. This sequential treatment regimen is highly effective as front-line therapy for follicular lymphoma, particularly for low- or intermediate-risk FLIPI patients. © 2005 by American Society of Clinical Oncology.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

2 (Phase 2, Erstlinie) 2/10 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007086171 AU: Rummel MJ; Al-Batran SE; Kim S-Z; Welslau M; Hecker R; Kofahl-Krause D; Josten

K-M; Dürk H; Rost A; Neise M; Von Grünhagen U; Chow KU; Hansmann M-L; Hoelzer D; Mitrou PS

Titel: Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma

Quelle: Journal of Clinical Oncology; VOL: 23 (15); p. 3383-3389 /2005/ Sprache: ENGLISH

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AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND Corporate Source:

Dr. M.J. Rummel, Department of Internal Medicine, Hematology/Oncology, University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt/Main Germany [email protected]

COU: Germany DT: Journal RN: 0024 TE: bendamustine/16506-27-7; bendamustine/3543-75-7; bleomycin/11056-06-7;

chlorambucil/305-03-3; cladribine/4291-63-8; cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; epirubicin/56390-09-1; epirubicin/56420-45-2; fludarabine/21679-14-1; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; prednisone/53-03-2; procarbazine/366-70-1; procarbazine/671-16-9; rituximab/174722-31-7; vincristine/57-22-7

CR: 16506-27-7; 3543-75-7; 11056-06-7; 305-03-3; 4291-63-8; 50-18-0; 23214-92-8; 25316-40-9; 56390-09-1; 56420-45-2; 21679-14-1; 65271-80-9; 70476-82-3; 53-03-2; 366-70-1; 671-16-9; 174722-31-7; 57-22-7

AB: Purpose: The aim of this multicenter-study was to evaluate the progression-free survival, response rate and toxicity of the combination of bendamustine and rituximab (BR) in patients with mantle cell or low-grade lymphomas in first to third relapse or refractory to previous treatment. Patients and Methods: A total of 245 courses (median, four courses per patient) were administered to 63 patients. Bendamustine was given at a dose of 90 mg/m² as a 30-minute infusion on days 1 and 2, combined with 375 mg/m² rituximab on day 1, for a maximum of four cycles every 4 weeks. Histologies were 24 follicular, 16 mantle cell, 17 lymphoplasmacytoid, and six marginal zone lymphoma. Results: Fifty-seven of 63 patients responded to BR, corresponding to an overall response rate of 90% (95% CI, 80% to 96%) with a complete remission rate (CR) of 60% (95% CI, 47% to 72%). The median time of progression-free survival was 24 months (range, 5 to 44+ months), and the median duration of overall survival has not yet been reached. In mantle cell lymphomas, BR showed a considerable activity, achieving a response rate of 75% (95% CI, 48% to 93%) with a CR rate of 50%. Myelosuppression was the major toxicity, with 16% grade 3 and 4 leukocytopenia. Thrombocytopenia was rare, with only 3% grade 3 and 4. Conclusion: These results demonstrate that the BR combination is a highly active regimen in the treatment of low-grade lymphomas and mantle cell lymphomas. © 2005 by American Society of Clinical Oncology.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Public Health, Social Medicine and Epidemiology Hematology Drug Literature Index Adverse Reactions Titles

3 2/11 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007079104 AU: Czuczman MS; Koryzna A; Mohr A; Stewart C; Donohue K; Blumenson L; Bernstein

ZP; McCarthy P; Alam A; Hernandez-Ilizaliturri F; Skipper M; Brown K; Chanan-Khan A; Klippenstein D; Loud P; Rock MK; Benyunes M; Grillo-Lopez A; Bernstein SH

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Titel: Rituximab in combination with fludarabine chemotherapy in low-grade or follicular lymphoma

Quelle: Journal of Clinical Oncology; VOL: 23 (4); p. 694-704 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND Corporate Source:

Dr. M.S. Czuczman, Division of Hematologic Oncology, Roswell Park Cancer Institute, Elm and Carlton Sts, Buffalo, NY 14263 United States [email protected]

COU: United States DT: Journal RN: 0045 TE: aciclovir/59277-89-3; fludarabine/21679-14-1; gallium/7440-55-3; protein bcl

2/219306-68-0; rituximab/174722-31-7 CR: 59277-89-3; 21679-14-1; 7440-55-3; 219306-68-0; 174722-31-7 AB: Purpose: To evaluate the safety and efficacy of fludarabine plus rituximab in

treatment-naive or relapsed patients with low-grade and/or follicular non-Hodgkin's lymphoma. Patients and Methods: This was an open-label, single-arm, single-center phase II study enrolling 40 patients. During the first week of the study, patients received two infusions of rituximab 375 mg/m ² administered 4 days apart. Seventy-two hours after the second infusion of rituximab, patients received the first of six cycles of fludarabine chemotherapy (25 mg/m²/d for 5 days on a 28-day cycle). Single infusions of rituximab were administered 72 hours before the second, fourth, and sixth cycles of fludarabine, and two infusions of rituximab were given 4 weeks after the last cycle of fludarabine. Treatment duration was 26 weeks. Results: An overall response rate of 90% (80% complete response rate) was achieved in the intent-to-treat population. Similar response rates were seen in treatment-naieve and previously treated patients. The median duration of response has not been reached at 40+ months. The median follow-up time in this study is 44 months (range, 15 to 66 months). In patients positive for the 14;18 translocation in blood and/or marrow at enrollment, molecular remission was achieved in 88% of cases, with patients remaining negative for up to 4 years to date. Hematologic toxicity was manageable, and except for a 15% incidence of herpes simplex/zoster infections, infectious complications were rare. Nonhematologic toxicities were minimal. Conclusion: Rituximab plus fludarabine was well tolerated and associated with an excellent complete response rate, including molecular remissions, in patients with low-grade or follicular lymphoma. © 2005 by American Society of Clinical Oncology.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles General Pathology and Pathological Anatomy

1 2/12 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007066431 AU: Kreitman RJ; Squires DR; Stetler-Stevenson M; Noel P; FitzGerald DJP; Wilson WH;

Pastan I

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Titel: Phase I trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with B-cell malignancies

Quelle: Journal of Clinical Oncology; VOL: 23 (27); p. 6719-6729 /20 SEP 2005/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND Corporate Source:

Dr. R.J. Kreitman, National Cancer Institute, National Institutes of Health, Bldg. 5124B, 9000 Rockville Pike, Bethesda, MD 20892 United States [email protected]

COU: United States DT: Journal RN: 0051 DN: vp 16 TE: bleomycin/11056-06-7; celecoxib/169590-42-5; chlorambucil/305-03-3;

cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; cladribine/4291-63-8; cyclophosphamide/50-18-0; cytarabine/147-94-4; cytarabine/69-74-9; dexamethasone/50-02-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; etanercept/185243-69-0; etanercept/200013-86-1; etoposide/33419-42-0; flavopiridol/131740-09-5; flavopiridol/146426-40-6; fludarabine/21679-14-1; ibuprofen/15687-27-1; ifosfamide/3778-73-2; indometacin/53-86-1; indometacin/74252-25-8; indometacin/7681-54-1; mesna/19767-45-4; mesna/3375-50-6; methylprednisolone/6923-42-8; methylprednisolone/83-43-2; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; naproxen/22204-53-1; naproxen/26159-34-2; pentostatin/53910-25-1; prednisone/53-03-2; rituximab/174722-31-7; vincristine/57-22-7

CR: 11056-06-7; 169590-42-5; 305-03-3; 15663-27-1; 26035-31-4; 96081-74-2; 4291-63-8; 50-18-0; 147-94-4; 69-74-9; 50-02-2; 23214-92-8; 25316-40-9; 185243-69-0; 200013-86-1; 33419-42-0; 131740-09-5; 146426-40-6; 21679-14-1; 15687-27-1; 3778-73-2; 53-86-1; 74252-25-8; 7681-54-1; 19767-45-4; 3375-50-6; 6923-42-8; 83-43-2; 65271-80-9; 70476-82-3; 22204-53-1; 26159-34-2; 53910-25-1; 53-03-2; 174722-31-7; 57-22-7

AB: Purpose: To conduct a phase I trial of recombinant immunotoxin BL22, an anti-CD22 Fv fragment fused to truncated Pseudomonas exotoxin. Patients and Methods: Forty-six pretreated patients with CD22+ non-Hodgkin's lymphoma (NHL; n = 4), chronic lymphocytic leukemia (CLL; n = 11), and hairy cell leukemia (HCL; n = 31) received 265 cycles at 3 to 50 µg/Kg every other day × 3 doses. Results: BL22 was active in HCL, with 19 complete remissions (CRs; 61%) and six partial responses (PRs; 19%) in 31 patients. Of 19 CRs, 11 were achieved after one cycle and eight after two to 14 cycles. All 25 responders benefited clinically with one cycle. The CR rate was 86% in patients enrolled at > 40 µg/Kg every other day × 3, and 41% at lower doses (P = .011). The median duration for CR was 36 months (range, 5 to 66 months), and eight patients remain in CR at 45 months (range, 29 to 66 months). Lower but significant activity occurred in CLL. Neutralizing antibodies occurred in 11 (24%) of 46 patients (all HCL). A reversible hemolytic uremic syndrome requiring plasmapheresis was observed in one patient with NHL during cycle 1 and in four patients with HCL during cycle 2 or 3. The maximum-tolerated dose (MTD) evaluated at cycle 1 was 40 µg/Kg IV. QOD × 3. The most common toxicities at 30 to 50 µg/Kg every other day × 3 included hypoalbuminemia, transaminase elevations, fatigue, and edema. Conclusion: BL22 was well tolerated and highly effective in HCL, even after one cycle. Phase II testing is underway to define the efficacy with one cycle and to study safety when additional cycles are needed for optimal response. Copyright © 2005 by American Society of Clinical Oncology. All rights reserved.

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CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Drug Literature Index Adverse Reactions Titles

3 2/13 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007002076 AU: Laurencet F; Ballabeni P; Rufener B; Hess U; Cerny T; Fey M; Luthi J-M; Plancherel

C; Zulian GB Titel: The multicenter trial SAKK 37/95 of cladribine, cyclophosphamide and prednisone in

the treatment of chronic lymphocytic leukemias and low-grade non-Hodgkin's lymphomas

Quelle: Acta Haematologica; VOL: 117 (1); p. 40-47 /2007/ Sprache: ENGLISH AL: ENGLISH CY: Switzerland ISSN: 0001-5792 CO: ACHAA Corporate Source:

Dr. G.B. Zulian, Cesco, Geneva University Hospitals, 11, chemin de la Savonnière, CH-1255 Collonge-Bellerive Switzerland [email protected]

COU: Switzerland DT: Journal RN: 0038 MN: Lipo,Switzerland; Lipo TE: cladribine/4291-63-8; cyclophosphamide/50-18-0; fludarabine/21679-14-1;

hemoglobin/9008-02-0; prednisone/53-03-2 CR: 4291-63-8; 50-18-0; 21679-14-1; 9008-02-0; 53-03-2 AB: A multicenter trial was performed to confirm the therapeutic efficacy and the toxicity

profile of the combination of cladribine, cyclophosphamide and prednisone in low-grade non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Twenty-three adults with previously treated (61%) or untreated (39%) NHL International Working Formulation A or Binet B and C CLL were administered cladribine 0.1 mg/kg/day as a subcutaneous bolus for 5 days, intravenous cyclophosphamide 500 mg/m² on day 1, and oral prednisone 40 mg/m² on days 1-5, every 4 weeks. Unexpected early hematological toxicities led to dose modifications for pretreated patients who received cladribine for 3 days only up to a maximum of five courses. Responses were observed in 75%, with 7 patients obtaining a complete clinical and hematological response. Median duration of complete response was 9 months. Median time to progression or relapse was 31 months. Myelosuppression and infections were dose limiting whereas posttreatment complications, including fatalities, resulted from infections. Median overall survival time from trial entry was 60 months. Activity of the combination of cladribine, cyclophosphamide and prednisone was confirmed. However, in the specific setting of a multicenter trial, unexpected fatal infectious episodes occurred in pretreated patients. Great caution is thus required in these susceptible patients and the routine use of corticosteroids should probably be abandoned. Copyright © 2007 S. Karger AG.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved.

Page 137: Fludara i.v. (2nd line NHL)

ET: Cancer Hematology Drug Literature Index Adverse Reactions Titles

3 2/14 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006627393 AU: Sieniawski M; Staak O; Glossmann J-P; Reineke T; Scheuß H; Diehl V; Engert A;

Josting A Titel: Rituximab added to an intensified salvage chemotherapy program followed by

autologous stem cell transplantation improved the outcome in relapsed and refractory aggressive non-Hodgkin lymphoma

Quelle: Annals of Hematology; VOL: 86 (2); p. 107-115 /2007/ Sprache: ENGLISH AL: ENGLISH CY: Germany ISSN: 0939-5555 CO: ANHEE Corporate Source:

M. Sieniawski, Department I of Internal Medicine, University Hospital Cologne, Kerpener Str. 62, 50924 Cologne Germany [email protected]

COU: Germany DT: Journal RN: 0030 DN: mabthera; vp 16 TE: alemtuzumab/216503-57-0; bleomycin/11056-06-7; carmustine/154-93-8;

cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; cyclophosphamide/50-18-0; cytarabine/147-94-4; cytarabine/69-74-9; dexamethasone/50-02-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; etoposide/33419-42-0; fludarabine/21679-14-1; lactate dehydrogenase/9001-60-9; melphalan/148-82-3; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5; prednisone/53-03-2; procarbazine/366-70-1; procarbazine/671-16-9; rituximab/174722-31-7; vincristine/57-22-7

CR: 216503-57-0; 11056-06-7; 154-93-8; 15663-27-1; 26035-31-4; 96081-74-2; 50-18-0; 147-94-4; 69-74-9; 50-02-2; 23214-92-8; 25316-40-9; 33419-42-0; 21679-14-1; 9001-60-9; 148-82-3; 15475-56-6; 59-05-2; 7413-34-5; 53-03-2; 366-70-1; 671-16-9; 174722-31-7; 57-22-7

AB: We investigated the addition of rituximab to an intensified salvage program followed by a myeloablative course with autologous stem cell transplantation (ASCT) in patients with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL). Patients with relapsed or progressive aggressive NHL were treated with two cycles of conventional salvage chemotherapy (DHAP) followed by high-dose sequential chemotherapy (cyclophosphamide, methotrexate with vincristine and etoposide) and a final myeloablative course (BEAM) with ASCT. Rituximab (375 mg/m²) was administered at each treatment cycle. This cohort was compared with a historical control group of patients treated with the same chemotherapy but without rituximab. Patients from both groups were matched by duration of first remission and lactate dehydrogenase serum levels. Forty-five patients were treated with chemotherapy and 22 with immunochemotherapy. The overall response rates (ORR) at the final evaluation were 63% for the immunochemotherapy group and 42% for the

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chemotherapy group (p=0.330). In the historical controlled analysis freedom from second failure (FF2F) at 2 years in the immunochemotherapy group was 57% and overall survival (OS) was 77%. FF2F in the chemotherapy group was 18% (p=0.0051) and OS was 37% (p=0.0051). In the matched-pair analysis, FF2F was 58% in the immunochemotherapy group compared to 16% in the chemotherapy group (p=0.0517); OS was 74 vs 33%, respectively (p=0.0424). The toxicity was tolerable and comparable in both groups. The addition of rituximab to an intensified salvage chemotherapy regimen seems to improve the prognosis. However, only prospective randomized trial can offer sufficient data of the value of rituximab in relapsed and refractory aggressive NHL. © Springer-Verlag 2006.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Radiology

Cancer Hematology Drug Literature Index Adverse Reactions Titles

3 2/15 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006579945 AU: Rao R; Shammo JM; Enschede SH; Porter C; Adler SS; Venugopal P; Gregory SA Titel: The combination of fludarabine, cyclophosphamide, and granulocyte-macrophage

colony-stimulating factor in the treatment of patients with relapsed chronic lymphocytic leukemnia and low-grade non-Hodgkin's lymphoma

Quelle: Clinical Lymphoma and Myeloma; VOL: 6 (1); p. 26-30 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1557-9190 Corporate Source:

Dr. R. Rao, Department of Hematology and Oncology, Rush University Medical Center, 1725 W Harrison St, Chicago, IL 60612 United States [email protected]

COU: United States DT: Journal RN: 0021 TE: cyclophosphamide/50-18-0; fludarabine/21679-14-1 CR: 50-18-0; 21679-14-1 AB: Purpose: The goal of this study was to evaluate the efficacy of the

fludarabine/cyclophosphamide combination in patients with relapsed chronic lymphocytic lymphoma (CLL) and low-grade non-Hodgkin's Lymphoma (NHL) and to assess the impact of adding granulocyte-macrophage colony-stimulating factor (GM-CSF) to this regimen in a randomized fashion. Patients and methods: Thirty-four patients (CLL, n = 16; low-grade NHL, n = 18) were enrolled. The median number of previous treatments was 2. Patients received (less-than or equal to) 6 cycles of fludarabine at 30 mg/m² per day and cyclophosphamide at 300 mg/m² per day on days 1-3 of a 28-day cycle. Patients were randomized to supportive care or to receive GM-CSF at 250 µg/m² per day, starting 24 hours after completion of chemotherapy and continuing up to 48 hours before the next cycle. Those who had received > 6 months of previous therapy with an alkylating agent or had preexisting cytopenias received a 25% dose reduction. Twenty-two patients (65%) were randomized to receive GM-CSF. Patients completed a median of 5 cycles of treatment (range, 1-6 cycles).

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Twenty-seven patients (80%) received (greater-than or equal to) 3 cycles of treatment and were evaluated for response. Results: Seven patients (26%) exhibited a complete response; 6 of the 7 had low-grade NHL. Fourteen patients (52%) exhibited a partial response, and 6 patients (22%) had stable disease. Notably, 6 of the 7 patients who exhibited complete response and 9 of 14 patients with partial responses were randomized to the GM-CSF arm. The duration of response ranged from 4 months to 26 months. The toxicities were mainly hematologic. Nineteen patients (70%) experienced (greater-than or equal to) 1 episode of grade 3/4 neutropenia, but only 4 (15%) experienced febrile neutropenia; 3 of those patients were assigned to the GM-CSF arm. Conclusions: The combination of fludarabine and cyclophosphamide is a well-tolerated and effective treatment regimen for patients with relapsed CLL and low-grade NHL. A higher percentage of complete responses were noted in patients with low-grade NHL compared with patients with CLL. Granulocyte-macrophage colony-stimulating factor did not seem to decrease the incidence of febrile neutropenia. However, the higher number of complete and partial responses noted on the GM-CSF arm is intriguing and warrants further investigation.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

1 2/16 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006530593 AU: Lonial S; Arellano M; Hutcherson D; Langston A; Flowers C; Heffner LT; Winton E;

Lechowicz MJ; Waller EK Titel: Results of a clinical phase I dose-escalation study of cytarabinein combination with

fixed-dose vinorelbine, paclitaxel, etoposide and cisplatin for the treatment of relapsed/refractory lymphoma

Quelle: Leukemia and Lymphoma; VOL: 47 (10); p. 2155-2162 /2006/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 EISSN: 1029-2403 CO: LELYE PII: X71728045356644P Corporate Source:

S. Lonial, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GAUnited States

COU: United States DT: Journal RN: 0029 TE: aciclovir/59277-89-3; bleomycin/11056-06-7; busulfan/55-98-1; carboplatin/41575-94-

4; chlormethine/51-75-2; chlormethine/55-86-7; chlormethine/82905-71-3; ciprofloxacin/85721-33-1; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; cyclophosphamide/50-18-0; cytarabine/147-94-4; cytarabine/69-74-9; dacarbazine/4342-03-4; doxorubicin/23214-92-8; doxorubicin/25316-40-9; etoposide/33419-42-0; fluconazole/86386-73-4; fludarabine/21679-14-1; guanine arabinoside/38819-10-2; ifosfamide/3778-73-2; methylprednisolone/6923-42-8;

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methylprednisolone/83-43-2; navelbine/71486-22-1; paclitaxel/33069-62-4; penicillin G/1406-05-9; penicillin G/61-33-6; prednisone/53-03-2; procarbazine/366-70-1; procarbazine/671-16-9; rituximab/174722-31-7; vinblastine/865-21-4; vincristine sulfate/2068-78-2; vincristine/57-22-7

CR: 59277-89-3; 11056-06-7; 55-98-1; 41575-94-4; 51-75-2; 55-86-7; 82905-71-3; 85721-33-1; 15663-27-1; 26035-31-4; 96081-74-2; 50-18-0; 147-94-4; 69-74-9; 4342-03-4; 23214-92-8; 25316-40-9; 33419-42-0; 86386-73-4; 21679-14-1; 38819-10-2; 3778-73-2; 6923-42-8; 83-43-2; 71486-22-1; 33069-62-4; 1406-05-9; 61-33-6; 53-03-2; 366-70-1; 671-16-9; 174722-31-7; 865-21-4; 2068-78-2; 57-22-7

AB: Management of relapsed lymphoma depends upon the variables of chemosensitive disease and successful stem cell mobilization. The microtubule specific agents, paclitaxel and vinorelbine, have efficacy in relapsed lymphoma and can enhance stem cell mobilization. We performed a phase I dose-escalation study of cytarabine combined with fixed doses of vinorelbine, paclitaxel, etoposide and cisplatin (VTEPA) for patients with relapsed/refractory lymphoma. The regimen consisted of paclitaxel 175 mg/m² and vinorelbine 30 mg/m² on day 1; cisplatin 20 mg/m² and etoposide 100 mg/m² over 4 h on days 2-5. Cytarabine 2 g m/m² over 4 h, in successive cohorts on 1, 2, or 3 consecutive days: cohort A day 5; cohort B days 4-5; and cohort C days 3-5. Sixteen patients (Hodgkin's disease, n = 6; non-Hodgkin's lymphoma, n = 10) were enrolled. Fourteen of 16 patients (88%) had refractory and seven patients (44%) had primary refractory disease. Major toxicities included hematologic toxicity, mucositis and infectious complications. Infectious complications (10/16 patients) included neutropenic fever, sepsis and fungal pneumonia. Dose-limiting toxicity was achieved in cohort C, which received three doses of cytarabine. There were 33% partial responses, 27% stable disease and 40% progressive disease following a single cycle of VTEPA. Two of 16 patients suffered treatment-related mortality. Five patients went on to receive autologous (n = 4) or allogeneic transplant (n = 1), and five out of seven patients in this heavily pretreated group who received VTEPA for mobilization of an autologous graft were successfully collected. The recommended dose of cytarabine for further evaluation in a phase II study is 2 g m/m² for 2 consecutive days in combination with VTEPA. Treatment of subjects with relapsed/refractory lymphoma using VTEPA as second- or third-line salvage therapy produced remissions in some patients and permitted collection of grafts and subsequent autologous transplantation, supporting a planned phase II trial.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Drug Literature Index Adverse Reactions Titles

3 2/17 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006530420 AU: Czuczman MS; Grillo-López AJ; Alkuzweny B; Weaver R; Larocca A; Mclaughlin P Titel: Prognostic factors for non-Hodgkin's lymphoma patients treated with chemotherapy

may not predict outcome in patients treated with rituximab Quelle: Leukemia and Lymphoma; VOL: 47 (9); p. 1830-1840 /2006/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 EISSN: 1029-2403

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CO: LELYE PII: U4782P45519PV246 Corporate Source:

A.J. Grillo-López, Neoplastic and Autoimmune Diseases Research Institute, Rancho Santa Fe, CA United States

COU: United States DT: Journal RN: 0042 DN: rituxan TE: rituximab/174722-31-7; protein bcl 2/219306-68-0; lactate dehydrogenase/9001-60-9;

beta 2 microglobulin/9066-69-7; cyclophosphamide/50-18-0; vincristine/57-22-7; prednisone/53-03-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; acepromazine/61-00-7; fludarabine/21679-14-1

CR: 174722-31-7; 219306-68-0; 9001-60-9; 9066-69-7; 50-18-0; 57-22-7; 53-03-2; 23214-92-8; 25316-40-9; 61-00-7; 21679-14-1

AB: Several factors predict outcome for patients with non-Hodgkin's lymphoma (NHL) after chemotherapy. However, predictors of response to rituximab have not been identified. Baseline characteristics for 166 NHL patients (130 follicular) in a phase III trial of rituximab were analysed by univariate and multivariate methods to determine whether any of 27 factors predict response and/or response duration. In a univariate analysis, response to rituximab was associated with follicular histology, no prior fludarabine therapy, prior autologous bone marrow transplantation (ABMT), lack of bone marrow involvement or extranodal disease, positive bcl-2 in blood, and fewer relapses. By univariate analysis, longer median time to progression (TTP) and/or duration of response (DR) after rituximab therapy was associated with International Prognostic Index lower-risk group, multiagent chemotherapy, and low/normal serum lactate dehydrogenase (LDH) or beta(sub(2)) microglobulin. In the multivariate analysis, response to rituximab correlated with follicular histology, prior ABMT, multiagent chemotherapy, and no bone marrow involvement; longer TTP and/or DR correlated with low/normal serum LDH or beta(sub(2)) microglobulin, high CD3+ cells, and response to last chemotherapy. The follicular lymphoma international prognostic index (FLIPI) did not correlate consistently with response to rituximab or response duration. Several factors associated with prognosis following chemotherapy did not correlate with response to rituximab or response duration. NHL patients can respond to rituximab despite having factors associated with a poor outcome to chemotherapy.

CNOTE: Copyright 2006 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index

3, 6 2/18 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006530418 AU: Pro B; Hagemeister FB; McLaughlin P; Romaguera J; Rodriguez MA; Cabanillas F;

Tiongson LP; Younes A Titel: Phase 2 study of fludarabine and paclitaxel in patients with recurrent low-grade non-

Hodgkin's lymphoma Quelle: Leukemia and Lymphoma; VOL: 47 (9); p. 1818-1821 /2006/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194

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EISSN: 1029-2403 CO: LELYE PII: TL21263743741003 Corporate Source:

A. Younes, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX United States

COU: United States DT: Journal RN: 0009 TE: doxorubicin/23214-92-8; doxorubicin/25316-40-9; fludarabine/21679-14-1;

paclitaxel/33069-62-4 CR: 23214-92-8; 25316-40-9; 21679-14-1; 33069-62-4 AB: Although numerous options are available for patients with recurrent low-grade non-

Hodgkin's lymphoma (NHL), responses are rarely durable. We previously conducted a phase I trial of fludarabine and paclitaxel in the treatement of recurrent low-grade lymphoma. The present phase II study was performed to determine the activity of fludarabine and paclitaxel in patients with recurrent low-grade NHL. Patients with histologically confirmed recurrent low-grade NHL were treated with fludarabine 20 mg/m²/day intravenously (i.v.) on days 1-5 plus paclitaxel 50 mg/m² given by i.v. continuous infusion over 72 h starting on day 1. Treatment was repeated at 4-week intervals for a maximum of six courses. Twenty-eight evaluable patients were entered into this phase II trial. The median age was 53 years and the median performance status (Zubrod) was 1. Twenty-two (78%) patients had grade 1 or 2 follicular lymphoma, and six patients (21%) had small lymphocytic lymphoma. The median number of prior chemotherapy regimens was 1 (range, 1-3). Objective responses occurred in 16 patients (57%); nine patients (32%) achieved a complete remission with a median duration of 32 months (range 4-84+ months), and seven patients (25%) had a partial remission. Grade 3 and 4 toxicities included neutropenia (72%), neutropenic fever (34%), infection (13%), mucositis (7%), and neuropathy (3%). The combination of fludarabine and paclitaxel has clinical activity in patients with recurrent low-grade NHL.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles General Pathology and Pathological Anatomy

1 2/19 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006356356 AU: Leonard JP; Furman RR; Coleman M Titel: Proteasome inhibition with bortezomib: A new therapeutic strategy for non-Hodgkin's

lymphoma Quelle: International Journal of Cancer; VOL: 119 (5); p. 971-979 /01 SEP 2006/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0020-7136 EISSN: 1097-0215 CO: IJCNA Corporat J.P. Leonard, Division of Hematology and Medical Oncology, Weill Medical College of

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e Source:

Cornell University, New York Presbyterian Hospital, 525 East 68th Street, New York, NY 10021 United States [email protected]

COU: United States DT: Journal RN: 0105 DN: velcade/Millennium; adriamycin MN: Millennium TE: bortezomib/179324-69-7; bortezomib/197730-97-5; docetaxel/114977-28-5;

gemcitabine/103882-84-4; carboplatin/41575-94-4; 4 hydroperoxycyclophosphamide/39800-16-3; cyclophosphamide/50-18-0; vincristine/57-22-7; prednisone/53-03-2; rituximab/174722-31-7; doxorubicin/23214-92-8; doxorubicin/25316-40-9; fludarabine/21679-14-1; cladribine/4291-63-8; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; chlorambucil/305-03-3; tositumomab i 131/192391-48-3; ibritumomab tiuxetan/206181-63-7; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5; dexamethasone/50-02-2; cytarabine/147-94-4; cytarabine/69-74-9; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; melphalan/148-82-3; thalidomide/50-35-1; flavopiridol/146426-40-6; etoposide/33419-42-0

CR: 179324-69-7; 197730-97-5; 114977-28-5; 103882-84-4; 41575-94-4; 39800-16-3; 50-18-0; 57-22-7; 53-03-2; 174722-31-7; 23214-92-8; 25316-40-9; 21679-14-1; 4291-63-8; 65271-80-9; 70476-82-3; 305-03-3; 192391-48-3; 206181-63-7; 15475-56-6; 59-05-2; 7413-34-5; 50-02-2; 147-94-4; 69-74-9; 15663-27-1; 26035-31-4; 96081-74-2; 148-82-3; 50-35-1; 146426-40-6; 33419-42-0

AB: The incidence of non-Hodgkin's lymphoma (NHL) has markedly increased in the US and other westernized countries in recent years and presents a considerable clinical challenge. NHL is divided into subtypes that follow an aggressive or indolent course. Follicular lymphoma (FL), the most common indolent subtype, and mantle cell lymphoma (MCL), an aggressive subtype that accounts for approximately 5% of cases, are generally incurable. MCL has a relatively poor prognosis, with a median survival of 3-4 years. Despite improving response rates with new agents and regimens, the lack of demonstrated improvement in overall survival in many subtypes supports the development of novel approaches, such as proteasome inhibition. Bortezomib is the first proteasome inhibitor to be evaluated in human studies. It has already been approved as second-line treatment in multiple myeloma and is now under active investigation in NHL. The US FDA has granted bortezomib fast-track designation for relapsed and refractory MCL. In vitro and in vivo studies have demonstrated single-agent activity against various lymphoid tumors, and additive or synergistic effects in combination with other agents, including standard chemotherapy drugs employed in NHL. Phase 2 clinical trials indicate that bortezomib is well tolerated and active in several NHL subtypes, with response rates of 18-60% in FL and 39-56% in MCL. A number of combination trials are currently underway with a range of standard agents. Bortezomib has the potential to play a significant role throughout the NHL treatment algorithm in the future. © 2006 Wiley-Liss, Inc.

CNOTE: Copyright 2006 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3

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2/20 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006314371 AU: Goranov St Titel: Follicular non-Hodgkin lymfomas: Therapeutic options and challenges Quelle: Clinical and Transfusion Haematology; VOL: 41 (1-2); p. 24-29 /2005/ Sprache: BULGARIAN AL: ENGLISH CY: Bulgaria ISSN: 0861-7880 CO: KTKLB Corporate Source:

St. Goranov, Clinic of Haematology, University Multiprofile Hospital for Active Treatment Sv. Georgri, Plovidv Bulgaria

COU: Bulgaria DT: Journal RN: 0024 DN: chlorbutin; mabthera; campath 1h; bexxar; zevalin TE: chlorambucil/305-03-3; bendamustine/16506-27-7; bendamustine/3543-75-7;

cyclophosphamide/50-18-0; fludarabine/21679-14-1; cladribine/4291-63-8; prednisolone/50-24-8; vincristine/57-22-7; prednisone/53-03-2; bleomycin/11056-06-7; doxorubicin/23214-92-8; doxorubicin/25316-40-9; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; cytarabine/147-94-4; cytarabine/69-74-9; dexamethasone/50-02-2; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5; ifosfamide/3778-73-2; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; etoposide/33419-42-0; carmustine/154-93-8; melphalan/148-82-3; rituximab/174722-31-7; alemtuzumab/216503-57-0; epratuzumab/205923-57-5; apolizumab/267227-08-7; tositumomab i 131/192391-48-3; ibritumomab tiuxetan/206181-63-7; sunitinib/341031-54-7; sunitinib/557795-19-4

CR: 305-03-3; 16506-27-7; 3543-75-7; 50-18-0; 21679-14-1; 4291-63-8; 50-24-8; 57-22-7; 53-03-2; 11056-06-7; 23214-92-8; 25316-40-9; 15663-27-1; 26035-31-4; 96081-74-2; 147-94-4; 69-74-9; 50-02-2; 15475-56-6; 59-05-2; 7413-34-5; 3778-73-2; 65271-80-9; 70476-82-3; 33419-42-0; 154-93-8; 148-82-3; 174722-31-7; 216503-57-0; 205923-57-5; 267227-08-7; 192391-48-3; 206181-63-7; 341031-54-7; 557795-19-4

AB: The follicullar non-Hodgkin lymphomas (F-NHL) represent the neoplastic equivalent of the normal cells in th germinative centre. The therapeutic strategy in F-NHL is based rather on the presence/absence of risk factors (RF) than on the clinical stage and histological variant (grade). Chronologically, the therapeutic choice is based on 4 consequent strategies: 1. "Watch and wait" in localized stages and lack of RF. 2. Intensive regimens in patients with RF - "More is better". 3. Transplantation. 4. Novel options for "Superadditive response rates". The scientific advance in the molecullar biology of lymphomas made available for clinical practice a new generation of therapeutic agents: the so-called drug-molecules. Their target is not only the separate structure of the lymphoma cell, but also the concrete phases of the malignant cell cycle; blockade of the auto- or paracrine signals regarding the proliferation, survival and apoptosis. Besides the monoclonal antibodies, now clinicians have a real therapeutic challenge in the face of idiotype DNA vaccines, proteasome inhibitors, the inhibitors of farnesyl transferase and neoangiogenesis and antisense oligonucleotides. These novel therapeutic options result in a significant increase of response rates; "purging" of the residual clonal population, improved control over the minimal residual disease, low toxicity and better efficacy of conventional chemotherapy.

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Hematology Drug Literature Index

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2/21 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006249274 AU: Cvetkovic RS; Perry CM Titel: Rituximab: A review of its use in non-Hodgkin's lymphoma and chronic lymphocytic

leukaemia Quelle: Drugs; VOL: 66 (6); p. 791-820 /2006/

http://drugs.adisonline.com/pt/re/drugs/pdfhandler.00003495-200666060-00005.pdf;jsessionid=GykTLcWPBmSn1MLJFMfc2kZ4QyTpyLGJYN8clVNch8fpL YsskHbz!50530596!-949856144!8091!-1

Sprache: ENGLISH AL: ENGLISH CY: New Zealand ISSN: 0012-6667 EISSN: 0012-6667 CO: DRUGA Corporate Source:

R.S. Cvetkovic, Adis International Limited, 41 Centorian Drive, Mairangi Bay, Auckland 1311 New Zealand [email protected]

COU: New Zealand DT: Journal RN: 0108 DN: mabthera; rituxan TE: rituximab/174722-31-7; cyclophosphamide/50-18-0; doxorubicin/23214-92-8;

doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2 CR: 174722-31-7; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2 AB: Rituximab (MabThera®, Rituxan®) is an anti-CD20 monoclonal antibody that induces

lysis and apoptosis of normal and malignant human B cells, and sensitises malignant B cells to the cytotoxic effect of chemotherapy. In phase III trials in patients with indolent or aggressive B-cell non-Hodgkin's lymphoma (NHL), intravenous rituximab in combination with chemotherapy was more effective as first- or second-line therapy than chemotherapy alone in providing tumour remission and patient survival. Likewise, in patients with chronic lymphocytic leukaemia (CLL), rituximab in combination with chemotherapy appeared more effective than chemotherapy alone as either first- or second-line treatment. In addition, rituximab maintenance therapy was shown to significantly prolong tumour remission and patient survival in patients with indolent B-cell NHL or CLL. The combination of rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) was cost effective as first-line therapy for advanced-stage diffuse large B-cell NHL compared with CHOP alone. Rituximab, either alone or in combination with chemotherapy, was generally well tolerated in patients with NHL or CLL. Overall, rituximab in combination with chemotherapy, is a valuable option for first- and second-line therapy in patients with advanced-stage indolent or aggressive B-cell NHL, and possibly those with B-cell CLL, and is included in current treatment guidelines for these indications. The drug is also potentially useful as maintenance therapy in patients with indolent B-cell NHL or CLL. Pharmacological Properties: Rituximab is a chimaeric murine/human monoclonal antibody directed against the surface antigen CD20 expressed on all normal and >90% of NHL and 14% of CLL malignant B cells. It induces lysis and apoptosis of all CD20-positive B cells and also sensitises malignant B cells to the

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cytotoxic effect of chemotherapy. At the recommended dose, rituximab causes rapid and profound B-cell lymphopenia in the majority of patients that lasts for up to 6 months and recovers (from haematopoietic stem cells) within 9-12 months after treatment. As maintenance therapy, rituximab would continue suppression of the B-cell population, including the malignant variety. Following intravenous administration of rituximab in patients with B-cell NHL, drug serum concentrations increase in a dose-proportional manner (within clinically relevant dosage range), are positively correlated with clinical tumour responses (i.e. they are significantly higher in patients responding to rituximab monotherapy than in nonresponders) and are inversely correlated to the absolute level of circulating peripheral B cells and the tumour bulk measurements at baseline. The pharmacokinetics of rituximab are also characterised by accumulation of the drug with repeated administrations (reflecting the change in the population of CD20-positive B cells) and wide interindividual variability (caused by variable tumour responsiveness and burden between patients). Clinically relevant drug concentrations are present in the serum (less-than or equal to)6 months after, and were also found in the CNS during treatment with rituximab. The pharmacokinetics of rituximab appear to be similar in patients with follicular or diffuse large B-cell NHL, and are unaffected by the coadministration of CHOP. Significantly lower serum concentrations of rituximab were found in patients with a lymphomatous form of B-cell CLL, compared with values in patients with B-cell NHL. Therapeutic Efficacy: Indolent NHL: In phase III trials in patients with previously untreated advanced-stage follicular NHL, the addition of rituximab 375 mg/m ² (as an intravenous infusion) to 6-8 cycles of standard chemotherapy regimens was more effective in achieving tumour remission (i.e. complete response [CR]) and short-term (2.5-year) event-free survival (EFS) rates than chemotherapy alone. In combination with cyclophosphamide, vincristine and prednisone (CVP), rituximab also significantly prolonged the duration of tumour response (>2-fold), failure-free (4-fold) and disease-free survival (DFS) [>2-fold], and more than doubled the time to disease progression. At the estimated 3-year follow-up, these effects have not yet translated into a significantly greater overall survival (OS) rate compared with CVP alone (89% vs 81%), although both results are clinically relevant. Importantly, however, patients receiving rituximab in addition to CVP spent significantly longer time without disease symptoms or toxicity, and had a substantially improved quality-adjusted survival than patients receiving CVP alone. In patients with advanced follicular NHL, first-line therapy with rituximab in combination with mitoxantrone, chlorambucil and prednisone (MCP) also resulted in significantly longer progression-free survival (PFS) and OS rates than MCP alone. As a second-line therapy in patients with relapsed or refractory follicular NHL, the addition of a single dose of rituximab to each of six cycles of CHOP or four cycles of fludarabine, cyclophosphamide and mitoxantrone (FCM) regimens significantly improved CR and objective response (OR) rates and prolonged PFS compared with chemotherapy alone in two phase III trials. A significantly improved 4-year OS rate was also reported in a trial with FCM. The significant survival benefit of adding rituximab to first- or second-line chemotherapy regimens in patients with follicular NHL was confirmed in a meta-analysis of data from several randomised, phase III trials As monotherapy, four once-weekly intravenous infusions of rituximab 375 mg/m² produced clinically relevant CR and OR rates in two phase II trials in patients with mucosa-associated lymphoid tissue B-cell NHL. One of the trials showed 2-fold longer (p = 0.001) failure-free survival in chemotherapy-naive than in chemotherapy-experienced patients receiving rituximab monotherapy. Likewise, maintenance therapy with single-agent rituximab 375 mg/m² (four once-weekly doses repeated every 6 months or single infusion every 2-3 months, for up to 2 years or until relapse), significantly increased CR and/or OR rates, and prolonged duration of remission, EFS and/or PFS after induction therapy in patients with follicular NHL or CLL (lymphomatous form), compared with rituximab re-treatment (at disease progression) [in a phase II trial] or observation (i.e. no further treatment) [in three phase III trials]. Rituximab maintenance therapy provided

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significantly greater 3- and 4-year PFS and OS rates in both previously treated and untreated patients with follicular NHL, compared with no further treatment. The estimated 3-year OS rates were high with both the rituximab maintenance and re-treatment approach, but results were not statistically significantly different (72% vs 68%) in previously untreated patients. Aggressive NHL: The combination of rituximab 375 mg/m² intravenous infusions with a CHOP or a CHOP-like regimen, administered in 6-8 cycles, was more effective than chemotherapy alone as the first-line treatment in patients with advanced-stage, diffuse large B-cell NHL or mantle cell lymphoma (MCL), in several phase III trials. Irrespective of the age of patients with diffuse, large B-cell NHL, the addition of rituximab resulted in significantly greater CR, 2- to 3-year failure-free survival and 2- to 5-year OS rates (the latter effect was observed only in low-risk patients). A significantly greater 5-year PFS rate was also reported with rituximab plus CHOP in a trial in older patients (age (greater-than or equal to)60 years) irrespective of disease prognosis. In younger patients (age <60 years) with low-risk disease, rituximab plus CHOP or CHOP-like regimen significantly decreased the relative risk of treatment failure (by 64%) compared with chemotherapy alone. Significantly greater 1-year failure-free or 4-year OS rates were observed in patients with MCL receiving intravenous infusions of rituximab 375 mg/m ² in combination with first-line CHOP (six cycles) or second-line FCM (four cycles), than those receiving chemotherapy alone, in two randomised, phase III trials. Meta-analysis of data from both trials confirmed the OS benefit of adding rituximab to chemotherapy in patients with MCL, both previously untreated or those with relapsed or refractory MCL. Rituximab did not improve either tumour response or survival rates in patients with HIV-related, aggressive B-cell NHL, while increasing the risk of infectious death, in a randomised, phase III trial. By contrast, the findings of previous phase I and II trials suggested that rituximab therapy may be beneficial in this patient population. Rituximab maintenance therapy was effective in patients with diffuse large B-cell NHL, only when the drug was not part of an induction regimen, and was ineffective in patients with MCL. CLL: Standard rituximab monotherapy (i.e. four intravenous infusions of 375 mg/m² once weekly) was less effective than fludarabine monotherapy in phase II trials in patients with B-cell CLL. However, the addition of rituximab 375 or 500 mg/m² to six cycles of fludarabine (with or without cyclophosphamide) significantly improved response (CR and/or OR) and survival (2- to 4-year PFS and/or OS) rates in these patients, compared with chemotherapy alone in retrospective comparative analyses of several phase II and III trials. Tolerability: Rituximab, alone or in combination with various chemotherapy regimens, was generally well tolerated in clinical trials in patients with advanced-stage indolent or aggressive B-cell NHL or B-cell CLL. The most common types of adverse events in these trials were infusion-related reactions, haematological adverse events and infections. © 2006 Adis Data Information BV. All rights reserved.

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3, 6 2/22 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006234911 AU: Waselenko JK; Reese A; Park K; Lucas M; Goodrich A; Willis CR; Diehl LF; Grever

MR; Byrd JC; Flinn IW

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Titel: A phase I/II study examining pentostatin, chlorambucil, and theophylline in patients with relapsed chronic lymphocytic leukemia and non-Hodgkin's lymphoma

Quelle: Annals of Hematology; VOL: 85 (5); p. 301-307 /2006/ Sprache: ENGLISH AL: ENGLISH CY: Germany ISSN: 0939-5555 CO: ANHEE Corporate Source:

J.K. Waselenko, Sarah Cannon Research Intitute, 250 25th Avenue, Nashville, TN 37203 United States [email protected]

COU: United States DT: Journal RN: 0029 TE: aciclovir/59277-89-3; chlorambucil/305-03-3; cotrimoxazole/8064-90-2; dapsone/80-

08-0; fludarabine/21679-14-1; granisetron/107007-99-8; granisetron/109889-09-0; pentostatin/53910-25-1; sodium chloride/7647-14-5; theophylline/58-55-9; theophylline/5967-84-0; theophylline/8055-07-0; theophylline/8061-56-1; theophylline/99007-19-9

CR: 59277-89-3; 305-03-3; 8064-90-2; 80-08-0; 21679-14-1; 107007-99-8; 109889-09-0; 53910-25-1; 7647-14-5; 58-55-9; 5967-84-0; 8055-07-0; 8061-56-1; 99007-19-9

AB: In an attempt to exploit bcl-2 overexpression and aberrant p53 function, two frequently encountered aberrations that predict marked treatment resistance and worse prognosis in patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), we combined theophylline, pentostatin, and chlorambucil at two dose levels (cohort I: 30 mg/m²; cohort II: 20 mg/m²) on a 21-day cycle for up to six courses. We employed a phase I/II design to determine feasibility, define the maximum tolerated dose (MTD), and explore the impact of biologic modulation on response and time to progression (TTP) in 20 patients with relapsed or refractory CLL and NHL. Eight patients were enrolled in cohort I. They demonstrated a response rate (RR) of 28% and a 16.5-month TTP after receiving a median of two cycles. A 50% RR was observed in this cohort when patients with adverse histologies were excluded. Because of myelotoxicity, this dose level defined the MTD, and de-escalation occurred. All 12 patients in cohort II received 20 mg/m² chlorambucil. A 50% RR and an 18-month TTP were observed after a median of 5.5 cycles. An RR of 47% and a complete remission (CR) of 5% were observed for the entire group, although responses and TTP varied greatly by histology. Significant activity was observed in patients with B-cell CLL and follicular lymphoma (FL). RR and TTP for fludarabine-sensitive/naieve and fludarabine-refractory (FR) B-cell CLL patients were 66 vs 25% and 20 vs 8.5 months, respectively. Both FL patients responded (one with partial remission and one with CR), with a 22.5-monthly median TTP. For responding patients, median TTP and overall survival (OS) was 21 and 69 months, respectively, compared to a median TTP of 2 months and an OS of 13.5 months for nonresponders. The combination of pentostatin, chlorambucil, and theophylline is the active regimen in patients with FL and B-cell CLL. © Springer-Verlag 2006.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

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3 2/23 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006055731 AU: Ogawa Y; Hotta T; Tobinai K; Watanabe T; Sasaki Y; Minami H; Morishima Y; Ogura

M; Seriu T Titel: Phase I and pharmacokinetic study of oral fludarabine phosphate in relapsed indolent

B-cell non-Hodgkin's lymphoma Quelle: Annals of Oncology; VOL: 17 (2); p. 330-333 /2006/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 0923-7534 EISSN: 1569-8041 CO: ANONE Corporate Source:

Dr. Y. Ogawa, Department of Hematology and Oncology, Tokai University School of Medicine, 143 Shimokasuya, Isehara-shi, Kanagawa Japan [email protected]

COU: Japan DT: Journal RN: 0012 MN: Schering AG,Japan; Schering AG TE: fludarabine phosphate/75607-67-9; rituximab/174722-31-7; alanine

aminotransferase/9000-86-6; alanine aminotransferase/9014-30-6; aspartate aminotransferase/9000-97-9; alkaline phosphatase/9001-78-9

CR: 75607-67-9; 174722-31-7; 9000-86-6; 9014-30-6; 9000-97-9; 9001-78-9 AB: Background: The primary objective of this study was to investigate the tolerability,

efficacy and pharmacokinetic profile of oral fludarabine phosphate in relapsed patients with indolent B-cell non-Hodgkin's lymphoma (B-NHL). Patients and methods: Patients received fludarabine phosphate orally for 5 days, for a total of one to three cycles. Tolerability was assessed using the National Cancer Institute Common Toxicity Criteria. Efficacy was assessed using the International Workshop Criteria for NHL. Pharmacokinetic samples were taken on day 1 and day 5 of the first treatment cycle. Results: Twelve patients were enrolled. One patient at 40 mg/m²/day developed grade 4 hyperuricemia. At 50 mg/m²/day, one patient developed grade 3 febrile neutropenia and grade 4 leukopenia, and another patient showed lasting grade 4 neutropenia. Most common toxicities included grade 3 or 4 lymphopenia (83%), leukopenia (50%) and neutropenia (50%). All the toxicities were reversible. The overall response rate was 67%. The AUC(sub(0-24h)) values on day 5 indicated a dose-dependent increase in systemically available 2-fluoro-arabinofuranosyl-adenine (2F-ara-A). Conclusions: Oral fludarabine phosphate is safe and effective for relapsed patients with indolent B-NHL. The dose of 40 mg/m²/day is recommended for a following pivotal phase II study. © 2005 European Society for Medical Oncology.

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Hematology Pharmacology

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Drug Literature Index Adverse Reactions Titles

3 2/24 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005559038 AU: Lissitchkov T; Arnaudov G; Peytchev D; Merkle Kh Titel: Phase-I/II study to evaluate dose limiting toxicity, maximum tolerated dose, and

tolerability of bendamustine HCl in pre-treated patients with B-chronic lymphocytic leukaemia (Binet stages B and C) requiring therapy

Quelle: Journal of Cancer Research and Clinical Oncology; VOL: 132 (2); p. 99-104 /2006/ Sprache: ENGLISH AL: ENGLISH CY: Germany ISSN: 0171-5216 CO: JCROD Corporate Source:

T. Lissitchkov, National Center of Haematology and Transfusiology, 6 Plovdivsko Pole, 1746 Sofia Bulgaria [email protected]

COU: Bulgaria DT: Journal RN: 0013 TE: bendamustine/16506-27-7; bendamustine/3543-75-7; fludarabine/21679-14-1;

bilirubin/18422-02-1; bilirubin/635-65-4 CR: 16506-27-7; 3543-75-7; 21679-14-1; 18422-02-1; 635-65-4 AB: Purpose: Bendamustine hydrochloride, an antineoplastic agent with unique

mechanism of action, is known to cause impressive remissions in relapsed non-Hodgkin's lymphoma and chronic lymphocytic leukaemia (CLL). Optimal bendamustine dosing for CLL patients had not been finally established and a phase I/II study was conducted to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of bendamustine. Methods: The open-label, single-centre phase I/II study was conducted from March 2001 to September 2002 in Sofia, Bulgaria. The 15 study patients were extendedly pre-treated, but fludarabine-naive (3 female, 12 male, 47-72 years of age, 61 years on average). Bendamustine was given at a starting dose of 100 mg/m² on days 1 and 2 every 3 weeks based on the previous results in lymphoma. Results: Bendamustine was well tolerated in spite of heavy pre-treatment of the study participants. Toxicity corresponded to the known safety profile of bendamustine, with the exception of bilirubin elevation. The level of 110 mg/m² was established as MTD. A bendamustine dose of 100 mg/m² is the recommended dose for further clinical investigations. A 4-week interval is recommended to allow for sufficient recovery. Efficacy results confirmed powerful anti-neoplastic activity of bendamustine even in extendedly pretreated CLL patients. Based on the remission criteria, nine patients were defined as responders (four CRs, two PR, three NC) and two patients as nonresponders to therapy. Four patients were not evaluable for response, because they had received less than three courses bendamustine. After a follow-up period of 15 months, the four patients with CR were still in remission. One patient with PR had relapsed, the other had ongoing response.

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Conclusions: Bendamustine is a very active and well-tolerated drug in patients with pre-treated and refractory CLL. Fludarabine-naivity of patients appears to markedly improve their bendamustine tolerability. First-line use of bendamustine is a safe option for CLL-patients requiring treatment, because bendamustine - owing to its unique pharmacodynamics - (1) is highly effective, (2) reasonably safe, and (3) does hardly produce cross-resistance against other anti-neoplastic drugs effective in this indication. © Springer-Verlag 2005.

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Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3 2/25 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005511520 AU: Soubeyran P; Monnereau A; Eghbali H; Soubeyran I; Kind M; Cany L; Buy E; Guibon

O; Hörni B Titel: Fludarabine phosphate-CVP in patients over 60 years of age with advanced, low-

grade and follicular lymphoma: A dose-finding study Quelle: European Journal of Cancer; VOL: 41 (17); p. 2630-2636 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 0959-8049 CO: EJCAE PII: S0959804905007239 Corporate Source:

[email protected]

DT: Journal RN: 0040 DN: fludara TE: creatinine/19230-81-0; creatinine/60-27-5; cyclophosphamide/50-18-0; fludarabine

phosphate/75607-67-9; prednisone/53-03-2 CR: 19230-81-0; 60-27-5; 50-18-0; 75607-67-9; 53-03-2 AB: The aim of this study was to establish a safe and effective regimen of fludarabine

phosphate, cyclophosphamide, vincristine and prednisone (F-CVP) as first-line treatment for elderly patients with advanced, low-grade non-Hodgkin's lymphoma. Twenty-three patients >60 years were assigned successively to eight treatment cycles (Dose level 1: low F, low CV [n = 4]; 2A: high F, low CV [n = 8]; 2B: low F, high CV [n = 4]; 3: high F, high CV [n = 7]). High and low levels were: F, 25 and 20 mg/m², respectively (Days 1-5); C, 750 and 500 mg/m², respectively (Day 1); and V, 1.4 and 1 mg/m², respectively (Day 1). Patients received P at 40 mg/m² on Days 1-5. Response was assessed after Cycles 2, 4, 6 and 8. At level 3, dose-limiting toxicity (opportunistic infections and neutropenia) became evident, particularly after Cycle 6. Further patients were recruited at Dose level 2A. All regimens proved effective, with an OR rate of 78% (65% CR), and 3-year survival of 65% (±10%). Among 18

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responders, 51% were still in response at 3 and 5 years. The study shows that this combination therapy is highly effective. The addition of F to CVP at Dose level 2A was feasible and increased the CR rate, with good tolerability in elderly patients. © 2005 Elsevier Ltd. All rights reserved.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

1 2/26 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005470646 AU: Alinari L; Musuraca G; Tani M; Stefoni V; Gabriele A; Marchi E; Fina M; de Vivo A;

Pileri S; Baccarani M; Zinzani PL Titel: Value of oxaliplatin treatment in heavily pretreated patients with non-Hodgkin's

lymphoma Quelle: Leukemia and Lymphoma; VOL: 46 (10); p. 1437-1440 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 CO: LELYE Corporate Source:

Dr. P.L. Zinzani, Istituto di Ematologia e Oncologia Medica Seràgnoli, Policlinico S. Orsola, Via Massarenti 9, 40138 Bologna Italy [email protected]

COU: Italy DT: Journal RN: 0017 DN: campath 1h MN: Labaz,Italy; Labaz; Aventis,Italy; Aventis TE: oxaliplatin/61825-94-3; etoposide/33419-42-0; mitoxantrone/65271-80-9;

mitoxantrone/70476-82-3; cyclophosphamide/50-18-0; vincristine/57-22-7; prednisolone/50-24-8; bleomycin/11056-06-7; doxorubicin/23214-92-8; doxorubicin/25316-40-9; fludarabine/21679-14-1; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5; rituximab/174722-31-7; ifosfamide/3778-73-2; epirubicin/56390-09-1; epirubicin/56420-45-2; alemtuzumab/216503-57-0; chlorambucil/305-03-3; ibritumomab tiuxetan/206181-63-7; busulfan/55-98-1; melphalan/148-82-3

CR: 61825-94-3; 33419-42-0; 65271-80-9; 70476-82-3; 50-18-0; 57-22-7; 50-24-8; 11056-06-7; 23214-92-8; 25316-40-9; 21679-14-1; 15475-56-6; 59-05-2; 7413-34-5; 174722-31-7; 3778-73-2; 56390-09-1; 56420-45-2; 216503-57-0; 305-03-3; 206181-63-7; 55-98-1; 148-82-3

AB: In order to assess the efficacy and toxicity profile of oxaliplatin, a third generation platinum derivate active against several solid tumors, we carried out a study in a group of heavily pretreated patients with non-Hodgkin's lymphoma (NHL). Between

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August 2003 and May 2004, 19 pretreated patients were enrolled in a phase II trial and were treated with oxaliplatin. The drug was administered intravenously on day 1 of a 21-day schedule, at a dose of 130 mg/m² for a total of 6 cycles. One (5%) patient achieved complete remission (CR) and 5 patients (27%) had partial response (PR), thus giving an overall response rate of 32%. The patient in CR suffered from an aggressive B NHL. One of the 5 patients in PR had an aggressive B NHL, whereas the remaining 4 had an indolent B NHL. The treatment was well tolerated with minimal hematologic and extrahematologic toxicity. These data suggest and confirm the efficacy and low toxicity of oxaliplatin in the treatment of patients with heavily pretreated NHL. Further trials using oxaliplatin alone or in combination with other conventional drugs are needed. © 2005 Taylor & Francis.

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Hematology Drug Literature Index Adverse Reactions Titles

3 2/27 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005394071 AU: van Besien K; Smith S; Lazarus HM Titel: Therapeutic options for patients with Hodgkin's disease and non-Hodgkin's

lymphoma who relapse after autologous transplant Quelle: Current Treatment Options in Oncology; VOL: 6 (4); p. 279-287 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1527-2729 CO: CTOOB Corporate Source:

Dr. K. van Besien, University of Chicago, Section of Hematology/Oncology, 5841 South Maryland Ave, Chicago, IL 60637 United States [email protected]

COU: United States DT: Journal RN: 0037 DN: zevalin/Biogen Idec,United States; bexxar/Corixa,United States; campath

1h/Berlex,United States MN: Biogen Idec,United States; Biogen Idec; Corixa,United States; Corixa; Berlex,United

States; Berlex TE: interleukin 2/85898-30-2; dexamethasone/50-02-2; cytarabine/147-94-4;

cytarabine/69-74-9; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; etoposide/33419-42-0; prednisolone/50-24-8; ifosfamide/3778-73-2; carmustine/154-93-8; rituximab/174722-31-7; cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; vincristine sulfate/2068-78-2; prednisone/53-03-2; carboplatin/41575-94-4; fludarabine/21679-14-1; pentostatin/53910-25-1; ibritumomab tiuxetan/206181-63-7; tositumomab i 131/192391-48-3; bortezomib/179324-69-7; bortezomib/197730-97-5; rapamycin 2,2

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bis(hydroxymethyl)propionate/162635-04-3; rapamycin 2,2 bis(hydroxymethyl)propionate/343261-52-9; thiotepa/52-24-4; busulfan/55-98-1; cyclosporin/79217-60-0; alemtuzumab/216503-57-0

CR: 85898-30-2; 50-02-2; 147-94-4; 69-74-9; 15663-27-1; 26035-31-4; 96081-74-2; 33419-42-0; 50-24-8; 3778-73-2; 154-93-8; 174722-31-7; 50-18-0; 23214-92-8; 25316-40-9; 2068-78-2; 53-03-2; 41575-94-4; 21679-14-1; 53910-25-1; 206181-63-7; 192391-48-3; 179324-69-7; 197730-97-5; 162635-04-3; 343261-52-9; 52-24-4; 55-98-1; 79217-60-0; 216503-57-0

AB: Although autologous stem cell transplantation for Hodgkin's disease and non-Hodgkin's lymphoma has become a safe and effective therapy, relapses after transplant are common. Emerging data indicate that an increasing number of patients can be re-induced into durable complete remission. Conventional dose-salvage chemotherapy and single-agent monoclonal antibody treatment provided limited success, but combination chemotherapy-monoclonal antibody treatments, second autografts, and reduced-intensity conditioning allografts provide encouraging results. For some patients, the best strategy may consist of participation in phase I to II studies of novel agents. New strategies designed to prevent relapse after autograft include cytokine therapy such as interleukin-2 in combination with monoclonal antibodies and the use of autologous antilymphoma vaccines. Copyright © 2005 by Current Science Inc.

CNOTE: Copyright 2005 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Drug Literature Index Adverse Reactions Titles

6 2/28 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005389891 AU: Kaplan LD; Lee JY; Ambinder RF; Sparano JA; Cesarman E; Chadburn A; Levine

AM; Scadden DT Titel: Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP

with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010

Quelle: Blood; VOL: 106 (5); p. 1538-1543 /01 SEP 2005/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0006-4971 CO: BLOOA Corporate Source:

L.D. Kaplan, Division of Hematology/Oncology, University of California, 400 Parnassus Ave, San Francisco, CA 94143 United States [email protected]

COU: United States DT: Journal RN: 0026

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MN: Genentech,United States; Genentech TE: rituximab/174722-31-7; cyclophosphamide/50-18-0; doxorubicin/23214-92-8;

doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2; protein bcl 2/219306-68-0; cotrimoxazole/8064-90-2; dapsone/80-08-0; pentamidine/100-33-4; cytarabine/147-94-4; cytarabine/69-74-9; immunoglobulin/9007-83-4; proteinase inhibitor/37205-61-1; alkaline phosphatase/9001-78-9; aspartate aminotransferase/9000-97-9; alanine aminotransferase/9000-86-6; alanine aminotransferase/9014-30-6; etoposide/33419-42-0; fludarabine/21679-14-1

CR: 174722-31-7; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2; 219306-68-0; 8064-90-2; 80-08-0; 100-33-4; 147-94-4; 69-74-9; 9007-83-4; 37205-61-1; 9001-78-9; 9000-97-9; 9000-86-6; 9014-30-6; 33419-42-0; 21679-14-1

AB: The addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy results in significant improvement in clinical outcome for individuals with non-HIV-associated aggressive B-cell lymphoma. To assess the potential risks and benefits of the addition of rituximab to CHOP for HIV-associated non-Hodgkin lymphoma (HIV-NHL) 150 patients receiving CHOP for HIV-NHL were randomized (2:1) to receive 375 mg/m ² rituximab with each chemotherapy cycle (n = 99) or no immunotherapy (n = 50) in a multicenter phase 3 trial. The complete response rate (CR + CRu) was 57.6% for R-CHOP and 47% for CHOP (P = .147). With a median follow-up of 137 weeks, time to progression, progression-free survival, and overall survival times were 125, 45, and 139 weeks, respectively, for R-CHOP and 85, 38, and 110 weeks, respectively, for CHOP (P = not significant, all comparisons). Treatment-related infectious deaths occurred in 14% of patients receiving R-CHOP compared with 2% in the chemotherapy-alone group (P = .035). Of these deaths, 60% occurred in patients with CD4 counts less than 50/mm³. Progression-free survival was significantly influenced by CD4(sup(+)) count (P < .001) and International Prognostic Index score (P = .022), but not bcl-2 status. The addition of rituximab to CHOP in patients with HIV-NHL may be associated with improved tumor responses. However, these benefits may be offset by an increase in infectious deaths, particularly in those individuals with CD4+ lymphocyte counts less than 50/mm³. © 2005 by The American Society of Hematology.

CNOTE: Copyright 2005 Elsevier B.V., All rights reserved. ET: Internal Medicine

Cancer Hematology Drug Literature Index Adverse Reactions Titles

3 2/29 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005350850 AU: Corradini P; Dodero A; Zallio F; Caracciolo D; Casini M; Bregni M; Narni F; Patriarca

F; Boccadoro M; Benedetti F; Rambaldi A; Gianni AM; Tarella C Titel: Graft-versus-lymphoma effect in relapsed peripheral T-cell non-Hodgkin's lymphomas

after reduced-intensity conditioning followed by allogeneic transplantation of hematopoietic cells

Quelle: Journal of Clinical Oncology; VOL: 22 (11); p. 2172-2176 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United States

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ISSN: 0732-183X CO: JCOND Corporate Source:

Dr. P. Corradini, Division of Hematology-Bone Marrow Transplantation, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian, 1, 20133 Milano Italy [email protected]

COU: Italy DT: Journal RN: 0016 TE: thiotepa/52-24-4; fludarabine/21679-14-1; cyclophosphamide/50-18-0;

cyclosporin/79217-60-0; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5

CR: 52-24-4; 21679-14-1; 50-18-0; 79217-60-0; 15475-56-6; 59-05-2; 7413-34-5 AB: Purpose: Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of

malignancies characterized by a poor prognosis. We performed a pilot study to investigate the role of reduced-intensity conditioning (RIC) followed by allogeneic stem-cell transplantation in relapsed or refractory PTCLs. Patients and Methods: We have conducted a phase II trial on 17 patients receiving salvage chemotherapy followed by RIC and allogeneic transplantation of hematopoietic cells. The RIC regimen consisted of thiotepa, fludarabine, and cyclophosphamide. The acute graft-versus-host disease prophylaxis consisted of cyslosporine and short course methotrexate. Results: Patients had a median age of 41 years (range, 23 to 60 years). Two patients were primary chemorefractory, and 15 had relapsed disease; eight patients (47%) had a disease relapse after an autologous transplantation. After a median follow-up of 28 months from the day of study entry (range, 3 to 57 months), 14 of 17 patients were alive (12 in complete remission, one in partial remission, and one with stable disease), two died as a result of progressive disease, and one died as a result of sepsis concomitant to acute graft-versus-host disease. The estimated 3-year overall and progression-free survival rates were 81% (95% CI, 62% to 100%) and 64% (95% CI, 39% to 89%), respectively. The estimated probability of nonrelapse mortality at 2 years was 6% (95% CI, 1% to 17%). Donor lymphocyte infusions induced a response in two patients progressing after allografting. Conclusion: RIC followed by allogeneic stem-cell transplantation is feasible, has a low treatment-related mortality, and seems to be a promising salvage treatment for relapsed PTCL. These findings suggest that the existence of a graft-versus-T-cell lymphoma effect. © 2004 by American Society of Clinical Oncology.

CNOTE: Copyright 2005 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index

5 2/30 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005338386 AU: Rao R; Shammo JM; Enschede SH; Porter C; Adler SS; Venugopal P; Gregory SA Titel: The combination of fludarabine, cyclophosphamide, and granulocyte-macrophage

colony-stimulating factor in the treatment of patients with relapsed chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphoma

Quelle: Clinical Lymphoma; VOL: 6 (1); p. 26-30 /2005/

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Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1526-9655 CO: CLLYA Corporate Source:

Dr. R. Rao, Section of Hematology and Oncology, Rush University Medical Center, 1725 W Harrison St., Chicago, IL 60612 United States [email protected]

COU: United States DT: Journal RN: 0021 TE: fludarabine/21679-14-1; cyclophosphamide/50-18-0; chlorambucil/305-03-3;

prednisone/53-03-2 CR: 21679-14-1; 50-18-0; 305-03-3; 53-03-2 AB: Purpose: The goal of this study was to evaluate the efficacy of the

fludarabine/cyclophosphamide combination in patients with relapsed chronic lymphocytic lymphoma (CLL) and low-grade non-Hodgkin's lymphoma (NHL) and to assess the impact of adding granulocyte-macrophage colony-stimulating factor (GM-CSF) to this regimen in a randomized fashion. Patients and methods: Thirty-four patients (CLL, n = 16; low-grade NHL, n = 18) were enrolled. The median number of previous treatments was 2. Patients received (less-than or equal to) 6 cycles of fludarabine at 30 mg/m² per day and cyclophosphamide at 300 mg/m² per day on days 1-3 of a 28-day cycle. Patients were randomized to supportive care or to receive GM-CSF at 250 µg/m² per day, starting 24 hours after completion of chemotherapy and continuing up to 48 hours before the next cycle. Those who had received > 6 months of previous therapy with an alkylating agent or had preexisting cytopenias received a 25% dose reduction. Twenty-two patients (65%) were randomized to receive GM-CSF Patients completed a median of 5 cycles of treatment (range, 1-6 cycles). Twenty-seven patients (80%) received 3 cycles of treatment and were evaluated for response. Results: Seven patients (26%) exhibited a complete response; 6 of the 7 had low-grade NHL. Fourteen patients (52%) exhibited a partial response, and 6 patients (22%) had stable disease. Notably, 6 of the 7 patients who exhibited complete response and 9 of 14 patients with partial responses were randomized to the GM-CSF arm. The duration of response ranged from 4 months to 26 months. The toxicities were mainly hematologic. Nineteen patients (70%) experienced alpha 1 episode of grade 3/4 neutropenia, but only 4 (15%) experienced febrile neutropenia; 3 of those patients were assigned to the GM-CSF arm. Conclusions: The combination of fludarabine and cyclophosphamide is a well-tolerated and effective treatment regimen for patients with relapsed CLL and low-grade NHL. A higher percentage of complete responses were noted in patients with low-grade NHL compared with patients with CLL. Granulocyte-macrophage colony-stimulating factor did not seem to decrease the incidence of febrile neutropenia. However, the higher number of complete and partial responses noted on the GM-CSF arm is intriguing and warrants further investigation.

CNOTE: Copyright 2005 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

1

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2/31 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005323999 AU: Glossmann J-P; Staak JO; Nogova L; Diehl V; Scheid C; Kisro J; Reis H-E; Peter N;

Engert A; Josting A Titel: Autologous tandem transplantation in patients with primary progressive or

relapsed/refractory lymphoma Quelle: Annals of Hematology; VOL: 84 (8); p. 517-525 /2005/ Sprache: ENGLISH AL: ENGLISH CY: Germany ISSN: 0939-5555 CO: ANHEE Corporate Source:

A. Josting, First Department of Internal Medicine, University Hospital Cologne, Cologne Germany [email protected]

COU: Germany DT: Journal RN: 0033 DN: vp 16; mabthera; zevalin TE: etoposide/33419-42-0; thiotepa/52-24-4; mitoxantrone/65271-80-9;

mitoxantrone/70476-82-3; carboplatin/41575-94-4; carmustine/154-93-8; cytarabine/147-94-4; cytarabine/69-74-9; melphalan/148-82-3; ifosfamide/3778-73-2; epirubicin/56390-09-1; epirubicin/56420-45-2; gemcitabine/103882-84-4; fludarabine/21679-14-1; navelbine/71486-22-1; rituximab/174722-31-7; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5; dexamethasone/50-02-2; bleomycin/11056-06-7; doxorubicin/23214-92-8; doxorubicin/25316-40-9; cyclophosphamide/50-18-0; vincristine/57-22-7; procarbazine/366-70-1; procarbazine/671-16-9; prednisone/53-03-2; vinblastine/865-21-4; dacarbazine/4342-03-4; ibritumomab tiuxetan/206181-63-7; yttrium 90/10098-91-6

CR: 33419-42-0; 52-24-4; 65271-80-9; 70476-82-3; 41575-94-4; 154-93-8; 147-94-4; 69-74-9; 148-82-3; 3778-73-2; 56390-09-1; 56420-45-2; 103882-84-4; 21679-14-1; 71486-22-1; 174722-31-7; 15475-56-6; 59-05-2; 7413-34-5; 50-02-2; 11056-06-7; 23214-92-8; 25316-40-9; 50-18-0; 57-22-7; 366-70-1; 671-16-9; 53-03-2; 865-21-4; 4342-03-4; 206181-63-7; 10098-91-6

AB: Patients with primary progressive or refractory Hodgkin's disease (HD) or aggressive non-Hodgkin's lymphoma (NHL) have a particularly poor prognosis. Here we report the results of autologous tandem transplantation in these patients. Patients aged 18-55 years with primary progressive or refractory relapsed HD and aggressive NHL were included. Patients received high-dose etoposide (2000 mg/m²) followed by peripheral blood stem cell harvest (PBSC). The first high-dose chemotherapy (TMC) consisted of thiotepa (750 mg/m²), mitoxantrone (40 mg/m²), and carboplatin (990 mg/m²). Patients with no change (NC), partial remission (PR), or complete remission (CR) after TMC then received BEAM with carmustine (300 mg/m²), etoposide (1200 mg/m²), cytarabine (1600 mg/m²), and melphalan (140 mg/m²). Patients with bulky disease (>5 cm) or residual lymphoma received involved field radiotherapy. Twenty-

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five patients were included (HD=10, NHL=15, median age 34 years). Two patients with HD achieved a CR and five patients a PR [response rate (RR) 70%]. Three patients (30%) experienced treatment failure including two deaths due to peritransplant complications. Five patients with aggressive NHL were in CR and two patients in PR (RR 46%). Of the eight patients (56%) with treatment failure, three had progressive disease and five died from peritransplant complications. Freedom from treatment failure (FFTF) and overall survival (OS) for all patients after 12 months was 28% and 40%, respectively. Tandem HDCT followed by autologous stem cell transplantation (ASCT) offers a chance of cure in these poor prognostic patients, but is associated with risks. © Springer-Verlag 2005.

CNOTE: Copyright 2005 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

3 2/32 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005204552 AU: Gertz MA; Geyer SM; Badros A; Kahl BS; Erlichman C Titel: Early results of a phase I trial of oblimersen sodium for relapsed or refractory

Waldenström's macroglobulinemia Quelle: Clinical Lymphoma; VOL: 5 (4); p. 282-284 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1526-9655 CO: CLLYA Corporate Source:

Dr. M.A. Gertz, Division of Hematology, Department of Internal Medicine, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 United States [email protected]

COU: United States DT: Journal RN: 0015 DN: acetaminophen TE: oblimersen/190977-41-4; protein bcl 2/219306-68-0; fludarabine/21679-14-1;

dexamethasone/50-02-2; rituximab/174722-31-7; immunoglobulin M/9007-85-6; allopurinol/315-30-0; paracetamol/103-90-2

CR: 190977-41-4; 219306-68-0; 21679-14-1; 50-02-2; 174722-31-7; 9007-85-6; 315-30-0; 103-90-2

AB: Oblimersen sodium is an antisense oligonucleotide to the first 6 codons of the B-cell leukemia gene 2 (bcl-2) open reading frame. It prevents the expression of the bcl-2 gene product and leads to apoptosis in cells that express Bcl-2. bcl-2 is one of the major apoptosis regulatory gene families and is found in a variety of low-grade B-cell non-Hodgkin's lymphomas. The in vitro use of oblimersen in Waldenström's macroglobulinemia (WM) cell line results in enhanced toxicity when exposed to fludarabine, dexamethasone, or rituximab. Oblimersen should also enhance the

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cytotoxic effect of chemotherapy in WM. Presented herein are early data on the phase I portion of a phase I/II study of oblimersen in WM to identify the maximum tolerated dose and to evaluate response in patients with symptomatic WM.

CNOTE: Copyright 2005 Elsevier B.V., All rights reserved. ET: Hematology

Immunology, Serology and Transplantation Drug Literature Index Adverse Reactions Titles

3 2/33 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005199677 AU: Davies AJ Titel: A review of tositumomab and I¹³¹ tositumomab radioimmunotherapy for the treatment

of follicular lymphoma Quelle: Expert Opinion on Biological Therapy; VOL: 5 (4); p. 577-588 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1471-2598 CO: EOBTA Corporate Source:

A.J. Davies, Cancer Res. UK Medical Oncology Unit, Barts/Roy. London Sch. of Med./Dent., Charterhouse Square, London, EC1M 6BQ United Kingdom [email protected]

COU: United Kingdom DT: Journal RN: 0083 DN: bexxar/Glaxo SmithKline,United States; zevalin/Biogen,United States MN: Glaxo SmithKline,United States; Glaxo SmithKline; Genentech,United States;

Genentech; Biogen,United States; Biogen TE: tositumomab/208921-02-2; tositumomab i 131/192391-48-3; rituximab/174722-31-7;

paracetamol/103-90-2; potassium iodide/7681-11-0; lugol/12298-68-9; cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; vincristine/57-22-7; prednisolone/50-24-8; fludarabine/21679-14-1; prednisone/53-03-2; ibritumomab tiuxetan/206181-63-7

CR: 208921-02-2; 192391-48-3; 174722-31-7; 103-90-2; 7681-11-0; 12298-68-9; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 50-24-8; 21679-14-1; 53-03-2; 206181-63-7

AB: The CD20 antigen has become a major therapeutic target in the management of follicular and other B cell non-Hodgkin's lymphomas. The murine monoclonal antibody, tositumomab, on binding CD20, is able to induce antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and apoptosis. In addition, when radioiodinated, the antibody exploits the tumour's sensitivity to ionising radiation by direct targeting of the malignant cell. Tositumomab and Iodine (I¹³¹) tositumomab (Bexxar®, GlaxoSmithKline, Philadelphia, PA, USA) is administered in two steps. The dosimetric step determines individual patient pharmacokinetics, allowing a patient-specific dose to be calculated. This is followed by the therapeutic

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step, with administration of the therapeutic dose between 7 and 14 days after the dosimetric dose. Over a decade's worth of experience in clinical trials has determined the efficacy and safety of the regimen in a variety of clinical circumstances; establishment of exactly where the regimen fits amongst the algorithm for the management of follicular lymphoma continues. © 2005 Ashley Publications Ltd.

CNOTE: Copyright 2005 Elsevier B.V., All rights reserved. ET: Cancer

Nuclear Medicine Health Policy, Economics and Management Drug Literature Index Adverse Reactions Titles

3 2/34 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005168883 AU: Ganjoo KN; Robertson MJ; Fisher W; Jung S-H; McClean J; Huh SY; Bufill J;

Williams S; Cripe LD Titel: A phase II study of single agent gemcitabine in relapsed or refractory follicular or

small lymphocytic non-Hodgkin lymphomas: A hoosier oncology group study Quelle: American Journal of Clinical Oncology: Cancer Clinical Trials; VOL: 28 (2); p. 169-

172 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0277-3732 CO: AJCOD Corporate Source:

Dr. K.N. Ganjoo, 535 Barnhill Dr. RT473, Indianapolis, IN 46202 United States [email protected]

COU: United States DT: Journal RN: 0024 TE: gemcitabine/103882-84-4; creatinine/19230-81-0; creatinine/60-27-5; bilirubin/18422-

02-1; bilirubin/635-65-4; aspartate aminotransferase/9000-97-9; fludarabine/21679-14-1; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; dexamethasone/50-02-2; ifosfamide/3778-73-2; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5; bleomycin/11056-06-7; cyclophosphamide/50-18-0; vincristine/57-22-7; prednisone/53-03-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; etoposide/33419-42-0; methylprednisolone/6923-42-8; methylprednisolone/83-43-2; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; cytarabine/147-94-4; cytarabine/69-74-9; folinic acid/58-05-9; folinic acid/68538-85-2; cladribine/4291-63-8

CR: 103882-84-4; 19230-81-0; 60-27-5; 18422-02-1; 635-65-4; 9000-97-9; 21679-14-1; 65271-80-9; 70476-82-3; 50-02-2; 3778-73-2; 15475-56-6; 59-05-2; 7413-34-5; 11056-06-7; 50-18-0; 57-22-7; 53-03-2; 23214-92-8; 25316-40-9; 33419-42-0; 6923-42-8; 83-43-2; 15663-27-1; 26035-31-4; 96081-74-2; 147-94-4; 69-74-9; 58-05-9; 68538-85-2; 4291-63-8

AB: Gemcitabine is a pyrimidine analog that is active in patients with aggressive

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lymphomas and Hodgkin disease. This study assessed tumor response in patients with previously treated follicular or small lymphocytic non-Hodgkin lymphoma. This was a 2-stage phase II trial with the first stage requiring 2 of 13 responses to proceed to the second stage. Gemcitabine was given as a single agent to patients with previously treated follicular or small lymphocytic lymphomas. Gemcitabine was administered at 1250 mg/mxb2 over 30 minutes on days 1 and 8 of a 21-day cycle for a maximum of 6 cycles. Thirteen patients were treated with 1 to 6 cycles of chemotherapy. Two patients experienced grade 4 toxicity with neutropenia. No grade 4 nonhematologic toxicity was seen. There was 1 partial response and 8 patients (61%) had either minimal response or stable disease. Single-agent gemcitabine administered at this dose and schedule produced 1 partial remission and half the patients had stable disease. However, the study had to be stopped early because of lack of meaningful response. Copyright © 2005 by Lippincott Williams & Wilkins.

CNOTE: Copyright 2005 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

3 2/35 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005168881 AU: Larson BJG; Waples JM; Pusateri A; Mendenhall NP; Lynch Jr JW Titel: A phase II study of gemcitabine in patients with relapsed or refractory low-grade non-

Hodgkin lymphoma Quelle: American Journal of Clinical Oncology: Cancer Clinical Trials; VOL: 28 (2); p. 165-

168 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0277-3732 CO: AJCOD Corporate Source:

Dr. J.W. Lynch Jr., Box J-100277 JHMHC, Division of Hematology/Oncology, Department of Medicine, Gainesville, FL 32610-0277 United States

COU: United States DT: Journal RN: 0010 TE: gemcitabine/103882-84-4; fludarabine/21679-14-1; cytarabine/147-94-4;

cytarabine/69-74-9; cladribine/4291-63-8 CR: 103882-84-4; 21679-14-1; 147-94-4; 69-74-9; 4291-63-8 AB: Purpose: The purpose of this study was to determine the tolerability, clinical response

rate, and time to disease progression of gemcitabine treatment in patients with low-grade non-Hodgkin lymphoma. (NHL) Patients and Methods: Twenty patients with low-grade NHL and progression of disease after at least 1 prior treatment regimen were prospectively enrolled. The treatment regimen consisted of 1200 mg/mxb2 gemcitabine intravenously administered weekly for 7 weeks followed by a 1-week rest. Subsequent treatment was given weekly for 3 weeks followed by a 1-week rest

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and repeated for a maximal treatment of 6 cycles until disease progression or unacceptable toxicity. Results: The predominant histologic subtypes among our patients were small lymphocytic (8 of 20) and follicular (7 of 20). Grade III/IV hematologic toxicity was observed in 15 of 20 patients and dose reductions or treatment delays occurred in 19 of 20 patients. Fatigue and asthenia were treatment-limiting in many patients. There were no complete or partial responses observed and only 2 patients had stable disease after 12 weeks of treatment. The average time to progression or off-study status was 2.3 months (95% confidence interval, 1.7-2.9) with 8 patients showing progression of disease. Twelve patients were taken off the study as a result of unacceptable toxicity before observed progression of disease. No patient completed the planned course of therapy. With a median follow up of 10.2 months, 10 of 20 patients remained alive. Conclusion: Gemcitabine as a single agent, in this dosage and schedule, has minimal clinical activity in relapsed or refractory low-grade lymphomas and was associated with considerable toxicity. Therefore, further study of gemcitabine in this setting is not justified. Copyright © 2005 by Lippincott Williams & Wilkins.

CNOTE: Copyright 2005 Elsevier B.V., All rights reserved. ET: Cancer

Drug Literature Index Adverse Reactions Titles

3 2/36 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004532699 AU: Morris GJ; Millenson MM; Padavic-Shaller K; Wang H; Rogatko A; Clyde J; Boyd RL;

Yeslow G; Halbherr T; Schilder RJ; Smith MR Titel: Phase II study of fludarabine and alpha-interferon in patients with low-grade non-

Hodgkin's lymphoma Quelle: Haematologica; VOL: 89 (12); p. 1484-1491 /2004/ Sprache: ENGLISH AL: ENGLISH CY: Italy ISSN: 0390-6078 CO: HAEMA Corporate Source:

Dr. M.R. Smith, Lymphoma Service, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111 United States [email protected]

COU: United States DT: Journal RN: 0045 DN: roferon/Hoffmann La Roche,United States MN: Hoffmann La Roche,United States; Hoffmann La Roche TE: doxorubicin/23214-92-8; doxorubicin/25316-40-9; fludarabine/21679-14-1;

rituximab/174722-31-7 CR: 23214-92-8; 25316-40-9; 21679-14-1; 174722-31-7 AB: Background and Objectives. Low-grade non-Hodgkin's lymphoma (NHL) remains

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incurable with standard dose chemotherapy. Nucleoside analogs such as fludarabine are effective, but even when used as initial therapy, the median duration of remission ranges from only 16 to 24 months. Interferon (IFN) is also active and has been investigated both by incorporating it into the chemotherapy regimen and/or as maintenance therapy, where it may prolong remission. We designed a phase II trial of alternating fludarabine and IFNalpha2a to determine response rate, time to progression and toxicity of this regimen in patients with advanced stage low-grade NHL or mantle cell lymphoma. Design and Methods. Patients had received 0-2 prior regimens that did not include nucleoside analogs or IFN and had adequate organ function. Fludarabine was administered intravenously at 25 mg/m²/day for 5 days once every 6 weeks with IFN in weeks 4 and 5 at 3×10(sup(6)) U/m² subcutaneously three times weekly for 6 doses. Treatment continued in responders for 2 cycles past maximal response (minimum 6 cycles). No maintenance was given. Results. Between 1994 and 1999, 31 patients were accrued and were evaluable for toxicity, with 29 eligible for evaluation of response. Toxicity was primarily myelosuppression, with grade 3 neutropenia in 12 patients and grade 4 thrombocytopenia in one patient. The overall response rate was 51.7% (15/29), including 6 complete and 9 partial responses. With a median follow-up of 35.6 months, the median overall survival was 60.8 months, and the median time to disease progression (TTP) was 12.6 months. Of the 15 responding patients, treatment-naieve patients had a median response duration of 39.6 months with a median TTP of 42.1 months, while the median response duration was 5.2 months with a median TTP of 14.5 months in patients who had received prior treatment (p=0.0065 and 0.0374, respectively). Interpretation and Conclusions. This schedule of alternating fludarabine with IFN does not seem to increase response rate appreciably, but there are some prolonged responses, particularly in previously untreated patients. Given the non-overlapping toxicities of IFN with those of chemotherapy and antibody-based therapeutics, there may be a role for combination therapies, especially if the biological basis of response to IFN can be elucidated.

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Drug Literature Index Adverse Reactions Titles

1 2/37 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004489693 AU: Van De Loosdrecht AA; Huijgens PC; Ossenkoppele GJ Titel: Antibody-targeted therapy: A paradigm of innovative treatment strategies in indolent

and aggressive B-cell non-Hodgkin lymphoma Quelle: Current Opinion in Hematology; VOL: 11 (6); p. 419-425 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1065-6251 CO: COHEF Corporate Source:

Dr. A.A. Van De Loosdrecht, Department of Hematology, VU University Medical Center, De Boelelaan 1117, 1081 HV Amsterdam Netherlands [email protected]

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COU: Netherlands DT: Journal RN: 0060 DN: idec 152; idec 114; rituxan; mabthera; bexxar; zevalin TE: colony stimulating factor 1/81627-83-0; interleukin 2/85898-30-2; rituximab/174722-

31-7; alemtuzumab/216503-57-0; fludarabine/21679-14-1; cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; vincristine sulfate/2068-78-2; prednisone/53-03-2; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; epratuzumab/205923-57-5; tositumomab i 131/192391-48-3; ibritumomab tiuxetan/206181-63-7; chlorambucil/305-03-3; fludarabine phosphate/75607-67-9; cytarabine/147-94-4; cytarabine/69-74-9; ifosfamide/3778-73-2; carboplatin/41575-94-4; etoposide/33419-42-0

CR: 81627-83-0; 85898-30-2; 174722-31-7; 216503-57-0; 21679-14-1; 50-18-0; 23214-92-8; 25316-40-9; 2068-78-2; 53-03-2; 65271-80-9; 70476-82-3; 205923-57-5; 192391-48-3; 206181-63-7; 305-03-3; 75607-67-9; 147-94-4; 69-74-9; 3778-73-2; 41575-94-4; 33419-42-0

AB: Purpose of review: This review outlines the principles of treatment of indolent and aggressive B-cell lymphoma based on current knowledge on the classification of hematologic malignancies and the rationale to implement new antibody-targeted immunotherapeutic approaches. Recent findings: An update is provided on the use of antibody-targeted therapies in clinical trials, with emphasis on new, emerging strategies of immunotherapy in B-cell non-Hodgkin lymphoma. Summary: The success of immune-mediated therapies has encouraged studies on antibody-targeted therapy in B-cell non-Hodgkin lymphoma. Promising new approaches combine classical dose-intense chemotherapy with "tumor-specific" antibody targeting during several phases of the disease. The safety and efficacy of anti-CD20 in the treatment of indolent and aggressive B-cell non-Hodgkin lymphoma at any stage of disease, either as a single agent or as part of multimodality regimes, as an unconjugated antibody or as radioimmunoconjugate have changed dramatically our treatment strategies. Increasing insights into basic molecular biology and immunology of B-cell non-Hodgkin lymphoma may identify subgroups of patients categorized in current classification systems who may benefit from tailored approaches with new modality antibody-targeted therapy in near future.

CNOTE: Copyright 2004 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3, 6 2/38 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004484885 AU: Chanan-Khan A Titel: Bcl-2 antisense therapy in hematologic malignancies Quelle: Current Opinion in Oncology; VOL: 16 (6); p. 581-585 /2004/ Sprache: ENGLISH AL: ENGLISH

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CY: United States ISSN: 1040-8746 CO: CUOOE Corporate Source:

A. Chanan-Khan, Roswell Park Cancer Institute, Buffalo, NY 14263 United States [email protected]

COU: United States DT: Journal RN: 0022 DN: genasense/Genta,United States MN: Genta,United States; Genta TE: oblimersen/190977-41-4; protein bcl 2/219306-68-0; chlorambucil/305-03-3;

fludarabine/21679-14-1; rituximab/174722-31-7; bortezomib/179324-69-7; bortezomib/197730-97-5; dexamethasone/50-02-2; thalidomide/50-35-1; vincristine/57-22-7; doxorubicin/23214-92-8; doxorubicin/25316-40-9; cyclophosphamide/50-18-0; prednisone/53-03-2; cytarabine/147-94-4; cytarabine/69-74-9; daunorubicin/12707-28-7; daunorubicin/20830-81-3; daunorubicin/23541-50-6

CR: 190977-41-4; 219306-68-0; 305-03-3; 21679-14-1; 174722-31-7; 179324-69-7; 197730-97-5; 50-02-2; 50-35-1; 57-22-7; 23214-92-8; 25316-40-9; 50-18-0; 53-03-2; 147-94-4; 69-74-9; 12707-28-7; 20830-81-3; 23541-50-6

AB: Purpose of review: Overexpression of the Bcl-2 oncoprotein is noted in various malignant disorders. In patients with hematologic malignancies, increased production of the Bcl-2 oncoprotein is associated with chemotherapy resistance, aggressive clinical course, and poor survival. Bcl-2 is an important molecular target. Downregulating Bcl-2 can potentially reverse inherent tumor resistance to, and possibly improve response to therapy. This review focuses on the preclinical data, as well as the current clinical information available on oblimersen, a novel antisense approach targeting Bcl-2 in malignant hematologic disorders. Recent findings: Early clinical trials have shown single-agent activity of oblimersen in patients with chronic lymphocytic leukemia and non-Hodgkin lymphoma, and thus, provide proof of principle for antisense therapy. Phase I and phase II studies using oblimersen in combination with conventional chemotherapy have shown encouraging results in patients with non-Hodgkin lymphoma, chronic lymphocytic leukemia, and acute myeloid leukemia. Phase III studies in patients with multiple myeloma and chronic lymphocytic leukemia have completed accrual and results are awaited. Summary: Bcl-2 is a clinically meaningful target in patients with hematologic malignancies. Downregulation of the Bcl-2 oncoprotein can be achieved with oblimersen (antisense molecule specific for Bcl-2). Early clinical results suggest a possible role of this antisense approach in targeting Bcl-2. Ongoing clinical trials will establish the clinical utility of oblimersen in patients with hematologic malignancies. © 2004 Lippincott Williams & Wilkins.

CNOTE: Copyright 2004 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3, 6

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2/39 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004471339 AU: Haddad N; Rowe JM Titel: Current indications for reduced-intensity allogeneic stem cell transplantation Quelle: Best Practice and Research in Clinical Haematology; VOL: 17 (3); p. 377-386 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1521-6926 CO: BPRCA PII: S1521692604000489 Corporate Source:

Dr. N. Haddad, Dept. Haematol./Bone Marrow Transpl., Rambam Medical Center and Technion, Israel Institute of Technology, Haifa 31096 Israel

COU: Israel DT: Journal RN: 0038 DN: campath 1 h; revimid; velcade TE: busulfan/55-98-1; carmustine/154-93-8; etoposide/33419-42-0; cytarabine/147-94-4;

cytarabine/69-74-9; melphalan/148-82-3; fludarabine/21679-14-1; cladribine/4291-63-8; alemtuzumab/216503-57-0; imatinib/152459-95-5; imatinib/220127-57-1; thalidomide/50-35-1; 3 (4 amino 1,3 dihydro 1 oxo 2h isoindol 2 yl)glutarimide/191732-72-6; bortezomib/179324-69-7; bortezomib/197730-97-5; interleukin 2/85898-30-2

CR: 55-98-1; 154-93-8; 33419-42-0; 147-94-4; 69-74-9; 148-82-3; 21679-14-1; 4291-63-8; 216503-57-0; 152459-95-5; 220127-57-1; 50-35-1; 191732-72-6; 179324-69-7; 197730-97-5; 85898-30-2

AB: Stem cell transplantation preceded by reduced-intensity conditioning (RIC) is based on the use of immunosuppressive agents as the sine qua non to ensure donor cell engraftment. It is a curative option for select patients suffering from haematological and non-haematological malignancies. The most beneficial results are observed when a full donor engraftment is achieved with 'tolerable' graft-vs-host disease (GVHD). To date, a vast amount of clinical data has been published, but in an uncontrolled manner. This review summarizes the currently known outcome of allogeneic transplants with RIC, with every disease category analysed separately. Unresolved problems include the optimal combination of immunosuppressive agxents, the degree of infectious complications, and GVHD that may appear in some patients. Directions to overcome these complications are discussed. Despite the paucity of controlled clinical data, the current indications for RIC allogeneic transplantation are summarized based on the best-available phase II data. © 2004 Elsevier Ltd. All rights reserved.

CNOTE: Copyright 2004 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Drug Literature Index Adverse Reactions Titles

3, 6

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2/40 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004445336 AU: Gordon LI; Witzig T; Molina A; Czuczman M; Emmanouilides C; Joyce R; Vo K;

Theuer C; Pohlman B; Bartlett N; Wiseman G; Darif M; White C Titel: Yttrium 90-labeled ibritumomab tiuxetan radioimmunotherapy produces high

response rates and durable remissions in patients with previously treated B-cell lymphoma

Quelle: Clinical Lymphoma; VOL: 5 (2); p. 98-101 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1526-9655 CO: CLLYA Corporate Source:

Dr. L.I. Gordon, Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, 676 N St. Clair, Chicago, IL 60611 United States [email protected]

COU: United States DT: Journal RN: 0011 TE: cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9;

fludarabine/21679-14-1; ibritumomab tiuxetan/206181-63-7; prednisone/53-03-2; rituximab/174722-31-7; vincristine/57-22-7

CR: 50-18-0; 23214-92-8; 25316-40-9; 21679-14-1; 206181-63-7; 53-03-2; 174722-31-7; 57-22-7

AB: We report updated time-to-event variables of a phase III randomized study comparing yttrium 90-labeled ibritumomab with rituximab standard therapy in 143 rituximab-naive patients with relapsed or refractory low-grade, follicular, or transformed CD20(sup(+)) non-Hodgkin's lymphoma (NHL). Most patients (79%) had follicular lymphoma. Patients were randomized to receive a single intravenous (I.V. dose of (sup(90))Y ibritumomab tiuxetan 0.4 mCi/kg (n = 73) or rituximab 375 mg/m² I.V. weekly for 4 doses (n = 70). The radioimmunotherapy group was pretreated with 2 rituximab doses (250 mg/m²) to improve biodistribution and one dose of Indium 111-labeled ibritumomab tiuxetan for imaging. The overall response rate was 80% versus 56% (P = 0.002) and complete response (CR)/CR unconfirmed (CRu) rates were 34% for (sup(90))Y ibritumomab tiuxetan versus 20% for rituximab. With a median follow-up of 44 months, the data are mature as all ongoing patients in both groups exceeded the median Kaplan-Meier estimated time to progression (TTP), duration of response (DR), and time to next therapy. Although this study was not powered to detect differences in time-to-event variables, the results from this randomized trial demonstrate trends toward longer median TTP (15 vs. 10.2 months; P = 0.07), DR (16.7 vs. 11.2 months; P = 0.44) and time to next therapy (21.1 vs. 13.8 months; P = 0.27) in follicular NHL patients treated with (sup(90))Y ibritumomab tiuxetan compared with the rituximab control arm. In patients achieving a CR/CRu, the median TTP was 24.7 months for patients treated with (sup(90))Y ibritumomab tiuxetan compared with 13.2 months for rituximab-treated patients (P = 0.41), and ongoing responses of >5 years have been observed. These results confirm that (sup(90))Y ibritumomab tiuxetan produces high response rates and durable remissions in patients with previously treated low-grade, follicular, and transformed NHL.

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CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Drug Literature Index

3 2/41 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004415939 AU: Rao S; Watkins D; Cunningham D; Dunlop D; Johnson P; Selby P; Hancock BW;

Fegan C; Culligan D; Schey S; Morris TCM; Lissitchkov T; Oliver JW; Holmlund JT Titel: Phase II study of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C

alpha, in patients with previously treated low-grade non-Hodgkin's lymphoma Quelle: Annals of Oncology; VOL: 15 (9); p. 1413-1418 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 0923-7534 CO: ANONE Corporate Source:

Prof. D. Cunningham, Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT United Kingdom [email protected]

COU: United Kingdom DT: Journal RN: 0024 DN: adriamycin; isis 3521 TE: anthraquinone/84-65-1; chlorambucil/305-03-3; cyclophosphamide/50-18-0;

doxorubicin/23214-92-8; doxorubicin/25316-40-9; fludarabine/21679-14-1; gentamicin/1392-48-9; gentamicin/1403-66-3; gentamicin/1405-41-0; isis 3521/151879-73-1; prednisolone/50-24-8; rituximab/174722-31-7; vincristine/57-22-7; warfarin/129-06-6; warfarin/2610-86-8; warfarin/3324-63-8; warfarin/5543-58-8; warfarin/81-81-2

CR: 84-65-1; 305-03-3; 50-18-0; 23214-92-8; 25316-40-9; 21679-14-1; 1392-48-9; 1403-66-3; 1405-41-0; 151879-73-1; 50-24-8; 174722-31-7; 57-22-7; 129-06-6; 2610-86-8; 3324-63-8; 5543-58-8; 81-81-2

AB: Background: The purpose of this study was to assess the efficacy and safety of ISIS 3521, an anti-sense phosphorothioate oligonucleotide to protein kinase C alpha in patients with relapsed low-grade non-Hodgkin's lymphoma (NHL). Patients and methods: Twenty-six patients received ISIS 3521 (2 mg/kg/day) as a continuous infusion over 21 days of each 28-day cycle. Results: The median age of the patients was 53 years (range 37-77). Histological subtypes were low-grade follicular lymphoma (n = 22) and B-cell small lymphocytic lymphoma (n = 4). Twenty-one (81%) had stage III/IV disease. The median number of previous lines of chemotherapy was two (range one to six). A total of 87 cycles of ISIS 3521 were administered. Twenty-three patients were assessable for response. Three patients achieved a partial response. No complete responses were observed. Ten patients had stable disease. Grade 3-4 toxicity was as follows: neutropenia (3.8%) and

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thrombocytopenia (26.9%). Conclusions: ISIS 3521 has demonstrated anti-tumour activity in patients with relapsed low-grade NHL. There may be a potential role for this agent in combination with conventional chemotherapy for advanced low-grade lymphoma, and further trials are warranted. © 2004 European Society for Medical Oncology.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

3 2/42 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004412268 AU: Piotrowska M; Nowak WS; Skotnicki AB Titel: ROLA ANTYSENSOWYCH OLIGONUKLEOTYDOW ANTY BCL-2 (OBLIMERSEN

SODOWY) W TERAPII PRZECIWNOWOTWOROWEJ The role of anti- Bcl-2 antisense oligonucleotides in anti-neoplastic therapy

Quelle: Acta Haematologica Polonica; VOL: 35 (2); p. 145-156 /2004/ Sprache: POLISH AL: POLISH CY: Poland ISSN: 0001-5814 CO: AHPLB DT: Journal RN: 0043 DN: g 3139; genasense; filgrastim TE: protein bcl 2/219306-68-0; oblimersen/190977-41-4; DNA/9007-49-2;

docetaxel/114977-28-5; paclitaxel/33069-62-4; chlorambucil/305-03-3; fludarabine/21679-14-1; cyclophosphamide/50-18-0; dexamethasone/50-02-2; etoposide/33419-42-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; recombinant granulocyte colony stimulating factor/121181-53-1

CR: 219306-68-0; 190977-41-4; 9007-49-2; 114977-28-5; 33069-62-4; 305-03-3; 21679-14-1; 50-18-0; 50-02-2; 33419-42-0; 23214-92-8; 25316-40-9; 15663-27-1; 26035-31-4; 96081-74-2; 121181-53-1

AB: The Bcl-2 protein inhibits apoptosis and is responsible for cellular resistance to chemotherapy, radiotherapy and monoclonal antibody therapy. Oblimersen sodium (G3139, Genasense) is an antisense nucleotide, which specifically binds to 6 mRNA Bcl-2 codons, causes degradation and decreases Bcl-2 protein synthesis. Clinical and laboratory studies show a strong synergistic action with typical antineoplastic drugs. A number of randomized third phase clinical studies are currently performed in order to assess the effect and toxicity of oblimersen sodium in the treatment of chronic lymphocytic leucaemia (CLL), malignant lymphoma, multiple myeloma (MM) and non-small cell lung cancer (NSCLC). Increased anti-neoplastic effect of oblimersen sodium is also assessed in patients with acute myeloblastica leucaemia (AML), non-Hodgkin's lymphoma (NHL) and prostate cancer resistant to hormonal treatment. Implementation of this new treatment concept based on anti-apoptotic mechanism

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inhibition creates a chance of increasing the efficacy of currently applied anti-neoplastic therapy regimens.

CNOTE: Copyright 2004 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index

3, 6 2/43 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004290058 AU: Forero A; Weiden PL; Vose JM; Knox SJ; LoBuglio AF; Hankins J; Goris ML; Picozzi

VJ; Axworthy DB; Breitz HB; Sims RB; Ghalie RG; Shen S; Meredith RF Titel: Phase 1 trial of a novel anti-CD20 fusion protein in pretargeted radioimmunotherapy

for B-cell non-Hodgkin lymphoma Quelle: Blood; VOL: 104 (1); p. 227-236 /01 JUL 2004/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0006-4971 CO: BLOOA Corporate Source:

A. Forero, University of Alabama, Comprehensive Cancer Center, WTI 22, 1824 Sixth Ave South, Birmingham, AL 35294-3300 United States [email protected]

COU: United States DT: Journal RN: 0029 DN: rituxan/Idec,United States; mabthera/Idec,United States; zevalin/Idec,United States;

bexxar/Corixa,United States MN: Idec,United States; Idec; Corixa,United States; Corixa TE: single chain fragment variable antibody/334577-34-3; single chain fragment variable

antibody/334577-38-7; streptavidin/9013-20-1; rhenium 186/14998-63-1; 1,4,7,10 tetraazacyclododecane 1,4,7,10 tetraacetic acid/60239-18-1; biotin/58-85-5; indium 111/15750-15-9; cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2; fludarabine/21679-14-1; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; etoposide/33419-42-0; methylprednisolone/6923-42-8; methylprednisolone/83-43-2; cytarabine/147-94-4; cytarabine/69-74-9; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; mitoguazone/459-86-9; ifosfamide/3778-73-2; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5; rituximab/174722-31-7; dexamethasone/50-02-2; chlorambucil/305-03-3; ibritumomab tiuxetan/206181-63-7; tositumomab i 131/192391-48-3

CR: 334577-34-3; 334577-38-7; 9013-20-1; 14998-63-1; 60239-18-1; 58-85-5; 15750-15-9; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2; 21679-14-1; 65271-80-9; 70476-82-3; 33419-42-0; 6923-42-8; 83-43-2; 147-94-4; 69-74-9; 15663-27-1; 26035-31-4; 96081-74-2; 459-86-9; 3778-73-2; 15475-56-6; 59-05-2; 7413-34-5; 174722-31-7; 50-02-2; 305-03-3; 206181-63-7; 192391-48-3

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AB: Pretargeted radioimmunotherapy (PRIT) has the potential to increase the dose of radionuclide delivered to tumors while limiting radiation to normal tissues. The purpose of this phase 1 trial is to assess safety of this multistep approach using a novel tetrameric single-chain anti-CD20-streptavidin fusion protein (B9E9FP) as the targeting moiety in patients with B-cell non-Hodgkin lymphoma (NHL), and to characterize its pharmacokinetics and immunogenicity. All patients received B9E9FP (160 mg/m² or 320 mg/m²); either 48 or 72 hours later, a synthetic clearing agent (sCA) was administered (45 mg/m²) to remove circulating unbound B9E9FP. (sup(9O))Yttrium ((sup(90))Y; 15 mCi/m²)/¹¹¹In (5 mCi)-DOTA-biotin was injected 24 hours later. There were 15 patients enrolled in the study. B9E9FP had a mean plasma half-life (T1/2) of 25 ± 6 hours with a reduction in plasma level of more than 95% within 6 hours of sCA administration. (sup(90))Y/¹¹¹In-DOTA-biotin infusion resulted in rapid tumor localization and urinary excretion. The ratio of average tumor to whole-body radiation dose was 49:1. No significant hematologic toxicities were noted in 12 patients. There were 2 patients who had hematologic toxicity related to progressive disease. There were 2 complete remissions (90 and 325 days) and one partial response (297 days). B9E9FP performs well as the targeting component of PRIT with encouraging dosimetry, safety, and efficacy. A dose escalation trial of (sup(90))Y-DOTA-biotin in this format is warranted. © 2004 by The American Society of Hematology.

CNOTE: Copyright 2004 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Drug Literature Index Adverse Reactions Titles

3 2/44 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004248902 AU: Buser AS; Heim D; Bucher C; Tichelli A; Gratwohl A; Passweg JR Titel: High-dose chemotherapy using BEAM for tumor debulking without stem cell support

followed by early allogeneic reduced intensity conditioning transplantation to induce a graft-versus-lymphoma effect in patients with high risk or refractory lymphoma

Quelle: Bone Marrow Transplantation; VOL: 33 (10); p. 1011-1014 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 0268-3369 CO: BMTRE Corporate Source:

Dr. J.R. Passweg, Division of Hematology, University Hospitals Basel, Petersgraben 4, CH-4031 Basel Switzerland [email protected]

COU: Switzerland DT: Journal RN: 0015 TE: alemtuzumab/216503-57-0; carmustine/154-93-8; cisplatin/15663-27-1;

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cisplatin/26035-31-4; cisplatin/96081-74-2; cyclosporin/79217-60-0; cytarabine/147-94-4; cytarabine/69-74-9; etoposide/33419-42-0; fludarabine/21679-14-1; melphalan/148-82-3; mycophenolic acid 2 morpholinoethyl ester/116680-01-4; mycophenolic acid 2 morpholinoethyl ester/128794-94-5; rituximab/174722-31-7

CR: 216503-57-0; 154-93-8; 15663-27-1; 26035-31-4; 96081-74-2; 79217-60-0; 147-94-4; 69-74-9; 33419-42-0; 21679-14-1; 148-82-3; 116680-01-4; 128794-94-5; 174722-31-7

AB: In patients with refractory lymphoma, we tested the hypothesis that high-dose chemotherapy (BEAM) without stem cell support followed by a reduced intensity (RIC) allogeneic transplant with fludarabine and 2 Gy TBI 28 days later results in tumor debulking and establishment of a graft vs lymphoma effect, with acceptable toxicity. In a pilot protocol we treated 10 patients, 22-62 (median 47) years of age with high-risk or refractory Hodgkin's or non-Hodgkin's lymphoma. Donors were HLA identical siblings (eight) or unrelated volunteers. None died during the neutropenic phase after BEAM which lasted up to the RIC HSCT. The duration of neutropenia was 31-43 (median 36) days. All patients engrafted and nine achieved CR. All developed acute GvHD (median grade III) and all patients at risk developed chronic GvHD. Three patients died of GvHD. One relapsed and six patients are in continuous CR 10-32 (median 15) months after HSCT. This approach appears feasible and results in a high response rate. Neutropenia duration is of concern. It remains to be tested whether separation of debulking chemotherapy and induction of allogeneic effects confers an advantage. © 2004 Nature Publishing Group All rights reserved.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Pharmacology Drug Literature Index Adverse Reactions Titles

5 2/45 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004185248 AU: Goy A; Gilles F Titel: Update on the proteasome inhibitor bortezomib in hematologic malignancies Quelle: Clinical Lymphoma; VOL: 4 (4); p. 230-237 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1526-9655 CO: CLLYA Corporate Source:

Dr. A. Goy, Department of Lymphoma/Myeloma, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030 United States [email protected]

COU: United States DT: Journal RN: 0097

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DN: ps 341 TE: bortezomib/179324-69-7; bortezomib/197730-97-5; ubiquitin/60267-61-0;

dexamethasone/50-02-2; thalidomide/50-35-1; melphalan/148-82-3; doxorubicin/23214-92-8; doxorubicin/25316-40-9; rituximab/174722-31-7; gemcitabine/103882-84-4; protein bcl 2/219306-68-0; fludarabine/21679-14-1; imatinib/152459-95-5; imatinib/220127-57-1; flavopiridol/146426-40-6; protein Bak/166801-28-1; protein bcl xl/151033-38-4; X linked inhibitor of apoptosis/391965-84-7; caspase 3/169592-56-7

CR: 179324-69-7; 197730-97-5; 60267-61-0; 50-02-2; 50-35-1; 148-82-3; 23214-92-8; 25316-40-9; 174722-31-7; 103882-84-4; 219306-68-0; 21679-14-1; 152459-95-5; 220127-57-1; 146426-40-6; 166801-28-1; 151033-38-4; 391965-84-7; 169592-56-7

AB: The ubiquitin-proteasome system plays a crucial role in eukaryotic cells in maintaining protein homeostasis. Through the disruption of a variety of pathways and cell cycle checkpoints, proteasome inhibition leads to apoptosis and in experimental models can overcome chemoresistance. Bortezomib is the first of its class of proteasome inhibitors tested in humans that showed promising activity in several tumor types, and especially in hematologic malignancies, in phase I studies. The remarkable results obtained in phase II studies in multiple myeloma (MM) led to its fast-track approval by the US Food and Drug Administration in May 2003 for relapsed MM. More recent observation also revealed promising activity in non-Hodgkin's lymphoma. This review will explore the rationale for the use of bortezomib in hematologic malignancies as well as provide an update on the results of ongoing studies and future directions for the use of this new agent in hematologic malignancies. The mechanism of action of bortezomib and its nonoverlapping toxicity profile make it a very appealing drug for combination with other chemotherapeutic or biologic agents. Bortezomib represents an excellent example of how progress in understanding the biology of cancer cells can impact clinical practice and lead toward a new era of rational therapeutics.

CNOTE: Copyright 2004 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3, 6 2/46 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004136592 AU: Mavromatis BH; Cheson BD Titel: Novel therapies for chronic lymphocytic leukemia Quelle: Blood Reviews; VOL: 18 (2); p. 137-148 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 0268-960X CO: BLORE Corporate Source:

B.D. Cheson, Lombardi Cancer Center, Georgetown University Medical Center, Washington, DC 20057 United States [email protected]

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COU: United States DT: Journal RN: 0076 DN: idec 152; hu1d10; idec 114; ontak; genasense; bl 22; e mab; lymphocide; zevalin;

bexxar; targretin; eb 1089 TE: alemtuzumab/216503-57-0; rituximab/174722-31-7; epratuzumab/205923-57-5;

denileukin diftitox/173146-27-5; oblimersen/190977-41-4; chlorambucil/305-03-3; fludarabine/21679-14-1; cyclophosphamide/50-18-0; bevacizumab/216974-75-3; aciclovir/59277-89-3; cotrimoxazole/8064-90-2; death receptor 5/197665-71-7; ibritumomab tiuxetan/206181-63-7; tositumomab i 131/192391-48-3; bexarotene/153559-49-0; bendamustine/16506-27-7; bendamustine/3543-75-7; seocalcitol/134404-52-7

CR: 216503-57-0; 174722-31-7; 205923-57-5; 173146-27-5; 190977-41-4; 305-03-3; 21679-14-1; 50-18-0; 216974-75-3; 59277-89-3; 8064-90-2; 197665-71-7; 206181-63-7; 192391-48-3; 153559-49-0; 16506-27-7; 3543-75-7; 134404-52-7

AB: New therapies for chronic lymphocytic leukemia (CLL) are moving away from non-specific cytotoxic to more targeted approaches. The monoclonal antibody alemtuzumab induces responses in 33% to 43% of patients with relapsed or refractory disease, with 2-5% CR. Side effects include infusional reactions as well as immunosuppressive effects. Rituximab has limited activity in relapsed refractory patients, but response rates are comparable to follicular non-Hodgkin's lymphoma in untreated patients. Other antibodies in early phases of development include anti-CD23 [IDEC-152], anti-CD22 [epratuzumab], Hu1D10 [apolizumab], and anti-CD80 [anti-B7, IDEC-114]. Other agents that are being studied include denileukin diftitox fusion protein (Ontak), and bcl-2 antisense [G3139, Genasense]. The mechanism of action of the new drugs and their role in CLL, as well as the emergence of new prognostic markers are discussed. ©2003 Elsevier Ltd. All rights reserved.

CNOTE: Copyright 2004 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

4, 6 2/47 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004121388 AU: Hillmen P Titel: Advancing Therapy for Chronic Lymphocytic Leukemia - The Role of Rituximab Quelle: Seminars in Oncology; VOL: 31 (1 SUPPL. 2); p. 22-26 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0093-7754 CO: SOLGA Corporate Source:

Dr. P. Hillmen, Pinderfields General Hospital, Aberford Road, Wakefield WF1 4DG United Kingdom

COU: United Kingdom

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DT: Journal RN: 0034 TE: cyclophosphamide/50-18-0; fludarabine/21679-14-1; rituximab/174722-31-7 CR: 50-18-0; 21679-14-1; 174722-31-7 AB: Chronic lymphocytic leukemia (CLL) remains incurable despite decades of clinical

trials. Some patients survive for long periods without requiring definitive therapy, while others die rapidly despite intensive treatment. Because most patients with CLL express CD20 on their malignant cells, the chimeric anti-CD20 monoclonal antibody rituximab has been incorporated into treatment regimens in efforts to improve outcome. Rituximab monotherapy has limited activity in previously untreated and refractory/relapsed CLL patients with response rates that are generally lower than those seen in non-Hodgkin's lymphoma. Although increased dosing intensity and frequency leads to higher response rates than seen in patients treated with standard dose rituximab, responses are almost always partial remissions and the doses used are not feasible in routine clinical practice. On the other hand, combining rituximab with chemotherapy has proved to be feasible and appears to be synergistic with fludarabine-based chemotherapy in the treatment of CLL on the basis of recent phase II trials. In these studies, response rates (including complete remissions) to rituximab in combination with fludarabine-containing regimens are higher than those reported in similar phase II studies with any other treatment regime. The highest response rates reported are for the combination of rituximab, fludarabine, and cyclophosphamide. A randomized phase III trial has been initiated to evaluate the addition of rituximab to fludarabine and cyclophosphamide in patients with relapsed CLL. The combination of rituximab with other agents is also being investigated, and these ongoing trials will help define the role of rituximab in CLL. © 2004 Elsevier Inc. All rights reserved.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3, 4, 6 2/48 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004067212 AU: Bordonaro R; Petralia G; Restuccia N; Todaro AM; Serraino D; Guiffrida D; Cordio S;

Giannitto-Giorgio C; Salice P; Ursino M; Novello G; Marletta F; Manusia M Titel: Fludarabine, mitoxantrone and dexamethasone as front-line therapy in elderly

patients affected by newly-diagnosed, low-grade non-Hodgkin's lymphomas with unfavorable prognostic factors: Results of a phase II study

Quelle: Leukemia and Lymphoma; VOL: 45 (1); p. 93-100 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 CO: LELYE Corporate R. Bordonaro, Oncology Unit, S. Luigi - S. Currò Hospital, Viale Fleming 24, 95100

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Source: Catania Italy [email protected]

COU: Italy DT: Journal RN: 0036 TE: cyclophosphamide/50-18-0; dexamethasone/50-02-2; doxorubicin/23214-92-8;

doxorubicin/25316-40-9; fludarabine/21679-14-1; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; prednisone/53-03-2; vincristine/57-22-7

CR: 50-18-0; 50-02-2; 23214-92-8; 25316-40-9; 21679-14-1; 65271-80-9; 70476-82-3; 53-03-2; 57-22-7

AB: About one-third of the cases of non-Hodgkin's lymphomas occur in patients aged 60 years or more. Nlevertheless, there are very few data in the literature regarding the optimal therapeutic approach for both aggressive and indolent histologies. Fludarabine-based combination regimens are an effective choice for younger patients affected by low-grade non-Hodgkin's lymphomas, but there is a lack of information about their tolerability and efficacy in older patients. We performed a phase II study to test the efficacy and safety of the combination of Fludarabine, Mitoxantrone and Dexamethasone (FND) in newly-diagnosed, chemo-naieve elderly patients affected by low-grade non-Hodgkin's lymphomas with unfavorable prognostic factors. From March 1999 to March 2002, 18 patients were enrolled into the study. All the patients were evaluated for toxicity and response. Neutropenia and thrombocytopenia have been registered as the main toxicities. Thirteen (72%) patients experienced a complete response and 4 (22%) a partial response: the overall response rate was 94%. At a median follow-up of 19 months, the median time for progression-free-survival and the median survival time were not reached yet. The 2-years projected progression-free-survival and overall-survival are 52% and 67% respectively. When administered as first-line treatment to a population of elderly patients affected by high-risk, low-grade non-Hodgkin's lymphomas, FND showed a high efficacy and a good toxicity profile. Our data compare favorably to those reported for the same schedule administered both as first- or second-line therapy in younger patients.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

1 2/49 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2003375106 AU: Tobinai K Titel: Rituximab and other emerging antibodies as molecular target-based therapy of

lymphoma Quelle: International Journal of Clinical Oncology; VOL: 8 (4); p. 212-223 /2003/ Sprache: ENGLISH AL: ENGLISH CY: Japan ISSN: 1341-9625

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CO: IJCOF Corporate Source:

K. Tobinai, Hematology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 Japan [email protected]

COU: Japan DT: Journal RN: 0076 DN: mylotarg/Wyeth,United States; zevalin/Idec,United States; bexxar/Corixa,United

States; campath 1h; lmb 2; cma 676 MN: Wyeth,United States; Wyeth; Idec,United States; Idec; Corixa,United States; Corixa TE: rituximab/174722-31-7; cyclophosphamide/50-18-0; doxorubicin/23214-92-8;

doxorubicin/25316-40-9; vincristine/57-22-7; prednisolone/50-24-8; ibritumomab tiuxetan/206181-63-7; tositumomab i 131/192391-48-3; trastuzumab/180288-69-1; alemtuzumab/216503-57-0; epratuzumab/205923-57-5; paracetamol/103-90-2; diphenhydramine/147-24-0; diphenhydramine/58-73-1; fludarabine/21679-14-1; dexamethasone/50-02-2; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5; cytarabine/147-94-4; cytarabine/69-74-9; yttrium 90/10098-91-6; samarium 153/15766-00-4; copper 67/15757-86-5; astatine 211/15755-39-2; iodine 131/10043-66-0; iodine 131/15124-39-7

CR: 174722-31-7; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 50-24-8; 206181-63-7; 192391-48-3; 180288-69-1; 216503-57-0; 205923-57-5; 103-90-2; 147-24-0; 58-73-1; 21679-14-1; 50-02-2; 15475-56-6; 59-05-2; 7413-34-5; 147-94-4; 69-74-9; 10098-91-6; 15766-00-4; 15757-86-5; 15755-39-2; 10043-66-0; 15124-39-7

AB: Among the monoclonal antibodies (mAbs) under clinical development, anti-CD20 mAbs have been most extensively investigated and have shown definitive clinical activities. Rituximab is a genetically engineered, chimeric anti-CD20 mAb with mouse variable and human constant regions. Consecutive clinical trials conducted in the United States, Europe, and Japan have revealed that rituximab is an effective agent, with acceptable toxicities, in the treatment of indolent and aggressive B-cell non-Hodgkin's lymphomas (B-NHLs). A recent European phase III study in elderly patients with untreated diffuse large B-cell lymphoma suggested that rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) chemotherapy is superior to CHOP chemotherapy alone in terms of complete response rate and event-free and overall survivals. Lymphoma is inherently a radiosensitive tumor. The aim of radioimmunotherapy is to use the mAb to target radiation to lymphoma tissue while minimizing toxicity to normal cells. Clinical trials of (sup(90))Y-ibritumomab tiuxetan and ¹³¹I-tositumomab showed that they have definitive efficacy in relapsed indolent B-NHL, with acceptable toxicities. A recent comparative study in relapsed indolent B-NHL showed that (sup(90))Y-ibritumomab tiuxetan produced a higher response rate than rituximab. In addition, BL22, a recombinant anti-CD22 immunotoxin, showed significant efficacy in patients with chemotherapy-resistant hairy cell leukemia. Monoclonal antibodies will have significant roles in the treatment of lymphoid malignancies in the future.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Radiology

Cancer Hematology Drug Literature Index Adverse Reactions Titles

3, 6

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2/50 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2003350710 AU: Jäger U Titel: Innovative strategies in lymphoma therapy Quelle: Wiener Klinische Wochenschrift; VOL: 115 (13-14); p. 462-470 /14 AUG 2003/ Sprache: ENGLISH AL: GERMAN CY: Austria ISSN: 0043-5325 CO: WKWOA Corporate Source:

Dr. U. Jäger, Div. of Hematol. and Hemostaseology, Department of Internal Medicine I, Währinger Gürtel 18-20, A-1090 Vienna Austria [email protected]

COU: Austria DT: Journal RN: 0122 DN: nsc 630176; pkc 412; g 3139 TE: rituximab/174722-31-7; alemtuzumab/216503-57-0; fludarabine/21679-14-1;

mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2; yttrium 90/10098-91-6; iodine 131/10043-66-0; iodine 131/15124-39-7; ibritumomab tiuxetan/206181-63-7; tositumomab i 131/192391-48-3; fr 901228/128517-07-7; n benzoylstaurosporine/120685-11-2; augmerosen/190977-41-4

CR: 174722-31-7; 216503-57-0; 21679-14-1; 65271-80-9; 70476-82-3; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2; 10098-91-6; 10043-66-0; 15124-39-7; 206181-63-7; 192391-48-3; 128517-07-7; 120685-11-2; 190977-41-4

AB: Treatment of malignant non-Hodgkin lymphomas (NHL) in the 21(sup(st)) century has been revolutionized by novel biological agents offering targeted approaches in addition to radio-chemotherapy. Monoclonal antibodies (MoAbs) against lymphatic surface antigens have been effective as monotherapeutic agents, and have already shown their superiority to conventional strategies when combined with chemotherapy. Radioimmunoconjugates are more effective than unlabelled antibodies. Specific inhibitors of neoangiogenesis as well as intracellular signal transduction pathways and antiapoptotic mechanisms have shown their efficacy in phase II studies. Long-term improvement in the setting of minimal residual disease has been observed after vaccination against surface antigens and non-myeloablative allogeneic stem cell transplantation is effective in controlling lymphoma growth. Novel specific antigens are currently identified using expression profiling of lymphomas. In the near future, combinations of biological agents will challenge conventional therapy. These exciting new strategies will improve the success rate in aggressive NHLs and may even challenge the paradigm of incurability of indolent lymphomas.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index

6

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2/51 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2003249604 AU: Economopoulos T; Fountzilas G; Pavlidis N; Kalantzis D; Papageorgiou E;

Christodoulou C; Hamilos G; Nicolaides C; Dimopoulos M Titel: Rituximab in combination with CNOP chemotherapy in patients withn previously

untreated indolent non-Hodgkin's lymphoma Quelle: Hematology Journal; VOL: 4 (2); p. 110-115 /2003/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1466-4860 CO: HJEOB Corporate Source:

T. Economopoulos, Evangelismos Hospital, Second Department of Internal Med., Athens 106 76 Greece [email protected]

COU: Greece DT: Journal RN: 0026 TE: rituximab/174722-31-7; cyclophosphamide/50-18-0; mitoxantrone/65271-80-9;

mitoxantrone/70476-82-3; vincristine/57-22-7; prednisone/53-03-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5; bleomycin/11056-06-7; folinic acid/58-05-9; folinic acid/68538-85-2; fludarabine/21679-14-1

CR: 174722-31-7; 50-18-0; 65271-80-9; 70476-82-3; 57-22-7; 53-03-2; 23214-92-8; 25316-40-9; 15475-56-6; 59-05-2; 7413-34-5; 11056-06-7; 58-05-9; 68538-85-2; 21679-14-1

AB: Rituximab, a chimeric monoclonal antibody, produces response rates of up to 73% in patients with previously untreated indolent non-Hodgkin's lymphoma (NHL), and has high activity when combined with chemotherapy. The purpose of this phase II study was to determine the efficacy and safety of rituximab plus cyclophosphamide, mitoxantrone, vincristine and prednisone (CNOP) chemotherapy in patients with indolent NHL. In all, 42 patients (median age 67 years) with previously untreated follicular, marginal zone or small lymphocytic/lymphoplasmacytic NHL received six infusions of rituximab (375 mg/m²) in combination with six cycles of CNOP. The overall response rate was 90% comprising 30 complete (71%) and eight partial (19%) responses. Although patients with marginal zone lymphoma or International Prognostic Index (IPI) score 3 had lower complete response rates, no significant difference in overall response rate was observed between the histological groups (P = 0.24) or between patients stratified according to IPI score (P>0.05). Median overall survival, time-to-progression and response duration had not been reached after a median 19.5-month follow-up. In all, 31 patients (74%) are currently free from progression and 38 (90%) remain alive. Treatment was well tolerated. One patient (2% experienced grade 3/4 infusion-related toxicity; 13 (31%) grade 3/4 leukopenia and 18 (43%) grade 3/4 neutropenia. Infection was observed in nine patients: eight (19%) grade 1/2 and one (2.4%) grade 3. This study demonstrates that combining rituximab with CNOP achieves high remission rates without significant additional toxicity in patients with previously untreated indolent NHL. Further follow-up will

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determine response duration and survival. CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

2 (Phase 2, Erstlinie) 2/52 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2003197250 AU: Schriever F; Huhn D Titel: New directions in the diagnosis and treatment of chronic lymphocytic leukaemia Quelle: Drugs; VOL: 63 (10); p. 953-969 /2003/ Sprache: ENGLISH AL: ENGLISH CY: New Zealand ISSN: 0012-6667 CO: DRUGA Corporate Source:

Dr. F. Schriever, Gartenstr. 26, 85456 Wartenberg Germany [email protected]

COU: Germany DT: Journal RN: 0108 DN: fk 228; fr 901228 TE: rituximab/174722-31-7; alemtuzumab/216503-57-0; chlorambucil/305-03-3;

prednisone/53-03-2; cyclophosphamide/50-18-0; vincristine/57-22-7; doxorubicin/23214-92-8; doxorubicin/25316-40-9; fludarabine/21679-14-1; cladribine/4291-63-8; bendamustine/16506-27-7; bendamustine/3543-75-7; fr 901228/128517-07-7; bryostatin 1/83314-01-6; flavopiridol/146426-40-6; CD40 ligand/226713-27-5

CR: 174722-31-7; 216503-57-0; 305-03-3; 53-03-2; 50-18-0; 57-22-7; 23214-92-8; 25316-40-9; 21679-14-1; 4291-63-8; 16506-27-7; 3543-75-7; 128517-07-7; 83314-01-6; 146426-40-6; 226713-27-5

AB: Chronic lymphocytic leukaemia (CLL) is the most common leukaemia of adults in Western countries. It is a systemic haematological malignancy that originates from B cells (B-CLL) in 95% of patients, while only a minority are derived through malignant transformation of T cells (T-CLL). Although B-CLL is classified as a non-Hodgkin's lymphoma, several issues make this leukaemia a unique entity among malignant lymphoma. Inhibition of the programmed cell death (apoptosis) and upregulation of the anti-apoptotic protein Bcl-2 are key elements of the pathophysiology of B-CLL cells and define clinical prognosis. Furthermore, B-CLL cells are arrested in G0/G1 phase of the cell cycle. Dysfunctional apoptosis and cell cycle are the main reasons for the clinical enigma, that CLL can not yet be cured with conventional chemotherapy. However, the molecular pathways that are responsible for this characteristic feature of the B-CLL cells still need further definition. Recently, considerable progress has been made in defining the molecular basis for the

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pathogenesis of CLL and in finding new therapeutic options. Recent studies indicate that B-CLL cells may be delineated from two main groups of normal B cells, i.e. pre- and postgerminal B cells, and can be distinguished through lack of or existence of mutations of the V heavy chain gene. This differential mutational status of the Ig V gene has significant impact on patient survival. Modern cytogenetic methods such as fluorescence in situ hybridisation (FISH) have opened a new era in the molecular analysis of CLL cells. Determining the chromosomal aberration of the leukaemic cells has become a standard scientific programme for each clinical trial. The cytogenetic profile may soon help to define a clinical risk profile and guide the various treatment strategies. Further progress has been made in the therapy of CLL. Purine analogues such as fludarabine were able to induce significant improvement in remission rates; however, they did not lead to improved survival. Chimera of murine or rat monoclonal antibodies and human antibodies were designed to treat CLL. Antibodies such as rituximab and alemtuzumab (Campath-1H), directed against CD20 and CD52, respectively, appear as attractive alternatives to conventional chemotherapy because of their lack of significant myelotoxicity. Studies using myeloablative chemotherapy followed by autologous or allogeneic stem cell transplantation were initiated with the hope of finding a cure for CLL. In contrast to autologous stem cell transplantation, allogeneic transplants appear to display a plateau of relapse rates. In conclusion, for many years CLL was considered as a chronic haematological malignancy that required only few diagnostic tools and for whom no hope of cure could be offered. The current review focuses on recent improvements in diagnosis and treatment of CLL that have opened a new era in the management of patients with this systemic malignancy.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

4, 6 2/53 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2003040517 AU: Roberts JD; Smith MR; Feldman EJ; Cragg L; Grant S Titel: Phase I study of bryostatin-1 and fludarabine in patients with chronic lymphocytic

leukemia and indolent non-Hodgkin's lymphoma Quelle: Clinical Lymphoma; VOL: 3 (3); p. 184-188 /2002/ Sprache: ENGLISH CY: United States ISSN: 1526-9655 CO: CLLYA Corporate Source:

Dr. J.D. Roberts, Massey Cancer Center, Virginia Commonwealth University, Department of Internal Medicine, PO Box 980037, Richmond, VA 23298-0037 United States [email protected]

COU: United States DT: Journal RN: 0039

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TE: bryostatin 1/83314-01-6; fludarabine/21679-14-1; cladribine/4291-63-8; rituximab/174722-31-7; alemtuzumab/216503-57-0; ibritumomab tiuxetan/206181-63-7; gamma interferon/82115-62-6; protein bcl 2/219306-68-0; prednisone/53-03-2; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5; doxorubicin/23214-92-8; doxorubicin/25316-40-9; cyclophosphamide/50-18-0; etoposide/33419-42-0; cytarabine/147-94-4; cytarabine/69-74-9; bleomycin/11056-06-7; vincristine/57-22-7; methylprednisolone/6923-42-8; methylprednisolone/83-43-2; platinum/7440-06-4; protein kinase C/141436-78-4; creatinine/19230-81-0; creatinine/60-27-5; uric acid/69-93-2; lactate dehydrogenase/9001-60-9

CR: 83314-01-6; 21679-14-1; 4291-63-8; 174722-31-7; 216503-57-0; 206181-63-7; 82115-62-6; 219306-68-0; 53-03-2; 15475-56-6; 59-05-2; 7413-34-5; 23214-92-8; 25316-40-9; 50-18-0; 33419-42-0; 147-94-4; 69-74-9; 11056-06-7; 57-22-7; 6923-42-8; 83-43-2; 7440-06-4; 141436-78-4; 19230-81-0; 60-27-5; 69-93-2; 9001-60-9

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

1 2/54 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2003028147 AU: Uppenkamp M; Engert A; Diehl V; Bunjes D; Huhn D; Brittinger G Titel: Monoclonal antibody therapy with CAMPATH-1H in patients with relapsed high- and

low-grade non-Hodgkin's lymphomas: A multicenter phase I/II study Quelle: Annals of Hematology; VOL: 81 (1); p. 26-32 /2002/ Sprache: ENGLISH AL: ENGLISH CY: Germany ISSN: 0939-5555 CO: ANHEE Corporate Source:

M. Uppenkamp, Medizinische Klinik A, Klin. der Stadt Ludwigshafen gGmbH, Bremserstr. 79, 67063 Ludwigshafen Germany [email protected]

COU: Germany DT: Journal RN: 0033 DN: campath 1h/Medac,Germany MN: Medac,Germany; Medac TE: alemtuzumab/216503-57-0; chlorambucil/305-03-3; prednisone/53-03-2;

cyclophosphamide/50-18-0; vincristine/57-22-7; doxorubicin/23214-92-8; doxorubicin/25316-40-9; ifosfamide/3778-73-2; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5; etoposide/33419-42-0; dexamethasone/50-02-2; carmustine/154-93-8; melphalan/148-82-3; cytarabine/147-94-4; cytarabine/69-74-9; idarubicin/57852-57-0; idarubicin/58957-92-9; fludarabine/21679-14-1; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3;

Page 184: Fludara i.v. (2nd line NHL)

cyclosporin/79217-60-0; paracetamol/103-90-2; clemastine/15686-51-8; pethidine/28097-96-3; pethidine/50-13-5; pethidine/57-42-1; aciclovir/59277-89-3

CR: 216503-57-0; 305-03-3; 53-03-2; 50-18-0; 57-22-7; 23214-92-8; 25316-40-9; 3778-73-2; 15475-56-6; 59-05-2; 7413-34-5; 33419-42-0; 50-02-2; 154-93-8; 148-82-3; 147-94-4; 69-74-9; 57852-57-0; 58957-92-9; 21679-14-1; 65271-80-9; 70476-82-3; 79217-60-0; 103-90-2; 15686-51-8; 28097-96-3; 50-13-5; 57-42-1; 59277-89-3

AB: CAMPATH-1H (CP-1H) is a humanized monoclonal antibody directed against the CD52 antigen with promising therapeutic effects in patients with small cell lymphocytic non-Hodgkin's lymphomas (NHL) of B- and T-cell type. We report about the response and toxicity of CP-1H in 18 patients with B-cell NHL who were treated in four clinical centers in Germany. Sixteen patients suffered from a low-grade and two from a high-grade NHL. All patients had received chemotherapy before and had either relapsed or were refractory to conventional therapy. Two patients received CP-1H in a dose-range finding trial once weekly and 16 patients as a fixed dose of 30 mg three times weekly. Of 18 patients, 8 (44%) achieved a clinical response, 2 (11%) had stable disease, and 5 (28%) had progressive disease. Four patients could not be evaluated for response because of death (two patients) and serious adverse events (two patients). All patients with response to CP1-H had a low-grade NHL. Nonhematological toxicity was severe in two patients who suffered from WHO grade III/IV bronchospasm. Common acute adverse events (WHO grade I-III) included fever, chills, rigor, urticaria, nausea, and vomiting. Eleven patients suffered from bacterial or viral infections; some had recurrent infections. A total of 12 different infections were reported. The most frequent infections were caused by herpesvirus (seven patients). Hematological toxicity included thrombocytopenia in four and lymphocytopenia in seven patients. Although the antibody is humanized, the nonhematological toxicity was substantial and probably due to a cytokine release syndrome. Prophylactic treatment of the side effects is strongly recommended for patients treated either with CP-1H alone or in combination with chemotherapy.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles Pharmacy

3 2/55 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2003009645 AU: Klasa RJ; Meyer RM; Shustik C; Sawka CA; Smith A; Guéin R; Maksymiuk A;

Rubinger M; Samosh M; Laplante S; Grenier J-F Titel: Randomized phase III study of fludarabine phosphate versus cyclophosphamide,

vincristine, and prednisone in patients with recurrent low-grade non-Hodgkin's lymphoma previously treated with an alkylating agent or alkylator-containing regimen

Quelle: Journal of Clinical Oncology; VOL: 20 (24); p. 4649-4654 /15 DEC 2002/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND

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Corporate Source:

R.J. Klasa, Division of Medical Oncology, British Columbia Cancer Agency, 600 W 10th Ave, Vancouver, BC V5Z 4E6 Canada [email protected]

COU: Canada DT: Journal RN: 0033 TE: fludarabine/21679-14-1; cyclophosphamide/50-18-0; vincristine/57-22-7;

prednisone/53-03-2 CR: 21679-14-1; 50-18-0; 57-22-7; 53-03-2 AB: Purpose: To compare in a phase III study the safety and efficacy of fludarabine to

that of cyclophosphamide, vincristine, and prednisone (CVP) in recurrent, low-grade, non-Hodgkin's lymphoma after previous response to systemic treatment. Patients and Methods: Patients were randomized to fludarabine (25 mg/m² intravenously on days 1 to 5, every 28 days) or CVP (cyclophosphamide 750 mg/m² and vincristine 1.2mg/m² both intravenously on day 1 and prednisone 40 mg/m² orally on days 1 to 5, every 21 days). The primary outcome assessed was progression-free survival (PFS); secondary outcomes included treatment-free survival (TFS), overall survival (OS), treatment-related toxicity, and quality of life (QoL) according to the European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire C-30 version 1.0 instrument. Results: Ninety-one patients were randomized, 47 to fludarabine and 44 to CVP. There was no difference in response rates, with 64% (complete response [CR], 9%) for fludarabine versus 52% (CR, 7%) for CVP (P = .72). With a median follow-up of 42 months, median PFS (11 months v 9.1 months; P = .03) and TFS (15 months v 11 months; P = .02) were superior in patients receiving fludarabine. No difference in median overall survival was detected (57 months for fludarabine v 44 months for CVP; P = .95). Three patients receiving fludarabine died of treatment-related toxicity compared with none of the patients receiving CVP. Peripheral neuropathy and alopecia were more common with CVP. Patients receiving fludarabine had higher scores for social function (P = .008); no other differences in QoL were detected. Conclusion: In recurrent low-grade lymphoma, fludarabine improves PFS, TFS, and social function scores in comparison with CVP but does not improve OS. © 2002 by American Society of Clinical Oncology.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

1 2/56 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2002432224 AU: Eucker J; Schille C; Schmid P; Jakob C; Schetelig J; Kingreen D; Mergenthaler H-G;

Huhn D; Possinger K; Sezer O Titel: The combination of fludarabine and cyclophosphamide results in a high remission

rate with moderate toxicity in low-grade non-Hodgkin's lymphomas Quelle: Anti-Cancer Drugs; VOL: 13 (9); p. 907-913 /01 OCT 2002/ Sprache: ENGLISH AL: ENGLISH

Page 186: Fludara i.v. (2nd line NHL)

CY: United Kingdom ISSN: 0959-4973 CO: ANTDE Corporate Source:

O. Sezer, Department of Hematology, Universitätsklinikum Charite, 10098 Berlin Germany [email protected]

COU: Germany DT: Journal RN: 0023 TE: fludarabine/21679-14-1; cyclophosphamide/50-18-0 CR: 21679-14-1; 50-18-0 AB: We undertook a prospective study to evaluate the role of the combination of

fludarabine and cyclophosphamide in patients with low-grade non-Hodgkin's lymphoma. Twenty-seven patients with low-grade non-Hodgkin's lymphoma were treated with i.v. fludarabine (30 mg/m²) and cyclophosphamide (250 mg/m²) on days 1-3. Cycles were given at 4-week intervals for a maximum of six courses. Fourteen patients (52%) were previously untreated, 13 patients (48%) had been treated with at least one chemotherapy regimen before. Of the 27 patients, 11 (41%) obtained a complete and 13 (48%) a partial remission, thus the overall response rate was 89%. The remission rate in untreated patients was slightly higher than in pretreated patients (93 versus 85%). The toxicity was mild, no treatment-related mortality occurred. Neutropenia was the most common side effect, grade 4 neutropenia of rather short duration was observed in less than 7% of the cycles. At the end of the treatment, the mean CD4(sup(÷)) count was 155/µl and the mean CD8(sup(÷)) count 204/µl. Severe infections did not occur. These results show that the combination of fludarabine and cyclophosphamide in the doses used in this study is an effective regimen with manageable toxicity in low-grade non-Hodgkin's lymphoma. © 2002 Lippincott Williams & Wilkins.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

1 2/57 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2002425983 AU: Cowan RA; Murby B; Gunton D; Owens SE; Hoyes KP; Sharma HL; Smith A-M;

Chang J; Van Kessel B; Nuttall PM; Crowther D Titel: Autologous lymphocytes as vectors to target therapeutic radiation, using indium-

114m, in patients with lymphoid cell malignancy Quelle: British Journal of Haematology; VOL: 119 (2); p. 459-466 /2002/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 0007-1048 CO: BJHEA

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Corporate Source:

R.A. Cowan, Department of Clinical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX United Kingdom [email protected]

COU: United Kingdom DT: Journal RN: 0023 TE: indium 114m/13981-55-0; indium/7440-74-6; chlorambucil/305-03-3;

cyclophosphamide/50-18-0; vincristine/57-22-7; prednisone/53-03-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; fludarabine/21679-14-1

CR: 13981-55-0; 7440-74-6; 305-03-3; 50-18-0; 57-22-7; 53-03-2; 23214-92-8; 25316-40-9; 21679-14-1

AB: Autologous lymphocytes provide a potential vector for the delivery of a cytotoxic agent in patients with lymphoid cell malignancy. This report describes a phase I-II study using autologous lymphocytes to target the radionuclide indium-114m ((sup(114m))In) in patients with refractory chronic lymphocytic leukaemia or small lymphocytic non-Hodgkin's lymphoma. Nineteen patients, the majority of whom had been heavily pretreated with conventional chemotherapy and radiotherapy, received between 69 and 211 MBq (sup(114m))In-labelled autologous lymphocytes. Approximately 80% of the administered activity was localized in the liver and spleen, with around 5% accumulating in the bone marrow. Ten patients (53%) responded (one complete response and nine partial responses). The median duration of response was 7 months. The median survival for the responders was 14 months and for the non-responders was 3 months. The first notable response in every patient was a fall in peripheral lymphocyte count. The indium treatment was not associated with any subjective toxicity, although all patients suffered from myelosuppression, with thrombocytopenia being the dose-limiting factor. This study has demonstrated a significant anti-tumour effect in a group of patients with late-stage highly resistant disease.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Nuclear Medicine Hematology Drug Literature Index Adverse Reactions Titles

3 2/58 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2002285313 AU: Lynch JW; Hei DL; Braylan RC; Rimzsa LM; Staab EV; Bewsher CJ; Mendenhall NP;

Hudson JK Titel: Phase II study of fludarabine combined with interferon-alpha-2a followed by

maintenance therapy with interferon-alpha-2a in patients with low-grade non-Hodgkin's lymphoma

Quelle: American Journal of Clinical Oncology: Cancer Clinical Trials; VOL: 25 (4); p. 391-397 /2002/

Sprache: ENGLISH AL: ENGLISH

Page 188: Fludara i.v. (2nd line NHL)

CY: United States ISSN: 0277-3732 CO: AJCOD Corporate Source:

Dr. J.W. Lynch, Division of and Oncology, Department of Medicine, Univ. of Florida College of Medicine, P.O. Box 100277, Gainesville, FL 32610 United States

COU: United States DT: Journal RN: 0027 DN: fludara/Berlex,United States; roferon a/Hoffmann La Roche,United States MN: Berlex,United States; Berlex; Hoffmann La Roche,United States; Hoffmann La RocheTE: fludarabine/21679-14-1; alpha2a interferon/76543-88-9; fludarabine

phosphate/75607-67-9 CR: 21679-14-1; 76543-88-9; 75607-67-9 AB: Randomized trials suggest improved disease-free survival in low-grade non-

Hodgkin's lymphoma (LGNHL) when interferon is combined with multiagent chemotherapy. This phase II trial was conducted to investigate the feasibility of combining fludarabine monophosphate (fludarabine) and IFN in a regimen for treatment of LGNHL. Twenty-one patients were evaluable. Median age was 55 years, and patients had been treated with an average of 1.7 chemotherapy regimens before enrollment. Patients received 25 mg/m² of fludarabine intravenously on days 1 through 5 followed by 2 × 10(sup(6)) U/m² of interferon-alpha-2a subcutaneously on days 22 through 26. Cycles were repeated every 4 weeks with delays and dose modifications for significant cytopenias. Patients were restaged after cycles 4 and 8, and those with at least a partial response to therapy were given maintenance therapy consisting of 2 × 10(sup(6)) U/m² interferon-alpha-2a subcutaneously three times per week for 6 months. The overall response rate was 76% with a 25% complete response (CR) rate. Overall response rates were 75% (3/4 with 2 CR's) for chemotherapy-naive patients and 76% (13/17 with 3 CR's) for previously treated patients. Median time to progression was 12 months, and currently two patients are without evidence of progression at a median follow-up of 55 months. Grade III or greater toxicities included neutropenia (39%), anemia (17%), thrombocytopenia (5%), fevers/chills (5%), and fatigue (5%). Fludarabine and interferon can be effectively and safely combined in a regimen with significant activity against LGNHL. A modification of this regimen may be suitable for further study.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

1 2/59 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2002149464 AU: Tsimberidou AM; O'Brien SM; Cortes JE; Faderl S; Andreeff M; Kantarjian HM;

Keating MJ; Giles FJ Titel: Phase II study of fludarabine, cytarabine (ara-C), cyclophosphamide, cisplatin and

GM-CSF (FACPGM) in patients with Richter's syndrome or refractory

Page 189: Fludara i.v. (2nd line NHL)

lymphoproliferative disorders Quelle: Leukemia and Lymphoma; VOL: 43 (4); p. 767-772 /2002/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 CO: LELYE Corporate Source:

F.J. Giles, Department of Leukemia, University of Texas, M.D. Anderson Cancer Center, 1400 Holcombe Boulevard, Houston, TX 77030 United States [email protected]

COU: United States DT: Journal RN: 0036 TE: fludarabine/21679-14-1; cytarabine/147-94-4; cytarabine/69-74-9;

cyclophosphamide/50-18-0; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; fluconazole/86386-73-4; aciclovir/59277-89-3; cotrimoxazole/8064-90-2

CR: 21679-14-1; 147-94-4; 69-74-9; 50-18-0; 15663-27-1; 26035-31-4; 96081-74-2; 86386-73-4; 59277-89-3; 8064-90-2

AB: A phase II study was conducted to evaluate the safety and efficacy of fludarabine, cytarabine (ara-C), cyclophosphamide, cisplatin and GM-CSF (FACPGM) treatment in patients with Richter's syndrome (RS), refractory prolymphocytic leukemia (PLL) or refractory non-Hodgkin's lymphoma (NHL). Twenty-two patients with RS, refractory PLL, or refractory NHL were entered into this trial between March 1997 and February 2001. Median age was 62 years (42-74); 77% were over 60 years of age. Histologic diagnosis was large cell NHL transformation in 15 patients with CLL, immunoblastic transformation of CLL in one, refractory PLL in three, and refractory NHL in three patients. Treatment consisted of fludarabine 30 mg/m² (days 1-3), ara-C 0.5 g/m² (days 3-4), cyclophosphamide 250 mg/m² (days 2-4), cisplatin 15 mg/m² IV CI (days 1-4) with GM-CSF 250 µg/m² from day 5 to recovery of neutrophils and antibiotic prophylaxis. Patients with response were to receive a maximum of six cycles of therapy. Eighteen patients were evaluable for response; one patient achieved a complete remission (5%), 12 stable disease/no response (67%) and five patients had progressive disease (28%). The median survival was 2.2 months (range, 1-19); the median failure-free survival was 1.5 months (range, 0.5-18.6). Grade III/IV toxicities were as follows: anemia in 62% of cycles; leucopoenia in 66%; granulocytopenia in 90%; thrombocytopenia in 83%; hyperbilirubinemia in 14%; hyperuricemia in 17%; hyponatremia in 17%; hypokalemia in 14%; hypophosphatemia in 10%; hypoalbulinemia in 14%; hypocalcemia in 7%; and hypercalcemia in 3%. One (3%) patient developed cardiac failure. Forty-one percent of the cycles were complicated with fever, 34% with non-neutropenic fever, and 55% cycles with infections (fungal 31%; bacterial 57%; HSV 6%; VZV 6%). FACPGM had very limited activity and significant toxicity in a cohort of patients with heavily pretreated refractory lymphoproliferative disorders.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

Page 190: Fludara i.v. (2nd line NHL)

1 2/60 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2002139565 AU: Wilder DD; Ogden JL; Jain VK Titel: Efficacy of fludarabine/mitoxantrone/dexamethasone alternating with CHOP in bulky

follicular non-Hodgkin's lymphoma Quelle: Clinical Lymphoma; VOL: 2 (4); p. 229-237 /2002/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1526-9655 CO: CLLYA Corporate Source:

Dr. V.K. Jain, Baylor-Charles A. Sammons Cancer Ctr, Baylor University Medical Center, 3535 Worth Street, Dallas, TX 75246 United States [email protected]

COU: United States DT: Journal RN: 0025 DN: filgrastim; roferon TE: fludarabine/21679-14-1; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3;

dexamethasone/50-02-2; cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2; beta 2 microglobulin/9066-69-7; teniposide/29767-20-2; cotrimoxazole/8064-90-2; recombinant granulocyte colony stimulating factor/121181-53-1; etoposide/33419-42-0; chlormethine/51-75-2; chlormethine/55-86-7; chlormethine/82905-71-3; procarbazine/366-70-1; procarbazine/671-16-9; rituximab/174722-31-7; ibritumomab tiuxetan/206181-63-7

CR: 21679-14-1; 65271-80-9; 70476-82-3; 50-02-2; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2; 9066-69-7; 29767-20-2; 8064-90-2; 121181-53-1; 33419-42-0; 51-75-2; 55-86-7; 82905-71-3; 366-70-1; 671-16-9; 174722-31-7; 206181-63-7

AB: This phase II study investigated the efficacy of alternating fludarabine/mitoxantrone/dexamethasone (FMD) with cyclophosphamide/doxorubicin/ vincristine/prednisone (CHOP) chemotherapy for patients with high tumor burden, follicular non-Hodgkin's lymphoma. Maintenance interferon was given in a nonrandomized fashion, and a retrospective analysis of its impact was performed. A total of 87 patients were included (44 females and 43 males). The median age of patients was 56 years (range, 25-86 years). All patients had high tumor burden as defined by the Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria. Eighty-four percent of patients (73/87) had stage III/IV disease and 99% of patients (86/87) had good performance status. The majority of patients had not been previously treated, with only 3 patients receiving prior oral alkylators or cyclophosphamide/vincristine/prednisone (COP). A total of 637 cycles of FMD/CHOP were administered and were well tolerated during this trial, the majority on an outpatient basis. The overall response rate was 95% (79 complete response/unconfirmed complete response/partial response) in the 83 evaluable patients. Event-free survival (EFS) was 28.7 months, with time to progression (TTP)

Page 191: Fludara i.v. (2nd line NHL)

at 29 months and time to treatment failure at 41 months. Overall survival was not reached. Patients had similar EFS and TTP as patients in the French GELF trial with a shorter duration of chemotherapy. Patients with a lower International Prognostic Index (IPI) score had better EFS when compared to those with a higher IPI score (median EFS not reached versus 22.6 months). Serum beta(sub(2))-microglobulin levels were not a significant predictive factor. An informal analysis of interferon maintenance therapy suggests that patients who tolerated the immune modifier did better than those who did not. Alternating FMD/CHOP is a feasible and effective therapeutic option for patients with high tumor burden, low-grade non-Hodgkin's lymphoma. While this regimen may not offer dramatic benefit over FMD alone, it is beneficial in those patients for whom a prompt treatment response is needed.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

1 2/61 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2002077937 AU: Hainsworth JD Titel: Rituximab as first-line and maintenance therapy for patients with indolent non-

Hodgkin's lymphoma: Interim follow-up of a multicenter phase II trial Quelle: Seminars in Oncology; VOL: 29 (1); p. 25-29 /2002/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0093-7754 CO: SOLGA Corporate Source:

Dr. J.D. Hainsworth, Sarah Cannon Cancer Center, Atrium, 250 25th Ave North, Nashville, TN 37203 United States

COU: United States DT: Journal RN: 0008 DN: rituxan/Genentech,United States; rituxan/Idec,United States MN: Genentech,United States; Genentech; Idec,United States; Idec TE: rituximab/174722-31-7; chlorambucil/305-03-3; fludarabine/21679-14-1;

cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2

CR: 174722-31-7; 305-03-3; 21679-14-1; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2

AB: The purpose of this study is to evaluate the activity of rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceuticals, San Diego, CA) in the first-line treatment of patients with indolent non-Hodgkin's lymphoma, and to evaluate the role of scheduled maintenance courses of rituximab in prolonging duration of

Page 192: Fludara i.v. (2nd line NHL)

remission. Sixty-two patients with stages II to IV indolent non-Hodgkin's lymphoma (follicular or small lymphocytic) who had received no previous systemic therapy entered this multicenter, community-based trial. All patients received rituximab 375 mg/m² weekly for 4 consecutive weeks, and were evaluated for response at week 6. Patients who had an objective response or stable disease continued treatment every 6 months with repeat 4-week courses of rituximab for a total of four treatment courses. Interim results of this ongoing trial are available. When evaluated at week 6, 28 of 60 evaluable patients (47%) had objective response and 27 patients (45%) had minor response or stable disease. With further follow-up and repeat courses of rituximab, the major response rate increased from 47% to 65% and the complete response rate increased from 7% to 27%. Response rates were similar in patients with follicular lymphoma and small lymphocytic lymphoma (63% and 66%, respectively). Median progression-free survival has not been reached, but will be greater than 24 months. There has been no cumulative toxicity observed with repeat courses of rituximab. Rituximab is highly effective as a first-line single agent for the treatment of indolent non-Hodgkin's lymphoma. The initial response rate can be improved by using scheduled maintenance courses of rituximab administered every 6 months. Final information regarding duration of response and time to progression awaits further follow-up. Copyright © 2002 by W.B. Saunders Company.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index

3 2/62 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2002058606 AU: Seymour JF; Grigg AP; Szer J; Fox RM Titel: Cisplatin, fludarabine, and cytarabine: A novel, pharmacologically designed salvage

therapy for patients with refractory, histologically aggressive or mantle cell non-Hodgkin lymphoma

Quelle: Cancer; VOL: 94 (3); p. 585-593 /01 FEB 2002/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0008-543X CO: CANCA Corporate Source:

J.F. Seymour, Leukemia/Lymphoma Service, Department of Hematology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett Street, East Melbourne, Vic. 8006 Australia [email protected]

COU: Australia DT: Journal RN: 0051 TE: cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; fludarabine/21679-

14-1; cytarabine/147-94-4; cytarabine/69-74-9 CR: 15663-27-1; 26035-31-4; 96081-74-2; 21679-14-1; 147-94-4; 69-74-9

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AB: BACKGROUND. Based on in vitro synergism, the combination of cytarabine (ara-C) and cisplatin is the basis of many salvage regimens for patients with aggressive non-Hodgkin lymphoma (NHL). However, patients with previously refractory disease are significantly less likely to respond, stimulating the search for novel salvage regimens. In vitro, fludarabine enhances the cytotoxicity of both ara-C and cisplatin, increasing ara-C incorporation into DNA and inhibiting repair of platinum/DNA adducts, suggesting that the combination of cisplatin, fludarabine, and ara-C (PFA) may have clinical utility. METHODS. A Phase-II study of a 96-hour continuous infusion of cisplatin with two timed-sequential couplets of fludarabine and ara-C together with granulocytecolony stimulating factor was performed in 45 patients with previously refractory, histologically aggressive or mantle cell NHL. RESULTS. Patients had predominantly diffuse large cell and/or immunoblastic NHL or its variants (80%), or they had mantle cell lymphoma (18%). Overall, 93% of patients had previously refractory disease, with a median International Prognostic Index score of 3. A median of 2 cycles per patient were delivered (range, 1-4 cycles) with significant myelosuppression; there were medians of 2 days of neutropenia < 0.5 × 10(sup(9))/L (range, 0-12 days) and 3 days of thrombocytopenia < 20 × 10(sup(9))/L (range, 0-24 days). This was more severe in older patients and was cumulative with successive cycles. Thirty-five percent of cycles were complicated by infections, nausea and emesis were prominent, but other nonhematologic toxicity was mild. Peripheral blood progenitor cells were mobilized adequately after the first cycle, but collections were impaired after more prolonged therapy. The overall response rate was 48% (7% of patients had complete responses, and 41% of patients had partial responses), with one toxic death due to tumor-lysis syndrome. Patients with mantle cell lymphoma were more likely to respond than patients with other histologies (88% vs. 39%, respectively; P = 0.019), although three of eight patients had relapsed rather than refractory disease. The median remission duration was 4 months, with 28% of potentially eligible patients able to proceed to subsequent high-dose therapy. The actuarial 2-year survival rates were 20% ± 6% overall and 50 ± 18% for patients with mantle cell lymphoma. CONCLUSIONS. Given the adverse outlook for these patients, the results are promising, particularly for patients with mantle cell lymphoma, and suggest that the addition of fludarabine as a potential biochemical modulator may enhance the activity of cisplatin and ara-C. This is associated with significant cumulative (but manageable) myelosuppression. This paradigm, in which a nuceloside analogue is used to inhibit the repair of platinum/DNA adducts, also may be applicable for the treatment of patients with other types of platinum-sensitive tumors. © 2002 American Cancer Society.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

1 2/63 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2002034390 AU: Emmanouilides C; Territo M; Andrey J; Mason J Titel: A randomized phase II study of amifostine used as stem cell protectant in non-

Hodgkin lymphoma patients receiving cisplatin-based salvage chemotherapy prior to stem cell transplant

Quelle: Journal of Hematotherapy and Stem Cell Research; VOL: 10 (6); p. 887-893 /2001/ Sprache: ENGLISH

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AL: ENGLISH CY: United States ISSN: 1525-8165 CO: JHERF Corporate Source:

Dr. C. Emmanouilides, 42-121 CHS, UCLA, Division of Hematology Oncology, 10833 Le Conte Avenue, Los Angeles, CA 90095 United States [email protected]

COU: United States DT: Journal RN: 0037 MN: Alza TE: amifostine/20537-88-6; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-

74-2; cytarabine/147-94-4; cytarabine/69-74-9; dexamethasone/50-02-2; recombinant granulocyte colony stimulating factor/121181-53-1; granisetron/107007-99-8; granisetron/109889-09-0; ondansetron/103639-04-9; ondansetron/116002-70-1; ondansetron/99614-01-4; famotidine/76824-35-6; fludarabine/21679-14-1; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; cladribine/4291-63-8; ifosfamide/3778-73-2; etoposide/33419-42-0

CR: 20537-88-6; 15663-27-1; 26035-31-4; 96081-74-2; 147-94-4; 69-74-9; 50-02-2; 121181-53-1; 107007-99-8; 109889-09-0; 103639-04-9; 116002-70-1; 99614-01-4; 76824-35-6; 21679-14-1; 65271-80-9; 70476-82-3; 4291-63-8; 3778-73-2; 33419-42-0

AB: Stem cell mobilization may be inadequate in many lymphoma patients in need for autologous stem cell transplant (SCT). In this study, we sought to evaluate a potential role of amifostine as a stem cell chemoprotective agent in lymphoma patients receiving DHAP chemotherapy in preparation for high-dose chemotherapy (HDC) and stem cell transplant (SCT). In the beginning of the DHAP course, patients were randomized 1:1 to receive amifostine at 740 mg/m². Stem cells were mobilized with GCSF after the last cycle of DHAP. Stem cell collection started upon ANC recovery over 1000/mm³. Standard 10 lt. apheresis daily with a goal of a minimum of 2 × 10(sup(6)) stem cells/kg were performed. Twenty-one patients have been enrolled; 10 received amifostine pretreatment (age, 20-64) and 11 were randomized to the control arm (age, 18-63). Prior chemotherapy was balanced in the two groups. The median number of DHAP treatments for each group was 2. Amifostine was well tolerated and was associated with higher stem cell collection. Toxicity and time to engraftment were comparable between the two groups. Our preliminary results may suggest a role of amifostine in protecting stem cells during salvage chemotherapy, thus facilitating stem cell collection.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

3 2/64 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2001382514

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AU: McCune SL; Gockerman JP; Rizzieri DA Titel: Monoclonal antibody therapy in the treatment of non-hodgkin lymphoma Quelle: Journal of the American Medical Association; VOL: 286 (10); p. 1149-1152 /12 SEP

2001/ Sprache: ENGLISH CY: United States ISSN: 0098-7484 CO: JAMAA Corporate Source:

Dr. D.A. Rizzieri, Division of Oncology, Duke University Medical Center, Box 3961 North Pavilion, 2400 Pratt St, Durham, NC 27710 United States [email protected]

COU: United States DT: Journal RN: 0031 TE: rituximab/174722-31-7; alemtuzumab/216503-57-0; yttrium 90/10098-91-6;

ibritumomab tiuxetan/206181-63-7; tositumomab/208921-02-2; iodine 131/10043-66-0; iodine 131/15124-39-7; abciximab/143653-53-6; interleukin 2 receptor antibody/179045-86-4; OKT 3/140608-64-6; palivizumab/188039-54-5; infliximab/170277-31-3; trastuzumab/180288-69-1; fludarabine/21679-14-1; cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2

CR: 174722-31-7; 216503-57-0; 10098-91-6; 206181-63-7; 208921-02-2; 10043-66-0; 15124-39-7; 143653-53-6; 179045-86-4; 140608-64-6; 188039-54-5; 170277-31-3; 180288-69-1; 21679-14-1; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Internal Medicine

Cancer Hematology Drug Literature Index Adverse Reactions Titles

3, 6 2/65 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2001344888 AU: Kaminski MS; Zelenetz AD; Press OW; Saleh M; Leonard J; Fehrenbacher L; Lister

TA; Stagg RJ; Tidmarsh GF; Kroll S; Wahl RL; Knox SJ; Vose JM Titel: Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or

transformed low-grade B-cell non-Hodgkin's lymphomas Quelle: Journal of Clinical Oncology; VOL: 19 (19); p. 3918-3928 /01 OCT 2001/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND Corporate Dr. M.S. Kaminski, University of Michigan Cancer Center, 1500 E Medical Center Dr,

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Source: Ann Arbor, MI 48109-0936 United States [email protected]

COU: United States DT: Journal RN: 0031 DN: bexxar/Corixa,United States; bexxar/Glaxo,United States; bexxar/Smith Kline and

French,United States MN: Corixa,United States; Corixa; Glaxo,United States; Glaxo; Smith Kline and

French,United States; Smith Kline and French; Pharmacia Upjohn,United States; Pharmacia Upjohn

TE: tositumomab i 131/192391-48-3; doxorubicin/23214-92-8; doxorubicin/25316-40-9; cyclophosphamide/50-18-0; fludarabine/21679-14-1; chlorambucil/305-03-3

CR: 192391-48-3; 23214-92-8; 25316-40-9; 50-18-0; 21679-14-1; 305-03-3 AB: Purpose: To evaluate the efficacy and safety of tositumomab and iodine I 131

tositumomab (Bexxar; Corixa Corp, Seattle, WA, and GlaxoSmithKline, Philadelphia, PA) in patients with chemotherapy-refractory low-grade or transformed low-grade non-Hodgkin's lymphoma (NHL) and to compare its efficacy to the patients' last qualifying chemotherapy (LQC) regimens. Patients and Methods: Sixty patients who had been treated with at least two protocol-specified qualifying chemotherapy regimens and had not responded or progressed within 6 months after their LQC were treated with a single course of iodine I 131 tositumomab. Results: Patients had received a median of four prior chemotherapy regimens. A partial or complete response (CR) was observed in 39 patients (65%) after iodine I 131 tositumomab, compared with 17 patients (28%) after their LQC (P < .001). The median duration of response (MDR) was 6.5 months after iodine I 131 tositumomab, compared with 3.4 months after the LQC (P < .001). Two patients (3%) had a CR after their LQC, compared with 12 (20%) after iodine I 131 tositumomab (P < .001). The MDR for CR was 6.1 months after the LQC and had not been reached with follow-up of more than 47 months after iodine I 131 tositumomab. An independent review panel verified that 32 (74%) of the 43 patients with nonequivalent durations of response (> 30 days difference) had a longer duration of response after iodine I 131 tositumomab (P < .001). Only one patient was hospitalized for neutropenic fever. Five patients (8%) developed human antimurine antibodies, and one (2%) developed an elevated TSH level after treatment. Myelodysplasia was diagnosed in four patients in follow-up. Conclusion: A single course of iodine I 131 tositumomab was significantly more efficacious than the LQC received by extensively pretreated patients with chemotherapy-refractory, low-grade, or transformed low-grade NHL and had an acceptable safety profile. © 2001 by American Society of Clinical Oncology.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Drug Literature Index Adverse Reactions Titles

3 2/66 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2001140182

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AU: Khorana A; Bunn P; McLaughlin P; Vose J; Stewart C; Czuczman MS Titel: A phase II multicenter study of CAMPATH-1H antibody in previously treated patients

with nonbulky non-Hodgkin's lymphoma Quelle: Leukemia and Lymphoma; VOL: 41 (1-2); p. 77-87 /2001/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 CO: LELYE Corporate Source:

Dr. M.S. Czuczman, Lymphoma Sec. Div. Hematol. Oncol., Bone Marrow Transplantation, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263 United States

COU: United States DT: Journal RN: 0025 DN: cytoxan; ara C; vp 16; novantrone TE: methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5;

bleomycin/11056-06-7; doxorubicin/23214-92-8; doxorubicin/25316-40-9; cyclophosphamide/50-18-0; vincristine/57-22-7; dexamethasone/50-02-2; prednisone/53-03-2; chlorambucil/305-03-3; fludarabine/21679-14-1; etoposide/33419-42-0; cytarabine/147-94-4; cytarabine/69-74-9; lomustine/13010-47-4; ifosfamide/3778-73-2; mesna/19767-45-4; mesna/3375-50-6; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; 5,6 dihydroazacitidine/62402-31-7; 5,6 dihydroazacitidine/62488-57-7

CR: 15475-56-6; 59-05-2; 7413-34-5; 11056-06-7; 23214-92-8; 25316-40-9; 50-18-0; 57-22-7; 50-02-2; 53-03-2; 305-03-3; 21679-14-1; 33419-42-0; 147-94-4; 69-74-9; 13010-47-4; 3778-73-2; 19767-45-4; 3375-50-6; 65271-80-9; 70476-82-3; 62402-31-7; 62488-57-7

AB: CAMPATH-1H is a humanized antilymphocyte monoclonal antibody (mAb) directed against the CD52 antigen expressed on normal and malignant lymphocytes. We report the results of a multicenter phase II trial using intravenous CAMPATH-1H in previously treated patients with nonbulky non-Hodgkin's lymphoma (NHL) or minimal residual NHL. Sixteen previously treated patients with nonbulky NHL and two patients with minimal residual NHL, were treated with CAMPATH-1H. Changes in peripheral blood lymphocyte subsets were analyzed by multiparameter flow cytometric techniques in eleven patients. The 18 patients enrolled in the studies received CAMPATH-1H for a median duration of 6 weeks (range, 3 to 14 weeks), and a median cumulative dose of 470 mg (range, 180 to 1185 mg). Two of the sixteen patients with nonbulky NHL achieved a complete response (CR) and one patient achieved a partial response (PR). One of the two patients with minimal residual NHL achieved a molecular CR. Infusional complications were seen with the majority of patients but were more common with initial infusions. Significant hematologic toxicity was also observed with grade 3/4 thrombocytopenia (n=10), grade 3/4 neutropenia (n=4) and grade 3 anemia (n=3). Due to excessive infectious complications observed with the patients enrolled, the trials were terminated early. Anti-tumor activity was demonstrated in a small subset of previously treated low-grade lymphoma patients with nonbulky or minimal residual disease. Future studies evaluating the effect of different drug schedules, modes of mAb administration, and concurrent use of prophylactic antibiotics/antiviral/antifungal agents to optimize anti-tumor activity and limit infectious toxicities are planned.

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CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Drug Literature Index Adverse Reactions Titles

3 2/67 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2001073331 AU: Grillo-López AJ Titel: Rituximab: An insider's historical perspective Quelle: Seminars in Oncology; VOL: 27 (6); p. 9-16 /2000/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0093-7754 CO: SOLGA Corporate Source:

Dr. A.J. Grillo-López, IDEC Pharmaceuticals, 3030 Callan Rd., San Diego, CA 92121United States

COU: United States DT: Journal RN: 0030 DN: orthoclone/Johnson and Johnson,United States; reopro/Centocor,United States;

rituxan/Genentech,United States; zevalin/Idec,United States; rituxan/Idec,United States; orthoclone/Ortho,United States; reopro/Lilly,United States; rituxan/Hoffmann La Roche,United States

MN: Johnson and Johnson,United States; Johnson and Johnson; Centocor,United States; Centocor; Genentech,United States; Genentech; Idec,United States; Idec; Ortho,United States; Ortho; Lilly,United States; Lilly; Hoffmann La Roche,United States; Hoffmann La Roche

TE: rituximab/174722-31-7; ibritumomab tiuxetan/206181-63-7; yttrium 90/10098-91-6; cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; prednisone/53-03-2; vincristine/57-22-7; fludarabine/21679-14-1; abciximab/143653-53-6

CR: 174722-31-7; 206181-63-7; 10098-91-6; 50-18-0; 23214-92-8; 25316-40-9; 53-03-2; 57-22-7; 21679-14-1; 143653-53-6

AB: Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA) is a unique monoclonal antibody for the treatment of non-Hodgkin's lymphoma. This chimeric mouse/human antibody was discovered in 1991 at IDEC Pharmaceuticals' laboratories, where the anti-body was genetically engineered and produced utilizing high-yield expression systems. It is a human IgGI kappa antibody with mouse variable regions isolated from a murine anti-CD20 antibody, IDEC-2B8, that binds with high affinity to cells expressing the CD20 antigen found on the surface of malignant and normal B cells, but not on other normal tissues. It mediates complement-dependent cell lysis in the presence of human complement, and antibody-dependent cellular cytotoxicity with human effector cells. Also, it has been shown to induce apoptosis and to sensitize chemoresistant human

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lymphoma cell lines in vitro. Clinical development was expedited (3 years) with the first patient entered in phase I trials in March 1993 and the last patient entered in the phase III study in March 1996. IDEC Pharmaceuticals began a collaboration with Genentech, Inc in March 1995 and with F. Hoffman-LaRoche (Nutley, NJ) shortly thereafter. Marketing approval was granted by the US Food and Drug Administration on November 26, 1997 (and by the European Union on June 2, 1998) for the indication of relapsed or refractory, CD20-positive, B-cell, low-grade or follicular non-Hodgkin's lymphoma. Rituximab is the first therapeutic monoclonal antibody approved for the treatment of cancer and the first single agent approved specifically for therapy for a lymphoma. Substantial research has been performed over the past 8 years to further the understanding of this novel therapeutic. Nevertheless, much remains to be accomplished in key areas such as mechanism of action and resistance, combinations with chemotherapy, biologics and radiotherapy/radioimmunotherapy, role within multimodality regimens, and nonmalignant applications. Research conducted in the coming years should be targeted toward resolving these important issues. Copyright © 2000 by W.B. Saunders Company.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Pharmacy

3, 6 2/68 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2001073330 AU: Fisher RI Titel: Current therapeutic paradigm for the treatment of non-Hodgkin's lymphoma Quelle: Seminars in Oncology; VOL: 27 (6); p. 2-8 /2000/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0093-7754 CO: SOLGA Corporate Source:

Dr. R.I. Fisher, Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S First Ave, Maywood, IL 60153 United States

COU: United States DT: Journal RN: 0035 DN: rituxan/Genentech,United States; zevalin/Idec,United States; rituxan/Idec,United

States MN: Genentech,United States; Genentech; Idec,United States; Idec TE: rituximab/174722-31-7; yttrium 90/10098-91-6; cyclophosphamide/50-18-0;

doxorubicin/23214-92-8; doxorubicin/25316-40-9; teniposide/29767-20-2; prednisone/53-03-2; alpha2b interferon/99210-65-8; vincristine/57-22-7; fludarabine/21679-14-1; dexamethasone/50-02-2; pentostatin/53910-25-1;

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mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5; etoposide/33419-42-0; cytarabine/147-94-4; cytarabine/69-74-9; bleomycin/11056-06-7; folic acid/59-30-3; folic acid/6484-89-5; carmustine/154-93-8; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2

CR: 174722-31-7; 10098-91-6; 50-18-0; 23214-92-8; 25316-40-9; 29767-20-2; 53-03-2; 99210-65-8; 57-22-7; 21679-14-1; 50-02-2; 53910-25-1; 65271-80-9; 70476-82-3; 15475-56-6; 59-05-2; 7413-34-5; 33419-42-0; 147-94-4; 69-74-9; 11056-06-7; 59-30-3; 6484-89-5; 154-93-8; 15663-27-1; 26035-31-4; 96081-74-2

AB: Patients with indolent non-Hodgkin's lymphoma may be treated with various approaches ranging from deferred initial therapy (watch and wait) to single-agent alkylating agents, radiation therapy, or combination chemotherapy. None of these approaches have produced curative results. Clearly, innovative treatment strategies are needed. The use of interferon, monoclonal antibodies with or without radioisotopes, purine analogues, and even high-dose therapy with stem-cell rescue are under investigation. Based on the fact that fewer than 40% of advanced-stage, aggressive non-Hodgkin's lymphoma patients are cured with cyclophosphamide/doxorubicin/vincristine/prednisone chemotherapy, the best approach for any patient is an experimental one. Examples include: (1) increasing the dose intensity of drugs used in standard regimens; (2) preventing the development of drug resistance; (3) combining monoclonal antibodies with chemotherapy; or (4) autologous stem-cell transplantation as a rescue from marrow-ablative chemotherapy. If a patient is not eligible or does not wish to participate in a clinical trial, cyclophosphamide/doxorubicin/vincristine/prednisone, as inadequate as it is, remains the gold standard. Copyright © 2000 by W.B. Saunders Company.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Health Policy, Economics and Management Drug Literature Index Adverse Reactions Titles

6 2/69 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2001053265 AU: Wood AM Titel: Rituximab: An innovative therapy for non-Hodgkin's lymphoma Quelle: American Journal of Health-System Pharmacy; VOL: 58 (3); p. 215-232 /01 FEB

2001/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1079-2082 CO: AHSPE Corporate Source:

A.M. Wood, Clinical Specialist, Oncology, HealthAnswers, Inc., 3 Acadia Branch Place, Woodlands, TX 77382 United States [email protected]

COU: United States

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DT: Journal RN: 0081 TE: rituximab/174722-31-7; chlorambucil/305-03-3; cyclophosphamide/50-18-0;

prednisone/53-03-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; vincristine/57-22-7; fludarabine/21679-14-1

CR: 174722-31-7; 305-03-3; 50-18-0; 53-03-2; 23214-92-8; 25316-40-9; 57-22-7; 21679-14-1

AB: The epidemiology, etiology, classification, and treatment of non-Hodgkin's lymphoma (NHL) are reviewed, and rituximab, a newly available therapy, is discussed. NHL comprises a group of lymphoproliferative disorders the frequency of which continues to rise. Although many classification systems exist for identifying specific histological subtypes, NHL is generally divided into indolent (low-grade) and aggressive (intermediate- and high-grade) forms. Low-grade NHL is characterized by a slowly progressive, continually relapsing course, with eventual transformation to a more rapidly progressive form that is usually fatal. Several options are available for the management of indolent NHL; none is curative. Rituximab, a human-mouse monoclonal antibody that targets the CD20 antigen expressed in over 90% of B-cell NHLs, provides an alternative to conventional chemotherapy that is relatively safe and effective. In a Phase III trial involving 166 patients with relapsed or refractory low-grade B-cell NHL, rituximab produced an overall response of 48%, with 20 of 80 responders still in remission more than 36 months after treatment. Study results in patients with bulky disease and those requiring retreatment have also been encouraging. Most adverse effects associated with rituximab are mild to moderate. Infusion-related reactions occur more commonly during initial infusions and in patients with evidence of increased tumor burden but can be effectively managed with premedication, supportive care, and adjusted infusion rates. Hematologic effects are generally mild and transient, and adverse immune responses are rare. Rituximab is an alternative to conventional chemotherapy for the treatment of relapsed or refractory low-grade or follicular CD20-positive B-cell NHL.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Radiology

Cancer Hematology Drug Literature Index Adverse Reactions Titles

3, 6 2/70 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2000381854 AU: Alas S; Bonavida B; Emmanouilides C Titel: Potentiation of fludarabine cytotoxicity on non-Hodgkin's lymphoma by pentoxifylline

and Rituximab Quelle: Anticancer Research; VOL: 20 (5); p. 2961-2966 /2000/ Sprache: ENGLISH AL: ENGLISH CY: Greece ISSN: 0250-7005 CO: ANTRD

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Corporate Source:

Dr. B. Bonavida, Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA 90095 United States

COU: United States DT: Journal RN: 0043 MN: Idec,United States; Idec; Berlex,United States; Berlex; Sigma,United States; Sigma TE: fludarabine/21679-14-1; pentoxifylline/6493-05-6; rituximab/174722-31-7 CR: 21679-14-1; 6493-05-6; 174722-31-7 AB: Background: Fludarabine has become a drug of prominent use in hematopoietic

malignancies exhibiting indolent growth profiles. Some studies show, however, that nearly 50% of patients are fludarabine-resistant from the very onset of therapy. Others relapse after an initial response rarely lasting more than 2 years. For this reason, modulating agents have been considered for use with fludarabine to potentiate fludarabine cytotoxicity and circumvent drug resistance. The chimeric anti-CD20 monoclonal antibody, Rituximab (IDEC-C2B8), is used to treat patients with low grade and follicular B-cell non-Hodgkin's lymphoma. Rituximab is known to inhibit the cell progression of tumor B cells and to sensitize them to chemotherapeutic drugs. A slower cell progression may enhance the efficacy of fludarabine incorporation, thus increasing its cytotoxicity. Therefore, the use of fludarabine and Rituximab in combination could potentiate fludarabine cytotoxicity. The methylxanthine, pentoxifylline, disrupts DNA repair mechanisms within a cell by not allowing a cell to arrest at the G2/M checkpoint. By not allowing cells to repair fludarabine DNA incorporation, pentoxifylline was thought to increase fludarabine- induced cytotoxicity in tumor cells. We tested these hypotheses in vitro. Materials and Methods: Analysis of cytotoxicity was performed using the XTT assay on tumor cell lines and patient samples. Results: Tumor cell models, including two B-cell non-Hodgkin's lymphoma cell lines and a T-cell leukemia cell line, were shown to respond more effectively to fludarabine therapy in the presence of Rituximab or pentoxifylline. Two freshly derived B-cell chronic lymphocytic leukemia patient samples were also seen to exhibit a better response with a combination of fludarabine and pentoxifylline than with either alone. Conclusion: This study proves the hypothesis that Rituximab and pentoxifylline may provide a clinical approach to hinder the outgrowth of drug refractory tumor cells and achieve a longer period of remission.

CNOTE: Copyright 2004 Elsevier B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index

2 (in vitro Testung) 2/71 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2000210929 AU: Van Den Neste E; Louviaux I; Michaux JL; Delannoy A; Michaux L; Sonet A; Bosly A;

Doyen C; Mineur P; Andre M; Straetmans N; Coche E; Venet C; Duprez T; Ferrant A Titel: Phase I/II study of 2-chloro-2'-deoxyadenosine with cyclophosphamide in patients

with pretreated B cell chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma

Quelle: Leukemia; VOL: 14 (6); p. 1136-1142 /2000/

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Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 0887-6924 CO: LEUKE Corporate Source:

E. Van Den Neste, Department of Hematology/Radiology, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, 10 Av. Hippocrate, 1200 Brussels Belgium

COU: Belgium DT: Journal RN: 0044 DN: vp 16 TE: cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9;

mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; vincristine/57-22-7; prednisone/53-03-2; etoposide/33419-42-0; dexamethasone/50-02-2; cytarabine/147-94-4; cytarabine/69-74-9; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; ifosfamide/3778-73-2; fludarabine/21679-14-1

CR: 50-18-0; 23214-92-8; 25316-40-9; 65271-80-9; 70476-82-3; 57-22-7; 53-03-2; 33419-42-0; 50-02-2; 147-94-4; 69-74-9; 15663-27-1; 26035-31-4; 96081-74-2; 3778-73-2; 21679-14-1

AB: Because of their substantial in vitro synergy, we conducted a dose-escalation study of cyclophosphamide (CP) added to 2-chloro-2'-deoxyadenosine (CdA) in patients with previously treated chronic lymphocytic leukemia and non-Hodgkin's lymphoma. CdA was given at a fixed dose (5.6 mg/m²/day) as a 2-h intravenous (i.v.) infusion, immediately followed by a 1-h i.v. infusion of CP, for 3 days. The initial daily CP dose was 200 mg/m², and was escalated by 100 mg/m² increments in successive cohorts of three to six patients to determine the maximum-tolerated dose (MTD). Additional patients were included at the MTD to extend toxicity and response analysis. Twenty-six patients received 68 cycles of chemotherapy. The MTD of CP after CdA 5.6 mg/m², was 300 mg/m². Acute neutropenia was the dose-limiting toxicity of this regimen, which was otherwise well tolerated. Delivery of repeated cycles was not feasible in eight patients (31%) because of prolonged thrombocytopenia. Severe infections were seen in three of 68 cycles (4%). The overall response rate was 58% (15 of 26; 95% Cl, 36-76%), with 15% complete responses and 42% partial responses. These data show the feasibility of the association of CdA with CP. Given the response rate observed, further studies of this regimen are warranted in untreated patients, in particular with chronic lymphocytic leukemia and with Waldenstrom macroglobulinemia.

CNOTE: Copyright 2004 Elsevier B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

3 2/72 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2000147901 AU: Feuring-Buske M; Buske C; Unterhalt M; Hiddemann W

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Titel: Recent advances in antigen-targeted therapy in non-Hodgkin's lymphoma Quelle: Annals of Hematology; VOL: 79 (4); p. 167-174 /2000/ Sprache: ENGLISH AL: ENGLISH CY: Germany ISSN: 0939-5555 CO: ANHEE Corporate Source:

Dr. M. Feuring-Buske, The Terry Fox Laboratory, BC Cancer Agency, 601 West 10th Avenue, Vancouver, BC V52 1L3 Canada [email protected]

COU: Canada DT: Journal RN: 0080 DN: idec c2b8 TE: chlorambucil/305-03-3; cyclophosphamide/50-18-0; fludarabine/21679-14-1;

interleukin 2/85898-30-2; iodine 131/10043-66-0; iodine 131/15124-39-7; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; rituximab/174722-31-7

CR: 305-03-3; 50-18-0; 21679-14-1; 85898-30-2; 10043-66-0; 15124-39-7; 65271-80-9; 70476-82-3; 174722-31-7

AB: Substantial advances in antigen-targeted lymphoma therapy have been achieved in recent years that make the use of monoclonal antibodies a highly attractive concept and promise further improvements in the clinical management of malignant lymphoma. The development of the chimeric anti-CD20 antibody IDEC-C2B8 (Rituximab) proved the concept of an effective therapy with a single unconjugated monoclonal antibody in lymphoma patients. Radioimmunoconjugates with myeloablative activity induced response rates of 80-100% in heavily pretreated patients. Progress in the genetic engineering of immunotoxins has improved the efficacy of these constructs. Ongoing prospective clinical trials will define the optimal use of these innovative therapeutic agents in patients with malignant lymphoma, and may establish therapeutic strategies with a high anti-lymphoma specificity and a low unspecific toxicity.

CNOTE: Copyright 2004 Elsevier B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Pharmacology Drug Literature Index Adverse Reactions Titles

3, 6 2/73 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2000108831 AU: Child JA; Johnson SA; Rule S; Smith GM; Morgan GJ; Johnson PWM; Prentice AG;

Tollerfield SM; Wareham E Titel: FLUDAP: Salvage chemotherapy for relapsed/refractory aggressive non-Hodgkin's

lymphoma

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Quelle: Leukemia and Lymphoma; VOL: 37 (3-4); p. 309-317 /2000/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 CO: LELYE Corporate Source:

Dr. J.A. Child, Department of Haematology, The General Infirmary, Great George Street, Leeds LS1 3EX United Kingdom

COU: United Kingdom DT: Journal RN: 0013 DN: ara C; lenograstim; granocyte TE: cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; cytarabine/147-94-

4; cytarabine/69-74-9; dexamethasone/50-02-2; fludarabine phosphate/75607-67-9; recombinant granulocyte colony stimulating factor/121181-53-1

CR: 15663-27-1; 26035-31-4; 96081-74-2; 147-94-4; 69-74-9; 50-02-2; 75607-67-9; 121181-53-1

AB: The aim of this study was to investigate the combination of fludarabine phosphate, dexamethasone, cytosine arabinoside and cis-platinum (FLUDAP) in the treatment of patients with relapsed/refractory aggressive non-Hodgkin's lymphoma (NHL). This regimen comprises: dexamethasone 100 mg/d continuous infusion (cont. inf.) d1-3; cytosine arabinoside (ara-C) 1 g/m²/d cont. inf. d 2,3; fludarabine phosphate 30 mg/m² short inf. 4 hr prior to each 24 hr ara-C inf.; cis-platinum 50 mg/m² 4 hr inf. at the start of each 24 hr ara-C inf. G-CSF (lenograstim, Granocyte®) is given at 263 µg s.c. daily from day 7 until the neutrophil count reaches 1.0 x 10(sup(9))/l. The regimen repeats at 21 day intervals. A total of 33 patients were registered (median age 47 years; 24 males, 9 females); the majority (73%) were refractory to their previous treatment and most had advanced disease by Ann Arbor stage. Thirteen (39%) of the 33 enrolled patients (52% of the 25 fully evaluable patients who received at least 2 courses of FLUDAP) responded to treatment. A maximum response of complete remission was achieved in 5 patients, good partial remission in 3, and partial remission in 5. Twelve patients went on to successful stem cell supported intensification therapy. Median survival times were higher in the responding patients, and in those patients transplanted post-FLUDAP. The toxicity associated with the FLUDAP regimen was generally predictable; frequently reported severe events included haematological toxicity and infection. In conclusion, the FLUDAP regimen shows promise as a salvage regimen and increases the available therapeutic options in the treatment of recurrent/refractory aggressive NHL.

CNOTE: Copyright 2004 Elsevier B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

1 2/74 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V.

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ND: EM2000099528 AU: Tondini C; Balzarotti M; Rampinelli I; Valagussa P; Luoni M; De Paoli A; Santoro A;

Bonadonna G Titel: Fludarabine and cladribine in relapsed/refractory low-grade non- Hodgkin's

lymphoma: A phase II randomized study Quelle: Annals of Oncology; VOL: 11 (2); p. 231-233 /2000/ Sprache: ENGLISH AL: ENGLISH CY: Netherlands ISSN: 0923-7534 CO: ANONE Corporate Source:

Dr. C. Tondini, Division of Medical Oncology, Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milano Italy [email protected]

COU: Italy DT: Journal RN: 0011 TE: fludarabine/21679-14-1; cotrimoxazole/8064-90-2; itraconazole/84625-61-6 CR: 21679-14-1; 8064-90-2; 84625-61-6 AB: Background: It is unclear whether the purine analogs fludarabine (Flu) and cladribine

(CdA) are non-resistant. Patients and methods: Sixty patients with relapsed or refractory low-grade NHL were randomly allocated to initial treatment with either Flu 25 mg/m², or CdA 0.14 mg/kg, each for five consecutive days every four weeks. Upon treatment failure, eligible patients were crossed over to the other study drug. Results: Overall response and CR were 68% and 48% with Flu, and 72% and 38% with CdA, respectively. For responders, actuarial three-year progression-free survival was 58% with Flu and 52% with CdA. Treatment with both drugs was well tolerated, with toxic effects primarily hematological. Two patients (8%) in the Flu group and 15 patients (47%, P = 0.001) in the CdA group were taken off study because of persistent hematological toxicity. After cross over, none of seven refractory patients responded, while eight of nine previously responsive patients achieved second responses. Conclusions: Our study confirms that Flu and CdA have similar response rates and durations. However, further studies are required to optimize the CdA schedule and dosage in order to ameliorate its toxic profile while maintaining antitumor activity. The two drugs appear to be cross-resistant.

CNOTE: Copyright 2004 Elsevier B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

1 2/75 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2000096128 AU: Gahn B; Brittinger G; Dolken G; Dohner H; Emmerich B; Franke A; Freund M; Huber

C; Kuse R; Scholten T; Hiddemann W

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Titel: Multicenter phase II study of oral idarubicin in treated and untreated patients with B-chronic lymphocytic leukemia

Quelle: Leukemia and Lymphoma; VOL: 37 (1-2); p. 169-173 /2000/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 CO: LELYE Corporate Source:

Dr. B. Gahn, Center for Cell and Gene Therapy, Texas Children's Hospital, 6621 Fannin Street, Houston, TX 77030 United States [email protected]

COU: United States DT: Journal RN: 0025 TE: idarubicin/57852-57-0; idarubicin/58957-92-9; chlorambucil/305-03-3;

fludarabine/21679-14-1 CR: 57852-57-0; 58957-92-9; 305-03-3; 21679-14-1 AB: Idarubicin is the first anthracycline that can be administered orally facilitating

antineoplastic chemotherapy at an improved quality of life. In different studies idarubicin has proved clinical effectiveness in patients with advanced low grade non Hodgkin's lymphoma. We performed a phase II study in 19 patients with untreated and pretreated B-CLL of Binet stage A-C. Idarubucin was administered orally at a dose of 15 mg/m² over 3 days every 4 weeks. Of 19 evaluable patients (m:f, 16:3, median age 64 years, range 41-80 years) 7 were previously untreated while 12 patients had received prior therapy with fludarabine, chlorambucil or similar non-anthracycline containing regimens. 12 pts had Binet stage C, 5 Binet stage B and 2 Binet stage A. Five patients achieved a partial remission (26%), 5 patients had stable disease (26%) and 9 patients showed progressive disease (47%), resulting in an overall response of 26% (5/19). There was no correlation of response rate with Binet stages or previous treatment regimens. Treatment associated side effects consisted predominantly of mild nausea and vomiting (26%) as well as minor infections (21%) and diarrhoea (16%). These data demonstrate that oral idarubicin as a single agent is well tolerated but of limited effectiveness in B-CLL. Further studies are needed to assess different doses and schedules of oral idarubucin and to test it in combination with other chemotherapeutic agents.

CNOTE: Copyright 2004 Elsevier B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

3 2/76 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2000078070 AU: Imrie K; Esmail R; Buckstein R; Berinstein N; Meyer R; Zahra HA; Chin- Yee I;

Costello B; Crump M; De Metz C; Dhaliwal D; Gospodarowicz M; Huebsch L; Kacsor M; Kaizer L; Kouroukis T; Matthews J; Meharchand J; Messner H; Sawka C; Smith A;

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Walker I Titel: Use of rituximab in the treatment of lymphoma: An evidence summary Quelle: Current Oncology; VOL: 6 (4); p. 228-235 /1999/ Sprache: ENGLISH AL: ENGLISH CY: Canada ISSN: 1198-0052 CO: CUONF Corporate Source:

R. Meyer, Haematology Disease Site Group, Hamilton Regional Cancer Centre, 699 Concession Street, Hamilton, Ont. L8V 5C2 Canada [email protected]

COU: Canada DT: Journal RN: 0036 TE: rituximab/174722-31-7; cyclophosphamide/50-18-0; doxorubicin/23214-92-8;

doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2; etoposide/33419-42-0; bleomycin/11056-06-7; fludarabine/21679-14-1

CR: 174722-31-7; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2; 33419-42-0; 11056-06-7; 21679-14-1

AB: Questions: 1. In what groups of lymphoma patients has rituximab been studied? 2. What beneficial treatment outcomes are associated with the use of rituximab in patients with lymphoma? 3. What is the toxicity of rituximab? 4. What patients are more-or-less likely to benefit from treatment with rituximab?. Perspective: Evidence was selected and reviewed by 2 people, one of whom is a member of the Cancer Care Ontario Practice Guidelines Initiatives Haematology Disease Site Group (DSG). This evidence summary has been reviewed, discussed, and approved by the DSG, which comprises haematologists, medical oncologists, radiation oncologists, methodologists, and community representatives. Methodology: Sources of Evidence: Relevant evidence was identified by a systematic search of the MEDLINE, CANCERLIT, HealthSTAR, CINAHL, PUBMED databases, and the Cochrane Library (using the text words 'rituxan,' 'rituximab,' 'ritux:,' and 'IDEC C2B8'). Also searched were the American Society of Hematology, the American Society of Clinical Oncology, and the Lugano meeting conference proceedings; the European Organisation for Research and Treatment of Cancer and the Physician Data Query databases; and reference lists from selected articles. Patient Population: Patients with non-Hodgkin's lymphoma. Outcomes of Interest: Survival, quality of life, time-to-progression, response duration, response rate, and toxicity were the primary outcomes of interest. Results: Search Results: Twenty-eight studies were identified: 1 randomised trial of 2 different dosing strategies for rituximab in intermediate-grade lymphoma; 11 reports of single-arm studies of rituximab in follicular, low-grade lymphoma, or mantle-cell lymphoma; 1 abstract of a published paper; 8 abstracts of single-arm studies of rituximab in low- and intermediate-grade lymphoma, Waldenstrom's macroglobulinaemia, and post-transplant lymphoproliferative disorders; 3 abstracts of single-arm studies of rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or interferon alpha in follicular, low- or intermediate-grade lymphoma; 1 paper of a single-arm study of rituximab in combination with CHOP in follicular or low- grade lymphoma; 1 abstract of a single-arm study of rituximab in combination with fludarabine; 1 abstract of rituximab in combination with cyclophosphamide; and 1 abstract of rituximab in combination with carmustine (BCNU), cyclophosphamide and etoposide in low-grade

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or follicular non- Hodgkin's lymphoma. Benefits: The response rates were highest in patients with follicular lymphoma (60%; 95% Confidence Interval (CI): 52-68%) and lowest for those with small lymphocytic lymphoma (18%; 95% CI: 8-28%). Response rates were higher for patients still sensitive to conventional chemotherapy. Data on 1-year survival for mantle-cell lymphoma patients was 80% with a median duration of response of 14.4 months. Data on quality of life were not available. Harms: Detailed toxicity data were provided in the published phase II study. The majority of patients (84%) treated with rituximab in this study had adverse events. The most common of these were: fever (43%), chills (28%), nausea (18%), headache (14%), and allergic symptoms (43%) including angio-oedema (14%). Severe (grade 3 or 4) toxicity was uncommon. Little haematologic toxicity was noted and there did not appear to be any increase in infections up to 1 year after therapy. The majority of adverse events occurred with the first infusion. A 'Dear Doctor' letter was issued indicating that following approval of the drug in the United States (November 1997) and in Europe (June 1998), there were reports of 8 fatalities resulting from cytokine-release syndrome in an estimated 12 000-14 000 treated patients. These reactions occurred early in the first infusion. This appears more common in patients with high tumour burden or who have more than 50 x 10(sup(9)) circulating malignant cells per litre. Future Steps: Rituximab alone, or in combination with chemotherapy, is being compared with conventional chemotherapy in patients with relapsed, as well as those with newly diagnosed, low-grade or follicular lymphoma. It is also being evaluated as part of initial therapy for intermediate-grade lymphoma. At present, the evidence does not allow a firm clinical recommendation on this topic. Please see the full report for a more detailed discussion of the evidence, an interpretive summary, and a description of the opinions of the Disease Site Group members.

CNOTE: Copyright 2004 Elsevier B.V., Amsterdam. All rights reserved. ET: Internal Medicine

Cancer Hematology Drug Literature Index Adverse Reactions Titles

3, 6 2/77 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM1999430580 AU: Solal-Celigny P; Colombat P Titel: ROLE DE L'IMMUNOTHERAPIE DANS LE TRAITEMENT DES LYMPHOMES NON

HODGKINIENS Immunotherapy for non-Hodgkin's lymphomas

Quelle: Hematologie; VOL: 5 (5); p. 393-404 /1999/ Sprache: FRENCH AL: FRENCH CY: France ISSN: 1264-7527 CO: HEMAF Corporate Source:

P. Solal-Celigny, Centre J.-Bernard, 9, rue Beauverger, 72000 Le Mans France [email protected]

COU: France DT: Journal

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RN: 0116 TE: interleukin 2/85898-30-2; rituximab/174722-31-7; iodine 131/10043-66-0; iodine

131/15124-39-7; yttrium 90/10098-91-6; cyclosporin A/59865-13-3; cyclosporin A/63798-73-2; fludarabine/21679-14-1; cyclophosphamide/50-18-0; cytarabine/147-94-4; cytarabine/69-74-9; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; vincristine/57-22-7; prednisone/53-03-2; epirubicin/56390-09-1; epirubicin/56420-45-2; procarbazine/366-70-1; procarbazine/671-16-9; etoposide/33419-42-0; chlorambucil/305-03-3; prednimustine/29069-24-7; chlormethine/51-75-2; chlormethine/55-86-7; chlormethine/82905-71-3

CR: 85898-30-2; 174722-31-7; 10043-66-0; 15124-39-7; 10098-91-6; 59865-13-3; 63798-73-2; 21679-14-1; 50-18-0; 147-94-4; 69-74-9; 15663-27-1; 26035-31-4; 96081-74-2; 23214-92-8; 25316-40-9; 65271-80-9; 70476-82-3; 57-22-7; 53-03-2; 56390-09-1; 56420-45-2; 366-70-1; 671-16-9; 33419-42-0; 305-03-3; 29069-24-7; 51-75-2; 55-86-7; 82905-71-3

AB: Immunotherapy consists of a group of treatment modalities whose goal are to correct immune deficiencies and to amplify the antitumor immune systems which are present at the initiation and during the course of non-Hodgkin's lymphomas. These treatment modalities are numerous: monoclonal antibodies directed against some lymphoid cell antigens (CD20) or tumor-specific antigens in some B-cell lymphomas (idiotypes); biologic response modifiers: interferon alpha, interleukin-2; allogenic lymphoid cells from a bone marrow transplantation or from donor lymphocyte transfusions; autologous lymphoid cells induced to develop an immune reaction against some tumor antigens (vaccination); antigen-presenting cells also transfected with genes. All these treatments, which have been developed in the recent years, are detailed in this review. Their respective participation in the treatment of NHLs remains to be assessed.

CNOTE: Copyright 2004 Elsevier B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Drug Literature Index Adverse Reactions Titles

3, 6 2/78 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM1999090154 AU: Lossos IS; Paltiel O; Polliack A Titel: Salvage chemotherapy using a combination of fludarabine and cyclophosphamide for

refractory or relapsing indolent and aggressive non-Hodgkin's lymphomas Quelle: Leukemia and Lymphoma; VOL: 33 (1-2); p. 155-160 /1999/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 CO: LELYE Corporate Source:

Prof. A. Polliack, Lymphoma and Leukemia Unit, Department of Hematology, Hadassah University Hospital, POB 12000, Jerusalem

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Israel COU: Israel DT: Journal RN: 0016 TE: fludarabine/21679-14-1; cyclophosphamide/50-18-0 CR: 21679-14-1; 50-18-0 AB: The prognosis of patients with refractory or relapsing non-Hodgkin's lymphoma (NHL)

after primary therapy is poor and multi-drug salvage treatments are associated with less than 60% response rates, usually of short duration. Here we report the results of a phase II study using a fludarabine-cyclophosphamide (FAMP-Cy) combination as a salvage failure regimen in refractory and relapsing low-grade (6) and intermediate-grade (9) NHL patients. Fifteen patients, who had received up to 4 regimens prior to therapy with FAMP-Cy were treated with fludarabine (25 mg/mlxb2) and cyclophosphamide (300 mg/mxb2) for 3 consecutive days followed by G-CSF (5 µg/kg). The overall response was 74%, 4 achieving complete responses (CR) and 7 partial responses (PR). All patients with low-grade NHL responded (4 CR, 2 PR); 5 patients with intermediate-grade NHL achieved PR lasting for a median of 5 months. The main toxicity encountered was moderate myelosuppression. Three patients had febrile neutropenia, one had drug-induced fever and a single patient developed severe neurotoxicity. Opportunistic infections due to lymphopenia were not seen. The combination of fludarabine and cyclophosphamide used as a salvage regimen showed an impressive response in a small group of heavily pretreated low-grade NHL patients who had previously received a large number of prior regimens. FAMP-Cy had limited effect in a similar group of intermediate-grade NHL patients. Results with this 'failure' regimen are encouraging, however further studies are needed in order to confirm these observations in a larger series of patients.

CNOTE: Copyright 2004 Elsevier B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

2 (n=15) 2/79 von 79 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM1999055165 AU: Nguyen DT; Amess JA; Doughty H; Hendry L; Diamond LW Titel: IDEC-C2B8 anti-CD20 (Rituximab) immunotherapy in patients with low- grade non-

Hodgkin's lymphoma and lymphoproliferative disorders: Evaluation of response on 48 patients

Quelle: European Journal of Haematology; VOL: 62 (2); p. 76-82 /1999/ Sprache: ENGLISH AL: ENGLISH CY: Denmark ISSN: 0902-4441 CO: EJHAE Corporate Source:

Dr. D.T. Nguyen, Department of Haematology, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE United Kingdom

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COU: United Kingdom DT: Journal RN: 0027 MN: Hoffmann La Roche,Switzerland; Hoffmann La Roche TE: rituximab/174722-31-7; chlorambucil/305-03-3; fludarabine/21679-14-1;

cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2

CR: 174722-31-7; 305-03-3; 21679-14-1; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2

AB: This study focused on the efficacy of IDEC-C2B8 (chimeric anti-CD20) immunotherapy relative to specific subtypes of low-grade lymphoproliferative disorders/non-Hodgkin's lymphomas (LPD/NHL). Forty-eight patients with resistant or relapsed disease completed the IDEC-C2B8 infusion schedule of 375 mg/mxb2/wk x 4 wk. The LPD/NHL subtypes included: (a) follicular centre cell lymphoma (FCC) in 22 patients; (b) mantle cell lymphoma (MCL) in 10; (c) 1 diffuse large cell lymphoma (DLCL); and (d) the category of small lymphocytic lymphoma/chronic lymphocytic leukaemia (SLL/CLL) and related disorders in 15 patients. No patient obtained a complete remission. Ten patients (21%) achieved partial remission: 6 FCC, 2 MCL, 1 DLCL and 1 patient from the SLL/CLL group. Twenty-eight patients had stable disease and 10 progressed during immunotherapy. In patients with CLL and MCL in leukaemic phase, there was no correlation between the marked decrease in circulating neoplastic cells following antibody infusions and amelioration of the tumour burden. The results suggest that the subtype of LPD/NHL and the intensity of CD20 on the tumour cells influence the effectiveness of IDEC-C2B8. The antibody was most efficacious against FCC lymphoma. The efficacy (at the dose schedule of 375 mg/mxb2/wk x 4) against MCL and SLL/CLL appeared to be limited, however.

CNOTE: Copyright 2004 Elsevier B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Drug Literature Index

3

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Anlage 8 Anmerkungen zur Auswahl der Literatur

Ausgewählt und in die Bewertung eingeschlossen wurden nur Literaturbeiträge, die alle folgenden Kriterien erfüllten: 1. Nicht in Medlinerecherche vom 08.07.2008 (siehe Anlage 1) enthalten und

2. Auswertungen klinischer Studien der Phase 2 mit Einschluss von mindestens 20 Patienten in der Rezidivtherapie bzw. Therapie primär refraktärer NHL (bei Einschluss vorbehandelter und nicht vorbehandelter Patienten getrennte Auswertung für vorbehandelte Patienten und mindestens 20 Patienten in dieser Untergruppe) oder klinische Studie der Phase 3 / Metaanalyse unabhängig von der Therapielinie, in der Auswertung als Endpunkt(e) Ansprechrate und / oder progessionsfreies Überleben o. ä. und / oder Gesamtüberleben und / oder krankheitsbezogene Lebensqualität und/oder nach anerkannter Skalierung erfasste Toxizität, und

3. intravenöses Fludarabin als Prüfmedikament und

4. geprüfte Indikation niedrig- oder intermediär malignes B-NHL außer CLL oder multiples Myelom, bei verschiedenen Unterformen getrennte Auswertung für CLL, andere niedrig und intermediär maligne B-NHL (mindestens 20 Patienten) und hoch maligne B-NHL und

5. geprüftes Therapiekonzept ist konventionell dosierte Chemotherapie ohne Hochdosistherapie und / oder Stammzelltransplantation und

6. Publikationstyp: Auswertung einer Studie, keine Übersichtsarbeit, kein „letter“, kein „editorial“

Fett gedruckte Titel wurden eingeschlossen Bei den übrigen Publikationen wurde in der letzten Zeile mindestens eines der Auswahlkriterien genannt, weshalb diese Arbeit nicht berücksichtigt wurde (siehe auch Abschnitt 8 des Gutachtens), ggf. Erläuterung in Klammern, sofern der Ausschlussgrund nicht schon aufgrund von Überschrift oder Abstract erkennbar war: Im Ergebnis erfüllte keine der unten aufgelisteten Publikationen sämtliche Einschlusskriterien 2. Recherche, 26.10.2007, EMBASE bei DIMDI, 62 Treffer Phase 3 Suchschritt : ((AU=PHASE ? OR (PHASE#)) AND FLUDARABINE# AND LYMPHOMA# AND NON# AND HODGKIN# AND FT=3) AND PY=1999 to 2007 3/1 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007484256 AU: Martin P; Furman RR; Coleman M; Leonard JP Titel: Phase I to III trials of anti-B cell therapy in non-Hodgkin's lymphoma Quelle: Clinical Cancer Research; VOL: 13 (18); p. 5636s-5642s /15 SEP 2007/

http://clincancerres.aacrjournals.org/cgi/reprint/13/18/5636sSprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1078-0432

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CO: CCREF Corporate Source:

J.P. Leonard, Weill Medical College of Cornell University, New York Presbyterian Hospital, Starr Building, 520 East 70th Street, New York, NY 10021 United States [email protected]

COU: United States DT: Journal RN: 0077 DN: sgn 40 TE: allopurinol/315-30-0; apolizumab/267227-08-7; cyclophosphamide/50-18-0;

diphenhydramine/147-24-0; diphenhydramine/58-73-1; doxorubicin/23214-92-8; doxorubicin/25316-40-9; epratuzumab/205923-57-5; fludarabine/21679-14-1; galiximab/357613-77-5; ibritumomab tiuxetan/206181-63-7; paracetamol/103-90-2; prednisone/53-03-2; rasburicase/352311-12-7; rituximab/174722-31-7; tositumomab i 131/192391-48-3; tumor necrosis factor receptor/129203-93-6; tumor necrosis factor receptor/184595-01-5; vincristine/57-22-7

CR: 315-30-0; 267227-08-7; 50-18-0; 147-24-0; 58-73-1; 23214-92-8; 25316-40-9; 205923-57-5; 21679-14-1; 357613-77-5; 206181-63-7; 103-90-2; 53-03-2; 352311-12-7; 174722-31-7; 192391-48-3; 129203-93-6; 184595-01-5; 57-22-7

AB: Led by the anti-CD20 antibody rituximab, therapeutic monoclonal antibodies have dramatically altered the treatment of patients with non-Hodgkin's lymphoma. As the understanding of the biology of this novel therapy improves, so does the potential for further progress. There are currently four monoclonal antibodies approved by the Food and Drug Administration for the treatment of B-cell malignancies and dozens more are in various stages of development. The indications for the currently available antibodies, both labeled and unlabeled, are being expanded to include first-line treatment, maintenance strategies, and combinations with chemotherapy. Newer agents are being engineered to target novel antigens, and to interact more specifically with the host immune system. These promising therapeutics face a significant challenge in evaluation and integration in the post-rituximab world. © 2007 American Association for Cancer Research.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

6 3/2 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007342872 AU: Xiao Y; Jiang Z-J; Lin J-R; Xiao H-W; Li S-W; Xiao Z-F; Yan D-A Titel: Effective factors for quantity and quality of auto-peripheral blood stem cells in

hematopoietic system of patients with malignant tumor Quelle: Journal of Clinical Rehabilitative Tissue Engineering Research; VOL: 11 (20); p. 4052-

4056 /20 MAY 2007/ Sprache: ENGLISH AL: CHINESE CY: China ISSN: 1673-8225 Corporate Source:

Y. Xiao, Department of Hematology, Guangzhou General Hospital, Guangzhou Military Area Command of Chinese PLA, Guangzhou 510010 Guangdong Province China

Page 215: Fludara i.v. (2nd line NHL)

[email protected] COU: China DT: Journal RN: 0023 MN: Chugai TE: cyclophosphamide/50-18-0; cytarabine/147-94-4; cytarabine/69-74-9;

etoposide/33419-42-0; fludarabine/21679-14-1; trypan blue/72-57-1 CR: 50-18-0; 147-94-4; 69-74-9; 33419-42-0; 21679-14-1; 72-57-1 AB: Background: Hematopoietic reconstruction of malignant tumor in hematopoietic

system is related to disease itself, pretreatment program and therapeutic tool after transplantation; especially, mobilization, collection and cryopreservation of auto-peripheral blood stem cell play a key role in successful reconstruction of hematopoietic system after transplantation. Objective: To investigate the reconstruction of hematopoietic system through mobilization, collection and cryopreservation of auto-peripheral blood stem cell in patients with malignant tumor and analyze the effective factors on quantity and quality of auto-peripheral blood stem cell. Design: Case analysis based on malignant tumor in hematopoietic system. Setting: Department of Blood, Guangzhou General Hospital of Guangzhou Military Area Command of Chinese PLA; Department of Blood, Zhujiang Hospital, Nanfang Medical University. Participants: A total of 18 patients with malignant tumor in hematopoietic system were selected from Department of Blood, Guangzhou General Hospital of Guangzhou Military Area Command of Chinese PLA. Their ages ranged from 16 to 56 years. Among them, 2 patients had acute myelogenous leukemia (AML), 1 acute lymphoblastic leukemia (ALL), 2 lymphoblastic leukemia (LL), 2 chronic granulocytic leukemia (CGL), 4 multiple myeloma (MM), and 7 non-Hodgkin lymphoma. Granulocyte colony-stimulating factor (G-CSF) was made by Chugai Pharmaceutical Company Limited (batch number: N3G31). Methods: 1 All patients were mobilized with associated chemotherapy + G-CSF. Associate chemotherapy: Patients with leukemia were given 2 g/m² arabinosyl cytosine every 12 hours from the first to the third days and 200 mg/m² etoposide or 50 mg/m² fludarabine from the first to the fifth days. In addition, patients with MM were treated with arabinosyl cytosine as the same way mentioned above and with 1 g/m² cyclophosphamide from the first to the second days. And patients with lymphoma were given 2 g/m² cyclophosphamide from the first to the second days. When numbers of leucocyte of all patients decreased below 1.0×10(sup(9)) L(sup(-1)) after chemotherapy, G-CSF started mobilization and the collection was stopped with 5 µg/(kg·d) subcutaneous injection. 2 When numbers of leucocyte increased to (4.0-10.0)× 10(sup(9)) L(sup(-1)), hemopoietic stem cells of peripheral blood were collected till the amount of mononuclear cells (greater-than or equal to) 4.0×1(sup(8))/kg or numbers of CD34(sup(+)) cells (greater-than or equal to) 2.0×10(sup(6))/kg. And then, the samples were dealt with cooling device, maintained in liquid nitrogen at -196 °C and defrosted in water bath at 37-40 °C. 3 Focal sites of patients were pretreated with local irradiation with 200 cGy/time and 5 times/week for 4 successive weeks. The total dosage was 40 Gy. At 48 hours leter, (55.3±28.7) mL hemopoietic stem cells of peripheral blood were transfused back, and the duration from transfusion to collection was about (56.5±22.3) days. 300 µg/d G-CSF was subcutaneously injected into all patients at 1 day after transplantation and the reaction was stopped at the phase of neutrophil (greater-than or equal to) 0.5×10(sup(9)) L(sup(-1)). Finally, refusing-staining rate of trypan blue of peripheral blood stem cell, amount of mononuclear cells, number of granulation-monophyly progenitor cell colony and percentage of CD34(sup(+)) cells were detected before and after thaw. Main outcome measures: 1 Collection of auto-peripheral blood stem cell; 2 survival rate and related markers of auto-peripheral blood stem cell after cryopreservation; 3 hematopoietic reconstruction of auto-peripheral blood stem cell after transplantation. Results: All 18 patients with malignant tumor in hematopoietic system were involved in the final analysis. The

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mean collection time of auto-peripheral blood stem cell was 12.6 days after chemotherapy, the collection times were 1.9, total number of leucocyte was (8.93±1.27) × 10(sup(9)) L(sup(-1)) on the first day, and collection rate of mononuclear cell was (138.33± 28.61)%. 2 Refusing-staining rate of trypan blue of auto-peripheral blood stem cell was similar before and after cryopreservation [(96.26±1.33)%, (92.75±2.04)%, P>0.05]. In addition, after cryopreservation, recovery rates of mononuclear cells, CD34(sup(+)) cells and granulation-monophyly progenitor cell were (91.96±1.37)%, (85.94±0.64 and (87.69±4.53)%, respectively. Collection rate of mononuclear cells, number of granulation-monophyly progenitor cell colony and percentage of CD34(sup(+)) cells were lower in patients with myeloma than in those with leukemia and lymphoma (t = 2.524-3.268, P < 0.05). 3 At 15 days after transplantation, 15 patients had the neutrophil (greater-than or equal to) 0.5 × 10(sup(9)) L(sup(-1)); at 20 days after transplantation, blood platelet was (greater-than or equal to) 20 × 10(sup(9)) L(sup(-1)). granulation-monophyly progenitor cells [(18.67-26.82) × 10(sup(5))/kg] of 5 patients grew poorly if the course of chemotherapy was more than 10 times. Among them, 3 patients had delayed hematopoietic reconstruction after transplantation of auto-peripheral blood stem cell. Conclusion: 1 High-dose chemotherapy combined with G-CSF can shorten collection time of peripheral blood stem cell and improve collection rate of mononuclear cells. 2 Increase of chemotherapy times before transplantation can affect quantity and quality of auto-peripheral blood stem cell and cause delayed hematopoietic reconstruction.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Radiology

Cancer Hematology Clinical Biochemistry Drug Literature Index

3, 5 3/3 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007312968 AU: Mones J; Coleman M; Kostakoglu L; Furman RR; Chadburn A; Shore TB; Muss D;

Stewart P; Kroll S; Vallabhajosula S; Goldsmith SJ; Leonard JP Titel: Dose-attenuated radioimmunotherapy with tositumomab and iodine 131 tositumomab

in patients with recurrent non-Hodgkin's lymphoma (NHL) and extensive bone marrow involvement

Quelle: Leukemia and Lymphoma; VOL: 48 (2); p. 342-348 /2007/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 EISSN: 1029-2403 CO: LELYE PII: 770740859 Corporate Source:

J.P. Leonard, Center for Lymphoma and Myeloma, Division of Hematology/Oncology, Nuclear Medicine, and Hematopathology, Weill Medical College of Cornell University, New York, NY United States

COU: United States DT: Journal RN: 0032 TE: alemtuzumab/216503-57-0; arabinoside/50986-18-0; bleomycin/11056-06-7;

chlorambucil/305-03-3; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-

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2; cyclophosphamide/50-18-0; cytosine/71-30-7; doxorubicin/23214-92-8; doxorubicin/25316-40-9; etoposide/33419-42-0; fludarabine/21679-14-1; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5; methylprednisolone/6923-42-8; methylprednisolone/83-43-2; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; prednisolone/50-24-8; prednisone/53-03-2; ranimustine/58994-96-0; rituximab/174722-31-7; thiotepa/52-24-4; tositumomab i 131/192391-48-3; tositumomab/208921-02-2; vincristine/57-22-7

CR: 216503-57-0; 50986-18-0; 11056-06-7; 305-03-3; 15663-27-1; 26035-31-4; 96081-74-2; 50-18-0; 71-30-7; 23214-92-8; 25316-40-9; 33419-42-0; 21679-14-1; 15475-56-6; 59-05-2; 7413-34-5; 6923-42-8; 83-43-2; 65271-80-9; 70476-82-3; 50-24-8; 53-03-2; 58994-96-0; 174722-31-7; 52-24-4; 192391-48-3; 208921-02-2; 57-22-7

AB: Radioimmunotherapy (RIT) with tositumomab and iodine 131 tositumomab can produce durable and complete responses in relapsed/refractory low-grade Non-Hodgkin's lymphoma. Patients with bone marrow involvement (BMI) with tumor > 25% of the intertrabecular space are generally excluded from RIT because of risk of excessive hematologic toxicity. The authors conducted a dose-escalation study of tositumomab and iodine 131 tositumomab to determine whether RIT is feasible in this population. Patients had baseline BMI of >25% and platelet count of (greater-than or equal to)150 000/ mm³. In contrast to the usual 75cGy total body dose of radiation, dose escalation of Iodine I 131 tositumomab began at a total body dose of 45 cGy, and increased to 55 cGy in a second cohort. Dose-limiting toxicity (DLT) was defined as absolute neutrophil count <500 cells/mm³ or platelets <25 000/mm³ for >17 days, or absolute neutrophil count <750/mm³ or platelets <50 000/mm³ for >24 days. Eleven subjects were enrolled (8 at 45 cGy and 3 at 55 cGy). Estimated BMI ranged from 30 to 65% (median approximately 40%). Patients had received a median of three prior chemotherapies (range 1-6). One of the six evaluable patients treated at 45 cGy experienced DLT. Three patients received 55 cGy, one had hematologic DLT concurrent with lymphoma progression and extensive BMI at relapse. Three of 11 (27%) patients received hematologic supportive care. Two patients had objective responses of 1 and 42.4+ months, respectively. RIT with attenuated dose iodine 131 tositumomab for patients with >25% BMI has acceptable toxicity and can result in lymphoma responses.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Radiology

Cancer Hematology Immunology, Serology and Transplantation Drug Literature Index Adverse Reactions Titles

3, 5 3/4 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007289667 AU: Wang Y; Serradell N; Bolós J; Rosa E Titel: Obatoclax mesilate: Bcl-2 inhibitor apoptosis inducer oncolytic Quelle: Drugs of the Future; VOL: 32 (3); p. 228-233 /2007/ Sprache: ENGLISH AL: ENGLISH CY: Spain ISSN: 0377-8282 CO: DRFUD Corporate Source:

Y. Wang, 8106 Runnymeade Dr., Frederick, MD 21702 United States

COU: United States

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DT: Journal RN: 0046 DN: abt 737; bh 311; bh 312; gw 2974; gx 015070; gx 15070 ms; gx 15070; ha 14 1; npi

0052 TE: bortezomib/179324-69-7; bortezomib/197730-97-5; chlorambucil/305-03-3;

cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; cytarabine/147-94-4; cytarabine/69-74-9; dexamethasone/50-02-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; fludarabine/21679-14-1; gefitinib/184475-35-2; gefitinib/184475-55-6; gefitinib/184475-56-7; gossypol/303-45-7; melphalan/148-82-3; protein bcl 2/219306-68-0; protein bcl xl/151033-38-4; rituximab/174722-31-7; somatomedin C/67763-96-6; vincristine/57-22-7

CR: 179324-69-7; 197730-97-5; 305-03-3; 15663-27-1; 26035-31-4; 96081-74-2; 147-94-4; 69-74-9; 50-02-2; 23214-92-8; 25316-40-9; 21679-14-1; 184475-35-2; 184475-55-6; 184475-56-7; 303-45-7; 148-82-3; 219306-68-0; 151033-38-4; 174722-31-7; 67763-96-6; 57-22-7

AB: Obatoclax mesilate (GX15-070, GX15-070MS) is a small molecule specifically designed to inhibit all relevant members of the Bcl-2 protein family, which play critical roles in regulating apoptosis. Preclinical studies demonstrated that obatoclax alone or in combination with other drugs induces apoptosis in many human cancer cell lines. Obatoclax has entered clinical development for the treatment of a variety of cancers, and early results have confirmed potential antitumor activity. Obatoclax is currently in phase II clinical development for the treatment of Hodgkin's lymphoma, myelodysplastic/myeloproliferative disorders and follicular lymphoma, as well as earlier clinical development for several other cancers. Copyright © 2007 Prous Science.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3 3/5 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007253221 AU: Dragovich T; Gordon M; Mendelson D; Wong L; Modiano M; Chow H-HS; Samulitis B;

O'Day S; Grenier K; Hersh E; Dorr R Titel: Phase I trial of imexon in patients with advanced malignancy Quelle: Journal of Clinical Oncology; VOL: 25 (13); p. 1779-1784 /01 MAY 2007/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND Corporate Source:

Dr. R. Dorr, Arizona Cancer Center, University of Arizona, 1515 N Campbell Ave, Tucson, AZ 85724 United States [email protected]

COU: United States DT: Journal RN: 0025 DN: nsc 714597/Ben Venue,United States

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MN: Ben Venue,United States; Ben Venue TE: cyclophosphamide/50-18-0; cystine/24645-67-8; cystine/56-89-3; cystine/6020-39-9;

docusate sodium/577-11-7; doxorubicin/23214-92-8; doxorubicin/25316-40-9; elsamicin A/97068-30-9; fludarabine/21679-14-1; granisetron/107007-99-8; granisetron/109889-09-0; ibritumomab tiuxetan/206181-63-7; imexon/59643-91-3; ondansetron/103639-04-9; ondansetron/116002-70-1; ondansetron/99614-01-4; prednisone/53-03-2; rituximab/174722-31-7; sodium dihydrogen phosphate/7558-80-7; sodium dihydrogen phosphate/7632-05-5; vincristine/57-22-7

CR: 50-18-0; 24645-67-8; 56-89-3; 6020-39-9; 577-11-7; 23214-92-8; 25316-40-9; 97068-30-9; 21679-14-1; 107007-99-8; 109889-09-0; 206181-63-7; 59643-91-3; 103639-04-9; 116002-70-1; 99614-01-4; 53-03-2; 174722-31-7; 7558-80-7; 7632-05-5; 57-22-7

AB: Purpose: Imexon, a pro-oxidant small molecule, has antitumor activity in preclinical models. The drug induces apoptosis through accumulation of reactive oxygen species. The purpose of this trial was to define the maximum-tolerated dose (MTD), toxicities, pharmacokinetics, and pharmacodynamics of imexon in patients with advanced cancers. Patients and Methods: Forty-nine patients with metastatic cancer received intravenous imexon over 30 to 45 minutes for 5 consecutive days (one course) every other week (days 1 through 5 and 15 through 19) monthly. Doses were initially escalated using an accelerated trial design and then a modified Fibonacci method. Plasma imexon levels and six different thiols were measured by high-performance liquid chromatography assays. Results: There were 13 dose levels evaluated, from 20 mg/m²/d to 1,000 mg/m²/d. The MTD recommended for phase II studies was 875 mg/m ²/d for 5 days every 2 weeks (n = 9 patients). The two dose-limiting toxicities at 1,000 mg/m²/d involved grade 3 abdominal pain and fatigue and grade 4 neutropenia, which occurred in one patient each. Other common toxicities included nausea and vomiting (58%) and constipation (63%); both were managed well with prophylactic medications. One partial response was obtained in a heavily pretreated patient with non-Hodgkin's lymphoma. Pharmacokinetic studies showed dose-independent clearance, with a 95-minute mean half-life. Plasma thiol studies showed a dose- and area under the curve-dependent decrease in cystine levels 8 hours after dosing at (greater-than or equal to) 750 mg/m²/d. Conclusion: The phase II recommended dose of imexon is 875 mg/m²/d for 5 days every other week. A decrease in plasma thiols did correlate with imexon exposure. © 2007 by American Society of Clinical Oncology.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Pharmacology Drug Literature Index Adverse Reactions Titles

3 3/6 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007207282 AU: Kaminski MS; Radford JA; Gregory SA; Leonard JP; Knox SJ; Kroll S; Wahl RL Titel: Re-treatment with I-131 tositumomab in patients with non-Hodgkin's lymphoma who

had previously responded to I-131 tositumomab Quelle: Journal of Clinical Oncology; VOL: 23 (31); p. 7985-7993 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND Corporate Source:

Dr. M.S. Kaminski, University of Michigan Comprehensive Cancer Center, Cancer Center, 1500 E Medical Center Drive, Ann Arbor, MI United States

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[email protected] COU: United States DT: Journal RN: 0018 TE: cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9;

fludarabine/21679-14-1; rituximab/174722-31-7; topotecan/119413-54-6; topotecan/123948-87-8; tositumomab i 131/192391-48-3

CR: 50-18-0; 23214-92-8; 25316-40-9; 21679-14-1; 174722-31-7; 119413-54-6; 123948-87-8; 192391-48-3

AB: Purpose: To study efficacy and safety of re-treatment with I-131 tositumomab in patients with low-grade, follicular, or transformed low-grade B-cell lymphoma who relapsed following a response to I-131 tositumomab. Patients and Methods: A prior response (greater-than or equal to) 3 months to I-131 tositumomab was required. The single therapeutic dose following a dosimetric dose was adjusted to give the same total body dose (in Gy) as that used for the original dose, or was attenuated if the platelet count was less than 150,000 per mm³ or if the prior treatment resulted in grade 4 cytopenias lasting longer than 7 days. Results: Of 32 patients enrolled, 28 completed the therapeutic dose. A median of four therapies were given before re-treatment. Eighteen (56%) of 32 patients had a complete or partial response (median duration, 15.2 months); eight (25%) had a complete response (median duration, 35 months). Five continue in response from 1.8 to 5.7 years, with a median follow-up of 35 months. The overall median response duration was not significantly different for the two treatments, with no clinical factors predicting response or its duration. Ten of 18 re-responders had longer responses with re-treatment, with five having responses (greater-than or equal to) 1.5 years longer. Grade 3/4 neutropenia and thrombocytopenia occurred in 50% and 43% of patients, respectively, similar to initial treatment. Antimouse antibodies developed in 10% of patients, and 12% developed elevated serum thyroid-stimulating hormone. Six patients were diagnosed with second malignancies, including four patients who developed myelodysplastic syndrome (one who had not received the therapeutic dose) and one with acute myelogenous leukemia. Conclusion: Re-treatment with I-131 tositumomab following a previous response can produce second responses that can be durable. © 2005 by American Society of Clinical Oncology.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Nuclear Medicine Hematology Drug Literature Index Adverse Reactions Titles

3 3/7 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007202851 AU: Hagenbeek A; Eghbali H; Monfardini S; Vitolo U; Hoskin PJ; De Wolf-Peeters C;

MacLennan K; Staab-Renner E; Kalmus J; Schott A; Teodorovic I; Negrouk A; Van Glabbeke M; Marcus R

Titel: Phase III intergroup study of fludarabine phosphate compared with cyclophosphamide, vincristine, and prednisone chemotherapy in newly diagnosed patients with stage III and IV Low-grade malignant non-Hodgkin's lymphoma

Quelle: Journal of Clinical Oncology; VOL: 24 (10); p. 1590-1596 /01 APR 2006/ Sprache: ENGLISH AL: ENGLISH CY: United States

Page 221: Fludara i.v. (2nd line NHL)

ISSN: 0732-183X CO: JCOND Corporate Source:

Dr. A. Hagenbeek, Academic Medical Center, Department of Hematology (F4-224), PO Box 22660, 1100 DD Amsterdam Netherlands [email protected]

COU: Netherlands DT: Journal RN: 0037 DN: fludara/Ben Venue,United States MN: Ben Venue,United States; Ben Venue TE: cyclophosphamide/50-18-0; fludarabine phosphate/75607-67-9; prednisone/53-03-2;

vincristine/57-22-7 CR: 50-18-0; 75607-67-9; 53-03-2; 57-22-7 AB: Purpose: To compare the efficacy and safety of fludarabine phosphate with

cyclophosphamide, vincristine, and prednisone (CVP) in 381 previously untreated, advanced-stage, low-grade (Ig) non-Hodgkin's lymphoma (NHL) patients in a phase III, multicenter study. Patients and Methods: Between 1993 and 1997, patients were randomly assigned to treatment with either fludarabine (25 mg/m² intravenously [IV] daily for 5 days every 4 weeks) or CVP (cyclophosphamide 750 mg/m² IV on day 1; vincristine, 1.4 mg/m² IV on day 1; and prednisone, 40 mg/m² orally on days 1 through 5 every 4 weeks). Results: Overall response (OR) rates were significantly improved in the fludarabine arm versus the CVP arm, both for the intent-to-treat (ITT) population and assessable patients (P < .001). Complete response (CR) rates in the ITT population were also higher after fludarabine treatment. The CR rate was 38.6% for fludarabine compared with 15.0% for CVP. There were no statistically significant differences in time to progression (TTP), time to treatment failure (TTF), and overall survival (OS) between treatment groups. WHO grades 3 and 4 hematologic adverse events were more common in the fludarabine arm. However, concerning the higher incidence of granulocytopenia, this did not translate to more infections in fludarabine-treated patients. Conclusion: Newly diagnosed IgNHL patients who received fludarabine achieved higher OR and CR rates compared with CVP-treated patients. No differences in TTP, TTF, and OS were noted. Fludarabine is a highly active single agent in IgNHL. Combination therapies incorporating fludarabine are now being further evaluated as first-line therapy in follicular NHL. © 2006 by American Society of Clinical Oncology.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Public Health, Social Medicine and Epidemiology Hematology Drug Literature Index Adverse Reactions Titles

1 3/8 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007197885 AU: Tobinai K; Watanabe T; Ogura M; Morishima Y; Ogawa Y; Ishizawa K-I; Minami H;

Utsunomiya A; Taniwaki M; Terauchi T; Nawano S; Matsusako M; Matsuno Y; Nakamura S; Mori S; Ohashi Y; Hayashi M; Seriu T; Hotta T

Titel: Phase II study of oral fludarabine phosphate in relapsed indolent B-cell non-Hodgkin's lymphoma

Quelle: Journal of Clinical Oncology; VOL: 24 (1); p. 174-180 /01 JAN 2006/ Sprache: ENGLISH

Page 222: Fludara i.v. (2nd line NHL)

AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND Corporate Source:

Dr. K. Tobinai, Hematology and Stem Cell Transplantation Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045 Japan [email protected]

COU: Japan DT: Journal RN: 0030 TE: cotrimoxazole/8064-90-2; fludarabine phosphate/75607-67-9; rituximab/174722-31-7 CR: 8064-90-2; 75607-67-9; 174722-31-7 AB: Purpose: Although intravenous (IV) fludarabine phosphate is effective against indolent

B-cell non-Hodgkin's lymphoma (B-NHL), IV administration for 3 to 5 consecutive days is inconvenient in an outpatient setting. To assess the efficacy and toxicity of oral fludarabine phosphate in patients with indolent B-NHL, we conducted a multicenter phase II study. Patients and Methods: Patients with relapsed indolent B-NHL received fludarabine phosphate tablets orally once daily on days 1 through 5 every 28 days for three to six cycles. The efficacy was separately analyzed in a mantle-cell lymphoma (MCL) cohort and indolent B-NHL except for MCL (IL) cohort. The primary end point was the overall response rate (ORR). Results: Fifty-two patients, including 46 in the IL cohort (41 with follicular lymphoma) and six in the MCL cohort, were registered, and all patients were eligible. Forty-one patients (79%) had received rituximab as prior therapy. In the IL cohort, the ORR and complete response rate were 65% (30 of 46 patients; 95% CI, 50% to 79%) and 30% (14 of 46 patients; 95% CI, 18% to 46%), respectively. One of six patients with MCL achieved a partial response. The median times to treatment failure for the 46 patients in the IL cohort and for the six patients in the MCL cohort were 8.6 and 6.1 months, respectively. Hematologic toxicities, including grade 4 neutropenia (37%), were the most frequent toxicities, and nonhematologic toxicities were mild. Conclusion: Oral fludarabine phosphate is highly effective in patients with relapsed indolent B-NHL who have mostly been pretreated with rituximab and is more convenient than the IV formulation. © 2006 by American Society of Clinical Oncology.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

1 3/9 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007190074 AU: Leonard JP; Coleman M; Ketas JC; Chadburn A; Ely S; Furman RR; Wegener WA;

Hansen HJ; Ziccardi H; Eschenberg M; Gayko U; Cesano A; Goldenberg DM Titel: Phase I/II trial of epratuzumab (humanized anti-CD22 antibody) in indolent non-

Hodgkin's lymphoma Quelle: Journal of Clinical Oncology; VOL: 21 (16); p. 3051-3059 /15 AUG 2003/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND

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Corporate Source:

Dr. J.P. Leonard, Division of Hematology and Oncology, Weill Medical College of Cornell University, New York Presbyterian Hospital, 520 East 70th Street, New York, NY 10021 United States [email protected]

COU: United States DT: Journal RN: 0031 TE: bleomycin/11056-06-7; carmustine/154-93-8; cisplatin/15663-27-1; cisplatin/26035-31-

4; cisplatin/96081-74-2; cladribine/4291-63-8; cyclophosphamide/50-18-0; cytarabine/147-94-4; cytarabine/69-74-9; dexamethasone/50-02-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; epratuzumab/205923-57-5; etoposide/33419-42-0; fludarabine/21679-14-1; ifosfamide/3778-73-2; mesna/19767-45-4; mesna/3375-50-6; methylprednisolone/6923-42-8; methylprednisolone/83-43-2; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; prednisone/53-03-2; rituximab/174722-31-7; thiotepa/52-24-4; tositumomab i 131/192391-48-3; vincristine/57-22-7

CR: 11056-06-7; 154-93-8; 15663-27-1; 26035-31-4; 96081-74-2; 4291-63-8; 50-18-0; 147-94-4; 69-74-9; 50-02-2; 23214-92-8; 25316-40-9; 205923-57-5; 33419-42-0; 21679-14-1; 3778-73-2; 19767-45-4; 3375-50-6; 6923-42-8; 83-43-2; 65271-80-9; 70476-82-3; 53-03-2; 174722-31-7; 52-24-4; 192391-48-3; 57-22-7

AB: Purpose: This single-center, dose-escalation study examines the safety, efficacy, and pharmacokinetics of epratuzumab (anti-CD22 humanized monoclonal antibody) in patients with recurrent indolent non-Hodgkin's lymphoma (NHL). Patients and Methods: Patients had indolent NHL and recurrent disease after at least one chemotherapy regimen. Epratuzumab was administered intravenously at 120 to 1,000 mg/m² over 30 to 60 minutes weekly for four treatments. Results: Fifty-five patients received epratuzumab and were assessable for safety; 51 patients were assessable for response. Patients were heavily pretreated (50% had at least four prior regimens) and 49% had bulky disease ((greater-than or equal to) 5 cm). Epratuzumab was well tolerated, with no dose-limiting toxicity. Circulating B cells transiently decreased without significant effects on T cells or immunoglobulin levels. More than 95% of infusions were completed in approximately 1 hour. Mean serum half-life was 23 days. Across all dose levels and histologies, nine patients (18%; 95% confidence interval, 8% to 31%) achieved objective response, including three complete responses (CRs). All responses were in patients with follicular NHL: 24% of these patients responded, including 43% in the 360 mg/m² dose group and 27% in the 480 mg/m² dose group. No responses were observed in other indolent histologies. Median duration of objective response was 79.3 weeks (range, 11.1 to 143.3 weeks), with median time to progression for responders of 86.6 weeks by Kaplan-Meier estimate. Conclusion: Epratuzumab was well tolerated at up to 1,000 mg/m²/wk (for 4 weeks) and had clinical activity. One third of responding patients achieved CR. A 43% objective response rate in follicular NHL patients treated at 360 mg/m²/wk indicates that this dose should be explored in additional studies. © 2003 by American Society of Clinical Oncology.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3 3/10 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V.

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ND: EM2007189679 AU: Vose JM; Bierman PJ; Loberiza FR; Bociek RG; Matso D; Armitage JO Titel: Phase I trial of (sup(90))Y-ibritumomab tiuxetan i patients with relapsed B-cell non-

Hodgkin's lymphoma following high-dose chemotherapy and autologous stem cell transplantation

Quelle: Leukemia and Lymphoma; VOL: 48 (4); p. 683-690 /2007/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 EISSN: 1029-2403 CO: LELYE PII: 777232254 Corporate Source:

J.M. Vose, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE United States

COU: United States DT: Journal RN: 0040 TE: diphenhydramine/147-24-0; diphenhydramine/58-73-1; fludarabine/21679-14-1;

ibritumomab tiuxetan/206181-63-7; paracetamol/103-90-2; rituximab/174722-31-7 CR: 147-24-0; 58-73-1; 21679-14-1; 206181-63-7; 103-90-2; 174722-31-7 AB: Between January 2001 and September 2005, 19 patients with progressive B-cell non-

Hodgkin's lymphoma were treated with a cohort-specific dose of yttrium-90 ibritumomab tiuxetan (0.10-0.20 mCi/kg) to determine appropriate dosing in patients who had previously received high-dose chemotherapy and autologous stem cell transplantation (ASCT). Patients were required to have adequate end organ function and bone marrow status. Patients had been treated with a median of three prior therapies (range, 1-9). The median time from ASCT to radioimmunotherapy was 28 months. Hematologic toxicities were dose-limiting and included grade 3-4 thrombocytopenia (53%), neutropenia (32%), and anemia (21%). The majority of grade 3-4 events occurred at the 0.2mCi/kg dose level. Nine patients responded (complete response, complete response unconfirmed, or partial response) to the therapy. At a median follow-up of 37 months, the 1-year event-free and overall survival rates were 26% and 57%, respectively. A dose of 0.2 mCi/kg ibritumomab tiuxetan is safe and effective for patients with progressive disease after high-dose chemotherapy and ASCT.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

3 3/11 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007086171 AU: Rummel MJ; Al-Batran SE; Kim S-Z; Welslau M; Hecker R; Kofahl-Krause D; Josten

K-M; Dürk H; Rost A; Neise M; Von Grünhagen U; Chow KU; Hansmann M-L; Hoelzer D; Mitrou PS

Titel: Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma

Quelle: Journal of Clinical Oncology; VOL: 23 (15); p. 3383-3389 /2005/ Sprache: ENGLISH

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AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND Corporate Source:

Dr. M.J. Rummel, Department of Internal Medicine, Hematology/Oncology, University Hospital, Theodor-Stern-Kai 7, 60590 Frankfurt/Main Germany [email protected]

COU: Germany DT: Journal RN: 0024 TE: bendamustine/16506-27-7; bendamustine/3543-75-7; bleomycin/11056-06-7;

chlorambucil/305-03-3; cladribine/4291-63-8; cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; epirubicin/56390-09-1; epirubicin/56420-45-2; fludarabine/21679-14-1; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; prednisone/53-03-2; procarbazine/366-70-1; procarbazine/671-16-9; rituximab/174722-31-7; vincristine/57-22-7

CR: 16506-27-7; 3543-75-7; 11056-06-7; 305-03-3; 4291-63-8; 50-18-0; 23214-92-8; 25316-40-9; 56390-09-1; 56420-45-2; 21679-14-1; 65271-80-9; 70476-82-3; 53-03-2; 366-70-1; 671-16-9; 174722-31-7; 57-22-7

AB: Purpose: The aim of this multicenter-study was to evaluate the progression-free survival, response rate and toxicity of the combination of bendamustine and rituximab (BR) in patients with mantle cell or low-grade lymphomas in first to third relapse or refractory to previous treatment. Patients and Methods: A total of 245 courses (median, four courses per patient) were administered to 63 patients. Bendamustine was given at a dose of 90 mg/m² as a 30-minute infusion on days 1 and 2, combined with 375 mg/m² rituximab on day 1, for a maximum of four cycles every 4 weeks. Histologies were 24 follicular, 16 mantle cell, 17 lymphoplasmacytoid, and six marginal zone lymphoma. Results: Fifty-seven of 63 patients responded to BR, corresponding to an overall response rate of 90% (95% CI, 80% to 96%) with a complete remission rate (CR) of 60% (95% CI, 47% to 72%). The median time of progression-free survival was 24 months (range, 5 to 44+ months), and the median duration of overall survival has not yet been reached. In mantle cell lymphomas, BR showed a considerable activity, achieving a response rate of 75% (95% CI, 48% to 93%) with a CR rate of 50%. Myelosuppression was the major toxicity, with 16% grade 3 and 4 leukocytopenia. Thrombocytopenia was rare, with only 3% grade 3 and 4. Conclusion: These results demonstrate that the BR combination is a highly active regimen in the treatment of low-grade lymphomas and mantle cell lymphomas. © 2005 by American Society of Clinical Oncology.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Public Health, Social Medicine and Epidemiology Hematology Drug Literature Index Adverse Reactions Titles

3 3/12 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007066431 AU: Kreitman RJ; Squires DR; Stetler-Stevenson M; Noel P; FitzGerald DJP; Wilson WH;

Pastan I Titel: Phase I trial of recombinant immunotoxin RFB4(dsFv)-PE38 (BL22) in patients with B-

cell malignancies

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Quelle: Journal of Clinical Oncology; VOL: 23 (27); p. 6719-6729 /20 SEP 2005/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND Corporate Source:

Dr. R.J. Kreitman, National Cancer Institute, National Institutes of Health, Bldg. 5124B, 9000 Rockville Pike, Bethesda, MD 20892 United States [email protected]

COU: United States DT: Journal RN: 0051 DN: vp 16 TE: bleomycin/11056-06-7; celecoxib/169590-42-5; chlorambucil/305-03-3;

cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; cladribine/4291-63-8; cyclophosphamide/50-18-0; cytarabine/147-94-4; cytarabine/69-74-9; dexamethasone/50-02-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; etanercept/185243-69-0; etanercept/200013-86-1; etoposide/33419-42-0; flavopiridol/131740-09-5; flavopiridol/146426-40-6; fludarabine/21679-14-1; ibuprofen/15687-27-1; ifosfamide/3778-73-2; indometacin/53-86-1; indometacin/74252-25-8; indometacin/7681-54-1; mesna/19767-45-4; mesna/3375-50-6; methylprednisolone/6923-42-8; methylprednisolone/83-43-2; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; naproxen/22204-53-1; naproxen/26159-34-2; pentostatin/53910-25-1; prednisone/53-03-2; rituximab/174722-31-7; vincristine/57-22-7

CR: 11056-06-7; 169590-42-5; 305-03-3; 15663-27-1; 26035-31-4; 96081-74-2; 4291-63-8; 50-18-0; 147-94-4; 69-74-9; 50-02-2; 23214-92-8; 25316-40-9; 185243-69-0; 200013-86-1; 33419-42-0; 131740-09-5; 146426-40-6; 21679-14-1; 15687-27-1; 3778-73-2; 53-86-1; 74252-25-8; 7681-54-1; 19767-45-4; 3375-50-6; 6923-42-8; 83-43-2; 65271-80-9; 70476-82-3; 22204-53-1; 26159-34-2; 53910-25-1; 53-03-2; 174722-31-7; 57-22-7

AB: Purpose: To conduct a phase I trial of recombinant immunotoxin BL22, an anti-CD22 Fv fragment fused to truncated Pseudomonas exotoxin. Patients and Methods: Forty-six pretreated patients with CD22+ non-Hodgkin's lymphoma (NHL; n = 4), chronic lymphocytic leukemia (CLL; n = 11), and hairy cell leukemia (HCL; n = 31) received 265 cycles at 3 to 50 µg/Kg every other day × 3 doses. Results: BL22 was active in HCL, with 19 complete remissions (CRs; 61%) and six partial responses (PRs; 19%) in 31 patients. Of 19 CRs, 11 were achieved after one cycle and eight after two to 14 cycles. All 25 responders benefited clinically with one cycle. The CR rate was 86% in patients enrolled at > 40 µg/Kg every other day × 3, and 41% at lower doses (P = .011). The median duration for CR was 36 months (range, 5 to 66 months), and eight patients remain in CR at 45 months (range, 29 to 66 months). Lower but significant activity occurred in CLL. Neutralizing antibodies occurred in 11 (24%) of 46 patients (all HCL). A reversible hemolytic uremic syndrome requiring plasmapheresis was observed in one patient with NHL during cycle 1 and in four patients with HCL during cycle 2 or 3. The maximum-tolerated dose (MTD) evaluated at cycle 1 was 40 µg/Kg IV. QOD × 3. The most common toxicities at 30 to 50 µg/Kg every other day × 3 included hypoalbuminemia, transaminase elevations, fatigue, and edema. Conclusion: BL22 was well tolerated and highly effective in HCL, even after one cycle. Phase II testing is underway to define the efficacy with one cycle and to study safety when additional cycles are needed for optimal response. Copyright © 2005 by American Society of Clinical Oncology. All rights reserved.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

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Hematology Immunology, Serology and Transplantation Drug Literature Index Adverse Reactions Titles

3 3/13 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2007002076 AU: Laurencet F; Ballabeni P; Rufener B; Hess U; Cerny T; Fey M; Luthi J-M; Plancherel

C; Zulian GB Titel: The multicenter trial SAKK 37/95 of cladribine, cyclophosphamide and prednisone in

the treatment of chronic lymphocytic leukemias and low-grade non-Hodgkin's lymphomas

Quelle: Acta Haematologica; VOL: 117 (1); p. 40-47 /2007/ Sprache: ENGLISH AL: ENGLISH CY: Switzerland ISSN: 0001-5792 CO: ACHAA Corporate Source:

Dr. G.B. Zulian, Cesco, Geneva University Hospitals, 11, chemin de la Savonnière, CH-1255 Collonge-Bellerive Switzerland [email protected]

COU: Switzerland DT: Journal RN: 0038 MN: Lipo,Switzerland; Lipo TE: cladribine/4291-63-8; cyclophosphamide/50-18-0; fludarabine/21679-14-1;

hemoglobin/9008-02-0; prednisone/53-03-2 CR: 4291-63-8; 50-18-0; 21679-14-1; 9008-02-0; 53-03-2 AB: A multicenter trial was performed to confirm the therapeutic efficacy and the toxicity

profile of the combination of cladribine, cyclophosphamide and prednisone in low-grade non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Twenty-three adults with previously treated (61%) or untreated (39%) NHL International Working Formulation A or Binet B and C CLL were administered cladribine 0.1 mg/kg/day as a subcutaneous bolus for 5 days, intravenous cyclophosphamide 500 mg/m² on day 1, and oral prednisone 40 mg/m² on days 1-5, every 4 weeks. Unexpected early hematological toxicities led to dose modifications for pretreated patients who received cladribine for 3 days only up to a maximum of five courses. Responses were observed in 75%, with 7 patients obtaining a complete clinical and hematological response. Median duration of complete response was 9 months. Median time to progression or relapse was 31 months. Myelosuppression and infections were dose limiting whereas posttreatment complications, including fatalities, resulted from infections. Median overall survival time from trial entry was 60 months. Activity of the combination of cladribine, cyclophosphamide and prednisone was confirmed. However, in the specific setting of a multicenter trial, unexpected fatal infectious episodes occurred in pretreated patients. Great caution is thus required in these susceptible patients and the routine use of corticosteroids should probably be abandoned. Copyright © 2007 S. Karger AG.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index

Page 228: Fludara i.v. (2nd line NHL)

Adverse Reactions Titles 3 3/14 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006579945 AU: Rao R; Shammo JM; Enschede SH; Porter C; Adler SS; Venugopal P; Gregory SA Titel: The combination of fludarabine, cyclophosphamide, and granulocyte-macrophage

colony-stimulating factor in the treatment of patients with relapsed chronic lymphocytic leukemnia and low-grade non-Hodgkin's lymphoma

Quelle: Clinical Lymphoma and Myeloma; VOL: 6 (1); p. 26-30 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1557-9190 Corporate Source:

Dr. R. Rao, Department of Hematology and Oncology, Rush University Medical Center, 1725 W Harrison St, Chicago, IL 60612 United States [email protected]

COU: United States DT: Journal RN: 0021 TE: cyclophosphamide/50-18-0; fludarabine/21679-14-1 CR: 50-18-0; 21679-14-1 AB: Purpose: The goal of this study was to evaluate the efficacy of the

fludarabine/cyclophosphamide combination in patients with relapsed chronic lymphocytic lymphoma (CLL) and low-grade non-Hodgkin's Lymphoma (NHL) and to assess the impact of adding granulocyte-macrophage colony-stimulating factor (GM-CSF) to this regimen in a randomized fashion. Patients and methods: Thirty-four patients (CLL, n = 16; low-grade NHL, n = 18) were enrolled. The median number of previous treatments was 2. Patients received (less-than or equal to) 6 cycles of fludarabine at 30 mg/m² per day and cyclophosphamide at 300 mg/m² per day on days 1-3 of a 28-day cycle. Patients were randomized to supportive care or to receive GM-CSF at 250 µg/m² per day, starting 24 hours after completion of chemotherapy and continuing up to 48 hours before the next cycle. Those who had received > 6 months of previous therapy with an alkylating agent or had preexisting cytopenias received a 25% dose reduction. Twenty-two patients (65%) were randomized to receive GM-CSF. Patients completed a median of 5 cycles of treatment (range, 1-6 cycles). Twenty-seven patients (80%) received (greater-than or equal to) 3 cycles of treatment and were evaluated for response. Results: Seven patients (26%) exhibited a complete response; 6 of the 7 had low-grade NHL. Fourteen patients (52%) exhibited a partial response, and 6 patients (22%) had stable disease. Notably, 6 of the 7 patients who exhibited complete response and 9 of 14 patients with partial responses were randomized to the GM-CSF arm. The duration of response ranged from 4 months to 26 months. The toxicities were mainly hematologic. Nineteen patients (70%) experienced (greater-than or equal to) 1 episode of grade 3/4 neutropenia, but only 4 (15%) experienced febrile neutropenia; 3 of those patients were assigned to the GM-CSF arm. Conclusions: The combination of fludarabine and cyclophosphamide is a well-tolerated and effective treatment regimen for patients with relapsed CLL and low-grade NHL. A higher percentage of complete responses were noted in patients with low-grade NHL compared with patients with CLL. Granulocyte-macrophage colony-stimulating factor did not seem to decrease the incidence of febrile neutropenia. However, the higher number of complete and partial responses noted on the GM-CSF arm is intriguing and warrants further investigation.

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CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

1 3/15 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006530593 AU: Lonial S; Arellano M; Hutcherson D; Langston A; Flowers C; Heffner LT; Winton E;

Lechowicz MJ; Waller EK Titel: Results of a clinical phase I dose-escalation study of cytarabinein combination with

fixed-dose vinorelbine, paclitaxel, etoposide and cisplatin for the treatment of relapsed/refractory lymphoma

Quelle: Leukemia and Lymphoma; VOL: 47 (10); p. 2155-2162 /2006/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 EISSN: 1029-2403 CO: LELYE PII: X71728045356644P Corporate Source:

S. Lonial, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GAUnited States

COU: United States DT: Journal RN: 0029 TE: aciclovir/59277-89-3; bleomycin/11056-06-7; busulfan/55-98-1; carboplatin/41575-94-

4; chlormethine/51-75-2; chlormethine/55-86-7; chlormethine/82905-71-3; ciprofloxacin/85721-33-1; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; cyclophosphamide/50-18-0; cytarabine/147-94-4; cytarabine/69-74-9; dacarbazine/4342-03-4; doxorubicin/23214-92-8; doxorubicin/25316-40-9; etoposide/33419-42-0; fluconazole/86386-73-4; fludarabine/21679-14-1; guanine arabinoside/38819-10-2; ifosfamide/3778-73-2; methylprednisolone/6923-42-8; methylprednisolone/83-43-2; navelbine/71486-22-1; paclitaxel/33069-62-4; penicillin G/1406-05-9; penicillin G/61-33-6; prednisone/53-03-2; procarbazine/366-70-1; procarbazine/671-16-9; rituximab/174722-31-7; vinblastine/865-21-4; vincristine sulfate/2068-78-2; vincristine/57-22-7

CR: 59277-89-3; 11056-06-7; 55-98-1; 41575-94-4; 51-75-2; 55-86-7; 82905-71-3; 85721-33-1; 15663-27-1; 26035-31-4; 96081-74-2; 50-18-0; 147-94-4; 69-74-9; 4342-03-4; 23214-92-8; 25316-40-9; 33419-42-0; 86386-73-4; 21679-14-1; 38819-10-2; 3778-73-2; 6923-42-8; 83-43-2; 71486-22-1; 33069-62-4; 1406-05-9; 61-33-6; 53-03-2; 366-70-1; 671-16-9; 174722-31-7; 865-21-4; 2068-78-2; 57-22-7

AB: Management of relapsed lymphoma depends upon the variables of chemosensitive disease and successful stem cell mobilization. The microtubule specific agents, paclitaxel and vinorelbine, have efficacy in relapsed lymphoma and can enhance stem cell mobilization. We performed a phase I dose-escalation study of cytarabine combined with fixed doses of vinorelbine, paclitaxel, etoposide and cisplatin (VTEPA) for patients with relapsed/refractory lymphoma. The regimen consisted of paclitaxel 175 mg/m² and vinorelbine 30 mg/m² on day 1; cisplatin 20 mg/m² and etoposide 100 mg/m² over 4 h on days 2-5. Cytarabine 2 g m/m² over 4 h, in successive cohorts on

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1, 2, or 3 consecutive days: cohort A day 5; cohort B days 4-5; and cohort C days 3-5. Sixteen patients (Hodgkin's disease, n = 6; non-Hodgkin's lymphoma, n = 10) were enrolled. Fourteen of 16 patients (88%) had refractory and seven patients (44%) had primary refractory disease. Major toxicities included hematologic toxicity, mucositis and infectious complications. Infectious complications (10/16 patients) included neutropenic fever, sepsis and fungal pneumonia. Dose-limiting toxicity was achieved in cohort C, which received three doses of cytarabine. There were 33% partial responses, 27% stable disease and 40% progressive disease following a single cycle of VTEPA. Two of 16 patients suffered treatment-related mortality. Five patients went on to receive autologous (n = 4) or allogeneic transplant (n = 1), and five out of seven patients in this heavily pretreated group who received VTEPA for mobilization of an autologous graft were successfully collected. The recommended dose of cytarabine for further evaluation in a phase II study is 2 g m/m² for 2 consecutive days in combination with VTEPA. Treatment of subjects with relapsed/refractory lymphoma using VTEPA as second- or third-line salvage therapy produced remissions in some patients and permitted collection of grafts and subsequent autologous transplantation, supporting a planned phase II trial.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Drug Literature Index Adverse Reactions Titles

3 3/16 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006530418 AU: Pro B; Hagemeister FB; McLaughlin P; Romaguera J; Rodriguez MA; Cabanillas F;

Tiongson LP; Younes A Titel: Phase 2 study of fludarabine and paclitaxel in patients with recurrent low-grade non-

Hodgkin's lymphoma Quelle: Leukemia and Lymphoma; VOL: 47 (9); p. 1818-1821 /2006/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 EISSN: 1029-2403 CO: LELYE PII: TL21263743741003 Corporate Source:

A. Younes, Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX United States

COU: United States DT: Journal RN: 0009 TE: doxorubicin/23214-92-8; doxorubicin/25316-40-9; fludarabine/21679-14-1;

paclitaxel/33069-62-4 CR: 23214-92-8; 25316-40-9; 21679-14-1; 33069-62-4 AB: Although numerous options are available for patients with recurrent low-grade non-

Hodgkin's lymphoma (NHL), responses are rarely durable. We previously conducted a phase I trial of fludarabine and paclitaxel in the treatement of recurrent low-grade lymphoma. The present phase II study was performed to determine the activity of fludarabine and paclitaxel in patients with recurrent low-grade NHL. Patients with

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histologically confirmed recurrent low-grade NHL were treated with fludarabine 20 mg/m²/day intravenously (i.v.) on days 1-5 plus paclitaxel 50 mg/m² given by i.v. continuous infusion over 72 h starting on day 1. Treatment was repeated at 4-week intervals for a maximum of six courses. Twenty-eight evaluable patients were entered into this phase II trial. The median age was 53 years and the median performance status (Zubrod) was 1. Twenty-two (78%) patients had grade 1 or 2 follicular lymphoma, and six patients (21%) had small lymphocytic lymphoma. The median number of prior chemotherapy regimens was 1 (range, 1-3). Objective responses occurred in 16 patients (57%); nine patients (32%) achieved a complete remission with a median duration of 32 months (range 4-84+ months), and seven patients (25%) had a partial remission. Grade 3 and 4 toxicities included neutropenia (72%), neutropenic fever (34%), infection (13%), mucositis (7%), and neuropathy (3%). The combination of fludarabine and paclitaxel has clinical activity in patients with recurrent low-grade NHL.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles General Pathology and Pathological Anatomy

1 3/17 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006379772 AU: Johnston PB; Bondly C; Micallef INM Titel: Ibritumomab tiuxetan for non-Hodgkin's lymphoma Quelle: Expert Review of Anticancer Therapy; VOL: 6 (6); p. 861-869 /2006/

http://www.future-drugs.com/doi/full/10.1586/14737140.6.6.861Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1473-7140 EISSN: 1744-8328 CO: ERATB Corporate Source:

Dr. I.N.M. Micallef, Division of Hematology, Department of Internal Medicine, Mayo Clinic College of Medicine, 200 First St. SW, Rochester, MN 55905 United States [email protected]

COU: United States DT: Journal RN: 0037 DN: zevalin; oprelvekin; bexxar TE: ibritumomab tiuxetan/206181-63-7; yttrium 90/10098-91-6; rituximab/174722-31-7;

cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2; recombinant granulocyte colony stimulating factor/121181-53-1; recombinant interleukin 11/145941-26-0; carmustine/154-93-8; etoposide/33419-42-0; cytarabine/147-94-4; cytarabine/69-74-9; melphalan/148-82-3; nitrosourea/13010-20-3; mitomycin/1404-00-8; erythropoietin/11096-26-7; fludarabine/21679-14-1; lenalidomide/191732-72-6; tositumomab i 131/192391-48-3

CR: 206181-63-7; 10098-91-6; 174722-31-7; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2; 121181-53-1; 145941-26-0; 154-93-8; 33419-42-0; 147-94-4; 69-74-9; 148-82-3; 13010-20-3; 1404-00-8; 11096-26-7; 21679-14-1; 191732-72-6; 192391-48-3

AB: Targeted radiation therapy, or radioimmunotherapy, has been an important recent

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advancement in the treatment of patients with B-cell non-Hodgkin's lymphoma (NHL). (sup(90))Y ibritumomab tiuxetan comprises the murine monoclonal antibody ibritumomab, the linker chelator tiuxetan and the radiolabeled isotope (sup(90))yttrium. (sup(90))Y ibritumomab tiuxetan has been demonstrated to be efficacious in the treatment of B-cell NHL. Initial Phase I/II trials established the therapeutic dose of ibritumomab tiuxetan for low-grade NHL to be 0.4 mCi/kg, or 0.3 mCi/kg for patients with mild thrombocytopenia. Currently, there are many ongoing trials of ibritumomab tiuxetan with different dose schedules and intensities, in combination with chemotherapy and with stem cell transplantation, in an attempt to improve response rate and duration and to study its effectiveness in other B-cell lymphomas, including diffuse large B-cell lymphoma and mantle cell lymphoma. Radioimmunotherapy has great promise and the safe incorporation of (sup(90))Y ibritumomab tiuxetan into treatment will hopefully result in improved survival for patients with NHL. © 2006 Future Drugs Ltd.

CNOTE: Copyright 2006 Elsevier B.V., All rights reserved. ET: Cancer

Nuclear Medicine Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3 3/18 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006356356 AU: Leonard JP; Furman RR; Coleman M Titel: Proteasome inhibition with bortezomib: A new therapeutic strategy for non-Hodgkin's

lymphoma Quelle: International Journal of Cancer; VOL: 119 (5); p. 971-979 /01 SEP 2006/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0020-7136 EISSN: 1097-0215 CO: IJCNA Corporate Source:

J.P. Leonard, Division of Hematology and Medical Oncology, Weill Medical College of Cornell University, New York Presbyterian Hospital, 525 East 68th Street, New York, NY 10021 United States [email protected]

COU: United States DT: Journal RN: 0105 DN: velcade/Millennium; adriamycin MN: Millennium TE: bortezomib/179324-69-7; bortezomib/197730-97-5; docetaxel/114977-28-5;

gemcitabine/103882-84-4; carboplatin/41575-94-4; 4 hydroperoxycyclophosphamide/39800-16-3; cyclophosphamide/50-18-0; vincristine/57-22-7; prednisone/53-03-2; rituximab/174722-31-7; doxorubicin/23214-92-8; doxorubicin/25316-40-9; fludarabine/21679-14-1; cladribine/4291-63-8; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; chlorambucil/305-03-3; tositumomab i 131/192391-48-3; ibritumomab tiuxetan/206181-63-7; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5;

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dexamethasone/50-02-2; cytarabine/147-94-4; cytarabine/69-74-9; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; melphalan/148-82-3; thalidomide/50-35-1; flavopiridol/146426-40-6; etoposide/33419-42-0

CR: 179324-69-7; 197730-97-5; 114977-28-5; 103882-84-4; 41575-94-4; 39800-16-3; 50-18-0; 57-22-7; 53-03-2; 174722-31-7; 23214-92-8; 25316-40-9; 21679-14-1; 4291-63-8; 65271-80-9; 70476-82-3; 305-03-3; 192391-48-3; 206181-63-7; 15475-56-6; 59-05-2; 7413-34-5; 50-02-2; 147-94-4; 69-74-9; 15663-27-1; 26035-31-4; 96081-74-2; 148-82-3; 50-35-1; 146426-40-6; 33419-42-0

AB: The incidence of non-Hodgkin's lymphoma (NHL) has markedly increased in the US and other westernized countries in recent years and presents a considerable clinical challenge. NHL is divided into subtypes that follow an aggressive or indolent course. Follicular lymphoma (FL), the most common indolent subtype, and mantle cell lymphoma (MCL), an aggressive subtype that accounts for approximately 5% of cases, are generally incurable. MCL has a relatively poor prognosis, with a median survival of 3-4 years. Despite improving response rates with new agents and regimens, the lack of demonstrated improvement in overall survival in many subtypes supports the development of novel approaches, such as proteasome inhibition. Bortezomib is the first proteasome inhibitor to be evaluated in human studies. It has already been approved as second-line treatment in multiple myeloma and is now under active investigation in NHL. The US FDA has granted bortezomib fast-track designation for relapsed and refractory MCL. In vitro and in vivo studies have demonstrated single-agent activity against various lymphoid tumors, and additive or synergistic effects in combination with other agents, including standard chemotherapy drugs employed in NHL. Phase 2 clinical trials indicate that bortezomib is well tolerated and active in several NHL subtypes, with response rates of 18-60% in FL and 39-56% in MCL. A number of combination trials are currently underway with a range of standard agents. Bortezomib has the potential to play a significant role throughout the NHL treatment algorithm in the future. © 2006 Wiley-Liss, Inc.

CNOTE: Copyright 2006 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3 3/19 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006326657 AU: Vose JM Titel: Personalized immunotherapy for the treatment of non-Hodgkin's lymphoma: A

promising approach Quelle: Hematological Oncology; VOL: 24 (2); p. 47-55 /2006/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 0278-0232 EISSN: 1099-1069 CO: HAOND Corporate Source:

Prof. J.M. Vose, Section of Oncology/Hematology, University of Nebraska Medical Center, Omaha, NE 681980-7680 United States [email protected]

COU: United States DT: Journal

Page 234: Fludara i.v. (2nd line NHL)

RN: 0064 TE: rituximab/174722-31-7; chlorambucil/305-03-3; cyclophosphamide/50-18-0;

vincristine/57-22-7; cladribine/4291-63-8; fludarabine/21679-14-1; prednisone/53-03-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; alemtuzumab/216503-57-0; epratuzumab/205923-57-5

CR: 174722-31-7; 305-03-3; 50-18-0; 57-22-7; 4291-63-8; 21679-14-1; 53-03-2; 23214-92-8; 25316-40-9; 216503-57-0; 205923-57-5

AB: The efficacy of immunotherapeutic strategies for the treatment of lymphoid malignancies has been demonstrated in recent years. In patients with B-cell lymphomas, particularly indolent lymphoma, the use of passive immunotherapy, such as the anti-CD20 monoclonal antibody rituximab, has made an impressive impact on patient outcome. Personalized immunotherapy, a method that triggers the immune system to mount a response against tumor cells, has shown promising results in early clinical trials in hematologic malignancies. This therapeutic modality appears safe, with the most common adverse events being transient, local reactions at the site of injection. Furthermore, personalized immunotherapy has the potential to generate immunologic memory, which could provide prolonged remission. Currently, 3 large phase III studies are evaluating the efficacy and safety of personalized immunotherapy in patients with follicular lymphoma [1-3]. It is hoped that the results of these studies will lead to the incorporation of this promising approach into the standard treatment of patients with lymphoma. Copyright © 2006 John Wiley & Sons, Ltd.

CNOTE: Copyright 2006 Elsevier B.V., All rights reserved. ET: Hematology

Immunology, Serology and Transplantation Pharmacology Drug Literature Index Adverse Reactions Titles

3 3/20 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006314371 AU: Goranov St Titel: Follicular non-Hodgkin lymfomas: Therapeutic options and challenges Quelle: Clinical and Transfusion Haematology; VOL: 41 (1-2); p. 24-29 /2005/ Sprache: BULGARIAN AL: ENGLISH CY: Bulgaria ISSN: 0861-7880 CO: KTKLB Corporate Source:

St. Goranov, Clinic of Haematology, University Multiprofile Hospital for Active Treatment Sv. Georgri, Plovidv Bulgaria

COU: Bulgaria DT: Journal RN: 0024 DN: chlorbutin; mabthera; campath 1h; bexxar; zevalin TE: chlorambucil/305-03-3; bendamustine/16506-27-7; bendamustine/3543-75-7;

cyclophosphamide/50-18-0; fludarabine/21679-14-1; cladribine/4291-63-8; prednisolone/50-24-8; vincristine/57-22-7; prednisone/53-03-2; bleomycin/11056-06-7; doxorubicin/23214-92-8; doxorubicin/25316-40-9; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; cytarabine/147-94-4; cytarabine/69-74-9;

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dexamethasone/50-02-2; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5; ifosfamide/3778-73-2; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; etoposide/33419-42-0; carmustine/154-93-8; melphalan/148-82-3; rituximab/174722-31-7; alemtuzumab/216503-57-0; epratuzumab/205923-57-5; apolizumab/267227-08-7; tositumomab i 131/192391-48-3; ibritumomab tiuxetan/206181-63-7; sunitinib/341031-54-7; sunitinib/557795-19-4

CR: 305-03-3; 16506-27-7; 3543-75-7; 50-18-0; 21679-14-1; 4291-63-8; 50-24-8; 57-22-7; 53-03-2; 11056-06-7; 23214-92-8; 25316-40-9; 15663-27-1; 26035-31-4; 96081-74-2; 147-94-4; 69-74-9; 50-02-2; 15475-56-6; 59-05-2; 7413-34-5; 3778-73-2; 65271-80-9; 70476-82-3; 33419-42-0; 154-93-8; 148-82-3; 174722-31-7; 216503-57-0; 205923-57-5; 267227-08-7; 192391-48-3; 206181-63-7; 341031-54-7; 557795-19-4

AB: The follicullar non-Hodgkin lymphomas (F-NHL) represent the neoplastic equivalent of the normal cells in th germinative centre. The therapeutic strategy in F-NHL is based rather on the presence/absence of risk factors (RF) than on the clinical stage and histological variant (grade). Chronologically, the therapeutic choice is based on 4 consequent strategies: 1. "Watch and wait" in localized stages and lack of RF. 2. Intensive regimens in patients with RF - "More is better". 3. Transplantation. 4. Novel options for "Superadditive response rates". The scientific advance in the molecullar biology of lymphomas made available for clinical practice a new generation of therapeutic agents: the so-called drug-molecules. Their target is not only the separate structure of the lymphoma cell, but also the concrete phases of the malignant cell cycle; blockade of the auto- or paracrine signals regarding the proliferation, survival and apoptosis. Besides the monoclonal antibodies, now clinicians have a real therapeutic challenge in the face of idiotype DNA vaccines, proteasome inhibitors, the inhibitors of farnesyl transferase and neoangiogenesis and antisense oligonucleotides. These novel therapeutic options result in a significant increase of response rates; "purging" of the residual clonal population, improved control over the minimal residual disease, low toxicity and better efficacy of conventional chemotherapy.

CNOTE: Copyright 2006 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index

3, 6 3/21 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006249274 AU: Cvetkovic RS; Perry CM Titel: Rituximab: A review of its use in non-Hodgkin's lymphoma and chronic lymphocytic

leukaemia Quelle: Drugs; VOL: 66 (6); p. 791-820 /2006/

http://drugs.adisonline.com/pt/re/drugs/pdfhandler.00003495-200666060-00005.pdf;jsessionid=GykTLcWPBmSn1MLJFMfc2kZ4QyTpyLGJYN8clVNch8fpL YsskHbz!50530596!-949856144!8091!-1

Sprache: ENGLISH AL: ENGLISH CY: New Zealand ISSN: 0012-6667 EISSN: 0012-6667 CO: DRUGA Corporate Source:

R.S. Cvetkovic, Adis International Limited, 41 Centorian Drive, Mairangi Bay, Auckland 1311 New Zealand

Page 236: Fludara i.v. (2nd line NHL)

[email protected] COU: New Zealand DT: Journal RN: 0108 DN: mabthera; rituxan TE: rituximab/174722-31-7; cyclophosphamide/50-18-0; doxorubicin/23214-92-8;

doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2 CR: 174722-31-7; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2 AB: Rituximab (MabThera®, Rituxan®) is an anti-CD20 monoclonal antibody that induces

lysis and apoptosis of normal and malignant human B cells, and sensitises malignant B cells to the cytotoxic effect of chemotherapy. In phase III trials in patients with indolent or aggressive B-cell non-Hodgkin's lymphoma (NHL), intravenous rituximab in combination with chemotherapy was more effective as first- or second-line therapy than chemotherapy alone in providing tumour remission and patient survival. Likewise, in patients with chronic lymphocytic leukaemia (CLL), rituximab in combination with chemotherapy appeared more effective than chemotherapy alone as either first- or second-line treatment. In addition, rituximab maintenance therapy was shown to significantly prolong tumour remission and patient survival in patients with indolent B-cell NHL or CLL. The combination of rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) was cost effective as first-line therapy for advanced-stage diffuse large B-cell NHL compared with CHOP alone. Rituximab, either alone or in combination with chemotherapy, was generally well tolerated in patients with NHL or CLL. Overall, rituximab in combination with chemotherapy, is a valuable option for first- and second-line therapy in patients with advanced-stage indolent or aggressive B-cell NHL, and possibly those with B-cell CLL, and is included in current treatment guidelines for these indications. The drug is also potentially useful as maintenance therapy in patients with indolent B-cell NHL or CLL. Pharmacological Properties: Rituximab is a chimaeric murine/human monoclonal antibody directed against the surface antigen CD20 expressed on all normal and >90% of NHL and 14% of CLL malignant B cells. It induces lysis and apoptosis of all CD20-positive B cells and also sensitises malignant B cells to the cytotoxic effect of chemotherapy. At the recommended dose, rituximab causes rapid and profound B-cell lymphopenia in the majority of patients that lasts for up to 6 months and recovers (from haematopoietic stem cells) within 9-12 months after treatment. As maintenance therapy, rituximab would continue suppression of the B-cell population, including the malignant variety. Following intravenous administration of rituximab in patients with B-cell NHL, drug serum concentrations increase in a dose-proportional manner (within clinically relevant dosage range), are positively correlated with clinical tumour responses (i.e. they are significantly higher in patients responding to rituximab monotherapy than in nonresponders) and are inversely correlated to the absolute level of circulating peripheral B cells and the tumour bulk measurements at baseline. The pharmacokinetics of rituximab are also characterised by accumulation of the drug with repeated administrations (reflecting the change in the population of CD20-positive B cells) and wide interindividual variability (caused by variable tumour responsiveness and burden between patients). Clinically relevant drug concentrations are present in the serum (less-than or equal to)6 months after, and were also found in the CNS during treatment with rituximab. The pharmacokinetics of rituximab appear to be similar in patients with follicular or diffuse large B-cell NHL, and are unaffected by the coadministration of CHOP. Significantly lower serum concentrations of rituximab were found in patients with a lymphomatous form of B-cell CLL, compared with values in patients with B-cell NHL. Therapeutic Efficacy: Indolent NHL: In phase III trials in patients with previously untreated advanced-stage follicular NHL, the addition of rituximab 375 mg/m ² (as an

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intravenous infusion) to 6-8 cycles of standard chemotherapy regimens was more effective in achieving tumour remission (i.e. complete response [CR]) and short-term (2.5-year) event-free survival (EFS) rates than chemotherapy alone. In combination with cyclophosphamide, vincristine and prednisone (CVP), rituximab also significantly prolonged the duration of tumour response (>2-fold), failure-free (4-fold) and disease-free survival (DFS) [>2-fold], and more than doubled the time to disease progression. At the estimated 3-year follow-up, these effects have not yet translated into a significantly greater overall survival (OS) rate compared with CVP alone (89% vs 81%), although both results are clinically relevant. Importantly, however, patients receiving rituximab in addition to CVP spent significantly longer time without disease symptoms or toxicity, and had a substantially improved quality-adjusted survival than patients receiving CVP alone. In patients with advanced follicular NHL, first-line therapy with rituximab in combination with mitoxantrone, chlorambucil and prednisone (MCP) also resulted in significantly longer progression-free survival (PFS) and OS rates than MCP alone. As a second-line therapy in patients with relapsed or refractory follicular NHL, the addition of a single dose of rituximab to each of six cycles of CHOP or four cycles of fludarabine, cyclophosphamide and mitoxantrone (FCM) regimens significantly improved CR and objective response (OR) rates and prolonged PFS compared with chemotherapy alone in two phase III trials. A significantly improved 4-year OS rate was also reported in a trial with FCM. The significant survival benefit of adding rituximab to first- or second-line chemotherapy regimens in patients with follicular NHL was confirmed in a meta-analysis of data from several randomised, phase III trials As monotherapy, four once-weekly intravenous infusions of rituximab 375 mg/m² produced clinically relevant CR and OR rates in two phase II trials in patients with mucosa-associated lymphoid tissue B-cell NHL. One of the trials showed 2-fold longer (p = 0.001) failure-free survival in chemotherapy-naive than in chemotherapy-experienced patients receiving rituximab monotherapy. Likewise, maintenance therapy with single-agent rituximab 375 mg/m² (four once-weekly doses repeated every 6 months or single infusion every 2-3 months, for up to 2 years or until relapse), significantly increased CR and/or OR rates, and prolonged duration of remission, EFS and/or PFS after induction therapy in patients with follicular NHL or CLL (lymphomatous form), compared with rituximab re-treatment (at disease progression) [in a phase II trial] or observation (i.e. no further treatment) [in three phase III trials]. Rituximab maintenance therapy provided significantly greater 3- and 4-year PFS and OS rates in both previously treated and untreated patients with follicular NHL, compared with no further treatment. The estimated 3-year OS rates were high with both the rituximab maintenance and re-treatment approach, but results were not statistically significantly different (72% vs 68%) in previously untreated patients. Aggressive NHL: The combination of rituximab 375 mg/m² intravenous infusions with a CHOP or a CHOP-like regimen, administered in 6-8 cycles, was more effective than chemotherapy alone as the first-line treatment in patients with advanced-stage, diffuse large B-cell NHL or mantle cell lymphoma (MCL), in several phase III trials. Irrespective of the age of patients with diffuse, large B-cell NHL, the addition of rituximab resulted in significantly greater CR, 2- to 3-year failure-free survival and 2- to 5-year OS rates (the latter effect was observed only in low-risk patients). A significantly greater 5-year PFS rate was also reported with rituximab plus CHOP in a trial in older patients (age (greater-than or equal to)60 years) irrespective of disease prognosis. In younger patients (age <60 years) with low-risk disease, rituximab plus CHOP or CHOP-like regimen significantly decreased the relative risk of treatment failure (by 64%) compared with chemotherapy alone. Significantly greater 1-year failure-free or 4-year OS rates were observed in patients with MCL receiving intravenous infusions of rituximab 375 mg/m ² in combination with first-line CHOP (six cycles) or second-line FCM (four cycles), than those receiving chemotherapy alone, in two randomised, phase III trials. Meta-analysis of data from both trials confirmed the OS benefit of adding rituximab to chemotherapy in patients with MCL, both previously untreated or those with relapsed or refractory MCL.

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Rituximab did not improve either tumour response or survival rates in patients with HIV-related, aggressive B-cell NHL, while increasing the risk of infectious death, in a randomised, phase III trial. By contrast, the findings of previous phase I and II trials suggested that rituximab therapy may be beneficial in this patient population. Rituximab maintenance therapy was effective in patients with diffuse large B-cell NHL, only when the drug was not part of an induction regimen, and was ineffective in patients with MCL. CLL: Standard rituximab monotherapy (i.e. four intravenous infusions of 375 mg/m² once weekly) was less effective than fludarabine monotherapy in phase II trials in patients with B-cell CLL. However, the addition of rituximab 375 or 500 mg/m² to six cycles of fludarabine (with or without cyclophosphamide) significantly improved response (CR and/or OR) and survival (2- to 4-year PFS and/or OS) rates in these patients, compared with chemotherapy alone in retrospective comparative analyses of several phase II and III trials. Tolerability: Rituximab, alone or in combination with various chemotherapy regimens, was generally well tolerated in clinical trials in patients with advanced-stage indolent or aggressive B-cell NHL or B-cell CLL. The most common types of adverse events in these trials were infusion-related reactions, haematological adverse events and infections. © 2006 Adis Data Information BV. All rights reserved.

CNOTE: Copyright 2006 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Health Policy, Economics and Management Drug Literature Index

6 3/22 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006059016 AU: Vose J Titel: Personalized immunotherapy for the treatment of non-Hodgkin lymphoma: A

promising approach Quelle: Clinical Advances in Hematology and Oncology; VOL: 3 (12); p. 923-932 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1543-0790 Corporate Source:

Dr. J. Vose, Section of Oncology/Hematology, University of Nebraska Medical Center, Omaha, NE 681980-7680 United States [email protected]

COU: United States DT: Journal RN: 0064 DN: rituxan/Genentech; zevalin/Biogen Idec; bexxar/Glaxo SmithKline; campath/Berlex;

myvax personalized immunotherapy/Genitope MN: Genentech; Biogen Idec; Glaxo SmithKline; Berlex; Amgen; Genitope TE: rituximab/174722-31-7; chlorambucil/305-03-3; cyclophosphamide/50-18-0;

cladribine/4291-63-8; fludarabine/21679-14-1; vincristine/57-22-7; prednisone/53-03-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; ibritumomab tiuxetan/206181-

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63-7; tositumomab i 131/192391-48-3; alemtuzumab/216503-57-0; epratuzumab/205923-57-5

CR: 174722-31-7; 305-03-3; 50-18-0; 4291-63-8; 21679-14-1; 57-22-7; 53-03-2; 23214-92-8; 25316-40-9; 206181-63-7; 192391-48-3; 216503-57-0; 205923-57-5

AB: The efficacy of immunotherapeutic strategies for the treatment of lymphoid malignancies has been demonstrated in recent years. In patients with B-cell lymphomas, particularly indolent lymphoma, the use of passive immunotherapy, such as the anti-CD20 monoclonal antibody rituximab, has made an impressive impact on patient outcome. Personalized immunotherapy, a method that triggers the immune system to mount a response against tumor cells, has shown promising results in early clinical trials in hematologic malignancies. This therapeutic modality appears safe, with the most common adverse events being transient, local reactions at the site of injection. Furthermore, personalized immunotherapy has the potential to generate immunologic memory, which could provide prolonged remission. Currently, 3 large phase III studies are evaluating the efficacy and safety of personalized immunotherapy in patients with follicular lymphoma. It is hoped that the results of these studies will lead to the incorporation of this promising approach into the standard treatment of patients with lymphoma.

CNOTE: Copyright 2006 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Drug Literature Index Adverse Reactions Titles Pharmacy

3 3/23 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006055731 AU: Ogawa Y; Hotta T; Tobinai K; Watanabe T; Sasaki Y; Minami H; Morishima Y; Ogura

M; Seriu T Titel: Phase I and pharmacokinetic study of oral fludarabine phosphate in relapsed indolent

B-cell non-Hodgkin's lymphoma Quelle: Annals of Oncology; VOL: 17 (2); p. 330-333 /2006/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 0923-7534 EISSN: 1569-8041 CO: ANONE Corporate Source:

Dr. Y. Ogawa, Department of Hematology and Oncology, Tokai University School of Medicine, 143 Shimokasuya, Isehara-shi, Kanagawa Japan [email protected]

COU: Japan DT: Journal RN: 0012 MN: Schering AG,Japan; Schering AG

Page 240: Fludara i.v. (2nd line NHL)

TE: fludarabine phosphate/75607-67-9; rituximab/174722-31-7; alanine aminotransferase/9000-86-6; alanine aminotransferase/9014-30-6; aspartate aminotransferase/9000-97-9; alkaline phosphatase/9001-78-9

CR: 75607-67-9; 174722-31-7; 9000-86-6; 9014-30-6; 9000-97-9; 9001-78-9 AB: Background: The primary objective of this study was to investigate the tolerability,

efficacy and pharmacokinetic profile of oral fludarabine phosphate in relapsed patients with indolent B-cell non-Hodgkin's lymphoma (B-NHL). Patients and methods: Patients received fludarabine phosphate orally for 5 days, for a total of one to three cycles. Tolerability was assessed using the National Cancer Institute Common Toxicity Criteria. Efficacy was assessed using the International Workshop Criteria for NHL. Pharmacokinetic samples were taken on day 1 and day 5 of the first treatment cycle. Results: Twelve patients were enrolled. One patient at 40 mg/m²/day developed grade 4 hyperuricemia. At 50 mg/m²/day, one patient developed grade 3 febrile neutropenia and grade 4 leukopenia, and another patient showed lasting grade 4 neutropenia. Most common toxicities included grade 3 or 4 lymphopenia (83%), leukopenia (50%) and neutropenia (50%). All the toxicities were reversible. The overall response rate was 67%. The AUC(sub(0-24h)) values on day 5 indicated a dose-dependent increase in systemically available 2-fluoro-arabinofuranosyl-adenine (2F-ara-A). Conclusions: Oral fludarabine phosphate is safe and effective for relapsed patients with indolent B-NHL. The dose of 40 mg/m²/day is recommended for a following pivotal phase II study. © 2005 European Society for Medical Oncology.

CNOTE: Copyright 2006 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3 3/24 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005559038 AU: Lissitchkov T; Arnaudov G; Peytchev D; Merkle Kh Titel: Phase-I/II study to evaluate dose limiting toxicity, maximum tolerated dose, and

tolerability of bendamustine HCl in pre-treated patients with B-chronic lymphocytic leukaemia (Binet stages B and C) requiring therapy

Quelle: Journal of Cancer Research and Clinical Oncology; VOL: 132 (2); p. 99-104 /2006/ Sprache: ENGLISH AL: ENGLISH CY: Germany ISSN: 0171-5216 CO: JCROD Corporate Source:

T. Lissitchkov, National Center of Haematology and Transfusiology, 6 Plovdivsko Pole, 1746 Sofia Bulgaria [email protected]

COU: Bulgaria DT: Journal RN: 0013 TE: bendamustine/16506-27-7; bendamustine/3543-75-7; fludarabine/21679-14-1;

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bilirubin/18422-02-1; bilirubin/635-65-4 CR: 16506-27-7; 3543-75-7; 21679-14-1; 18422-02-1; 635-65-4 AB: Purpose: Bendamustine hydrochloride, an antineoplastic agent with unique

mechanism of action, is known to cause impressive remissions in relapsed non-Hodgkin's lymphoma and chronic lymphocytic leukaemia (CLL). Optimal bendamustine dosing for CLL patients had not been finally established and a phase I/II study was conducted to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of bendamustine. Methods: The open-label, single-centre phase I/II study was conducted from March 2001 to September 2002 in Sofia, Bulgaria. The 15 study patients were extendedly pre-treated, but fludarabine-naive (3 female, 12 male, 47-72 years of age, 61 years on average). Bendamustine was given at a starting dose of 100 mg/m² on days 1 and 2 every 3 weeks based on the previous results in lymphoma. Results: Bendamustine was well tolerated in spite of heavy pre-treatment of the study participants. Toxicity corresponded to the known safety profile of bendamustine, with the exception of bilirubin elevation. The level of 110 mg/m² was established as MTD. A bendamustine dose of 100 mg/m² is the recommended dose for further clinical investigations. A 4-week interval is recommended to allow for sufficient recovery. Efficacy results confirmed powerful anti-neoplastic activity of bendamustine even in extendedly pretreated CLL patients. Based on the remission criteria, nine patients were defined as responders (four CRs, two PR, three NC) and two patients as nonresponders to therapy. Four patients were not evaluable for response, because they had received less than three courses bendamustine. After a follow-up period of 15 months, the four patients with CR were still in remission. One patient with PR had relapsed, the other had ongoing response. Conclusions: Bendamustine is a very active and well-tolerated drug in patients with pre-treated and refractory CLL. Fludarabine-naivity of patients appears to markedly improve their bendamustine tolerability. First-line use of bendamustine is a safe option for CLL-patients requiring treatment, because bendamustine - owing to its unique pharmacodynamics - (1) is highly effective, (2) reasonably safe, and (3) does hardly produce cross-resistance against other anti-neoplastic drugs effective in this indication. © Springer-Verlag 2005.

CNOTE: Copyright 2006 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3 3/25 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005511520 AU: Soubeyran P; Monnereau A; Eghbali H; Soubeyran I; Kind M; Cany L; Buy E; Guibon

O; Hörni B Titel: Fludarabine phosphate-CVP in patients over 60 years of age with advanced, low-

grade and follicular lymphoma: A dose-finding study Quelle: European Journal of Cancer; VOL: 41 (17); p. 2630-2636 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 0959-8049 CO: EJCAE

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PII: S0959804905007239 Corporate Source:

[email protected]

DT: Journal RN: 0040 DN: fludara TE: creatinine/19230-81-0; creatinine/60-27-5; cyclophosphamide/50-18-0; fludarabine

phosphate/75607-67-9; prednisone/53-03-2 CR: 19230-81-0; 60-27-5; 50-18-0; 75607-67-9; 53-03-2 AB: The aim of this study was to establish a safe and effective regimen of fludarabine

phosphate, cyclophosphamide, vincristine and prednisone (F-CVP) as first-line treatment for elderly patients with advanced, low-grade non-Hodgkin's lymphoma. Twenty-three patients >60 years were assigned successively to eight treatment cycles (Dose level 1: low F, low CV [n = 4]; 2A: high F, low CV [n = 8]; 2B: low F, high CV [n = 4]; 3: high F, high CV [n = 7]). High and low levels were: F, 25 and 20 mg/m², respectively (Days 1-5); C, 750 and 500 mg/m², respectively (Day 1); and V, 1.4 and 1 mg/m², respectively (Day 1). Patients received P at 40 mg/m² on Days 1-5. Response was assessed after Cycles 2, 4, 6 and 8. At level 3, dose-limiting toxicity (opportunistic infections and neutropenia) became evident, particularly after Cycle 6. Further patients were recruited at Dose level 2A. All regimens proved effective, with an OR rate of 78% (65% CR), and 3-year survival of 65% (±10%). Among 18 responders, 51% were still in response at 3 and 5 years. The study shows that this combination therapy is highly effective. The addition of F to CVP at Dose level 2A was feasible and increased the CR rate, with good tolerability in elderly patients. © 2005 Elsevier Ltd. All rights reserved.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

1 3/26 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005389891 AU: Kaplan LD; Lee JY; Ambinder RF; Sparano JA; Cesarman E; Chadburn A; Levine

AM; Scadden DT Titel: Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP

with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010

Quelle: Blood; VOL: 106 (5); p. 1538-1543 /01 SEP 2005/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0006-4971 CO: BLOOA Corporate Source:

L.D. Kaplan, Division of Hematology/Oncology, University of California, 400 Parnassus Ave, San Francisco, CA 94143 United States [email protected]

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COU: United States DT: Journal RN: 0026 MN: Genentech,United States; Genentech TE: rituximab/174722-31-7; cyclophosphamide/50-18-0; doxorubicin/23214-92-8;

doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2; protein bcl 2/219306-68-0; cotrimoxazole/8064-90-2; dapsone/80-08-0; pentamidine/100-33-4; cytarabine/147-94-4; cytarabine/69-74-9; immunoglobulin/9007-83-4; proteinase inhibitor/37205-61-1; alkaline phosphatase/9001-78-9; aspartate aminotransferase/9000-97-9; alanine aminotransferase/9000-86-6; alanine aminotransferase/9014-30-6; etoposide/33419-42-0; fludarabine/21679-14-1

CR: 174722-31-7; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2; 219306-68-0; 8064-90-2; 80-08-0; 100-33-4; 147-94-4; 69-74-9; 9007-83-4; 37205-61-1; 9001-78-9; 9000-97-9; 9000-86-6; 9014-30-6; 33419-42-0; 21679-14-1

AB: The addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy results in significant improvement in clinical outcome for individuals with non-HIV-associated aggressive B-cell lymphoma. To assess the potential risks and benefits of the addition of rituximab to CHOP for HIV-associated non-Hodgkin lymphoma (HIV-NHL) 150 patients receiving CHOP for HIV-NHL were randomized (2:1) to receive 375 mg/m ² rituximab with each chemotherapy cycle (n = 99) or no immunotherapy (n = 50) in a multicenter phase 3 trial. The complete response rate (CR + CRu) was 57.6% for R-CHOP and 47% for CHOP (P = .147). With a median follow-up of 137 weeks, time to progression, progression-free survival, and overall survival times were 125, 45, and 139 weeks, respectively, for R-CHOP and 85, 38, and 110 weeks, respectively, for CHOP (P = not significant, all comparisons). Treatment-related infectious deaths occurred in 14% of patients receiving R-CHOP compared with 2% in the chemotherapy-alone group (P = .035). Of these deaths, 60% occurred in patients with CD4 counts less than 50/mm³. Progression-free survival was significantly influenced by CD4(sup(+)) count (P < .001) and International Prognostic Index score (P = .022), but not bcl-2 status. The addition of rituximab to CHOP in patients with HIV-NHL may be associated with improved tumor responses. However, these benefits may be offset by an increase in infectious deaths, particularly in those individuals with CD4+ lymphocyte counts less than 50/mm³. © 2005 by The American Society of Hematology.

CNOTE: Copyright 2005 Elsevier B.V., All rights reserved. ET: Internal Medicine

Cancer Hematology Drug Literature Index Adverse Reactions Titles

3 3/27 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005350850 AU: Corradini P; Dodero A; Zallio F; Caracciolo D; Casini M; Bregni M; Narni F; Patriarca

F; Boccadoro M; Benedetti F; Rambaldi A; Gianni AM; Tarella C Titel: Graft-versus-lymphoma effect in relapsed peripheral T-cell non-Hodgkin's

lymphomas after reduced-intensity conditioning followed by allogeneic transplantation of hematopoietic cells

Quelle: Journal of Clinical Oncology; VOL: 22 (11); p. 2172-2176 /2004/

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Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND Corporate Source:

Dr. P. Corradini, Division of Hematology-Bone Marrow Transplantation, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian, 1, 20133 Milano Italy [email protected]

COU: Italy DT: Journal RN: 0016 TE: thiotepa/52-24-4; fludarabine/21679-14-1; cyclophosphamide/50-18-0;

cyclosporin/79217-60-0; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5

CR: 52-24-4; 21679-14-1; 50-18-0; 79217-60-0; 15475-56-6; 59-05-2; 7413-34-5 AB: Purpose: Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of

malignancies characterized by a poor prognosis. We performed a pilot study to investigate the role of reduced-intensity conditioning (RIC) followed by allogeneic stem-cell transplantation in relapsed or refractory PTCLs. Patients and Methods: We have conducted a phase II trial on 17 patients receiving salvage chemotherapy followed by RIC and allogeneic transplantation of hematopoietic cells. The RIC regimen consisted of thiotepa, fludarabine, and cyclophosphamide. The acute graft-versus-host disease prophylaxis consisted of cyslosporine and short course methotrexate. Results: Patients had a median age of 41 years (range, 23 to 60 years). Two patients were primary chemorefractory, and 15 had relapsed disease; eight patients (47%) had a disease relapse after an autologous transplantation. After a median follow-up of 28 months from the day of study entry (range, 3 to 57 months), 14 of 17 patients were alive (12 in complete remission, one in partial remission, and one with stable disease), two died as a result of progressive disease, and one died as a result of sepsis concomitant to acute graft-versus-host disease. The estimated 3-year overall and progression-free survival rates were 81% (95% CI, 62% to 100%) and 64% (95% CI, 39% to 89%), respectively. The estimated probability of nonrelapse mortality at 2 years was 6% (95% CI, 1% to 17%). Donor lymphocyte infusions induced a response in two patients progressing after allografting. Conclusion: RIC followed by allogeneic stem-cell transplantation is feasible, has a low treatment-related mortality, and seems to be a promising salvage treatment for relapsed PTCL. These findings suggest that the existence of a graft-versus-T-cell lymphoma effect. © 2004 by American Society of Clinical Oncology.

CNOTE: Copyright 2005 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index

1 3/28 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005338386 AU: Rao R; Shammo JM; Enschede SH; Porter C; Adler SS; Venugopal P; Gregory SA Titel: The combination of fludarabine, cyclophosphamide, and granulocyte-macrophage

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colony-stimulating factor in the treatment of patients with relapsed chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphoma

Quelle: Clinical Lymphoma; VOL: 6 (1); p. 26-30 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1526-9655 CO: CLLYA Corporate Source:

Dr. R. Rao, Section of Hematology and Oncology, Rush University Medical Center, 1725 W Harrison St., Chicago, IL 60612 United States [email protected]

COU: United States DT: Journal RN: 0021 TE: fludarabine/21679-14-1; cyclophosphamide/50-18-0; chlorambucil/305-03-3;

prednisone/53-03-2 CR: 21679-14-1; 50-18-0; 305-03-3; 53-03-2 AB: Purpose: The goal of this study was to evaluate the efficacy of the

fludarabine/cyclophosphamide combination in patients with relapsed chronic lymphocytic lymphoma (CLL) and low-grade non-Hodgkin's lymphoma (NHL) and to assess the impact of adding granulocyte-macrophage colony-stimulating factor (GM-CSF) to this regimen in a randomized fashion. Patients and methods: Thirty-four patients (CLL, n = 16; low-grade NHL, n = 18) were enrolled. The median number of previous treatments was 2. Patients received (less-than or equal to) 6 cycles of fludarabine at 30 mg/m² per day and cyclophosphamide at 300 mg/m² per day on days 1-3 of a 28-day cycle. Patients were randomized to supportive care or to receive GM-CSF at 250 µg/m² per day, starting 24 hours after completion of chemotherapy and continuing up to 48 hours before the next cycle. Those who had received > 6 months of previous therapy with an alkylating agent or had preexisting cytopenias received a 25% dose reduction. Twenty-two patients (65%) were randomized to receive GM-CSF Patients completed a median of 5 cycles of treatment (range, 1-6 cycles). Twenty-seven patients (80%) received 3 cycles of treatment and were evaluated for response. Results: Seven patients (26%) exhibited a complete response; 6 of the 7 had low-grade NHL. Fourteen patients (52%) exhibited a partial response, and 6 patients (22%) had stable disease. Notably, 6 of the 7 patients who exhibited complete response and 9 of 14 patients with partial responses were randomized to the GM-CSF arm. The duration of response ranged from 4 months to 26 months. The toxicities were mainly hematologic. Nineteen patients (70%) experienced alpha 1 episode of grade 3/4 neutropenia, but only 4 (15%) experienced febrile neutropenia; 3 of those patients were assigned to the GM-CSF arm. Conclusions: The combination of fludarabine and cyclophosphamide is a well-tolerated and effective treatment regimen for patients with relapsed CLL and low-grade NHL. A higher percentage of complete responses were noted in patients with low-grade NHL compared with patients with CLL. Granulocyte-macrophage colony-stimulating factor did not seem to decrease the incidence of febrile neutropenia. However, the higher number of complete and partial responses noted on the GM-CSF arm is intriguing and warrants further investigation.

CNOTE: Copyright 2005 Elsevier B.V., All rights reserved. ET: Cancer

Hematology

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Drug Literature Index Adverse Reactions Titles

1 3/29 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005199677 AU: Davies AJ Titel: A review of tositumomab and I¹³¹ tositumomab radioimmunotherapy for the treatment

of follicular lymphoma Quelle: Expert Opinion on Biological Therapy; VOL: 5 (4); p. 577-588 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1471-2598 CO: EOBTA Corporate Source:

A.J. Davies, Cancer Res. UK Medical Oncology Unit, Barts/Roy. London Sch. of Med./Dent., Charterhouse Square, London, EC1M 6BQ United Kingdom [email protected]

COU: United Kingdom DT: Journal RN: 0083 DN: bexxar/Glaxo SmithKline,United States; zevalin/Biogen,United States MN: Glaxo SmithKline,United States; Glaxo SmithKline; Genentech,United States;

Genentech; Biogen,United States; Biogen TE: tositumomab/208921-02-2; tositumomab i 131/192391-48-3; rituximab/174722-31-7;

paracetamol/103-90-2; potassium iodide/7681-11-0; lugol/12298-68-9; cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; vincristine/57-22-7; prednisolone/50-24-8; fludarabine/21679-14-1; prednisone/53-03-2; ibritumomab tiuxetan/206181-63-7

CR: 208921-02-2; 192391-48-3; 174722-31-7; 103-90-2; 7681-11-0; 12298-68-9; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 50-24-8; 21679-14-1; 53-03-2; 206181-63-7

AB: The CD20 antigen has become a major therapeutic target in the management of follicular and other B cell non-Hodgkin's lymphomas. The murine monoclonal antibody, tositumomab, on binding CD20, is able to induce antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity and apoptosis. In addition, when radioiodinated, the antibody exploits the tumour's sensitivity to ionising radiation by direct targeting of the malignant cell. Tositumomab and Iodine (I¹³¹) tositumomab (Bexxar®, GlaxoSmithKline, Philadelphia, PA, USA) is administered in two steps. The dosimetric step determines individual patient pharmacokinetics, allowing a patient-specific dose to be calculated. This is followed by the therapeutic step, with administration of the therapeutic dose between 7 and 14 days after the dosimetric dose. Over a decade's worth of experience in clinical trials has determined the efficacy and safety of the regimen in a variety of clinical circumstances; establishment of exactly where the regimen fits amongst the algorithm for the management of follicular lymphoma continues. © 2005 Ashley Publications Ltd.

CNOTE: Copyright 2005 Elsevier B.V., All rights reserved. ET: Cancer

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Nuclear Medicine Health Policy, Economics and Management Drug Literature Index Adverse Reactions Titles

3 3/30 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005168881 AU: Larson BJG; Waples JM; Pusateri A; Mendenhall NP; Lynch Jr JW Titel: A phase II study of gemcitabine in patients with relapsed or refractory low-grade non-

Hodgkin lymphoma Quelle: American Journal of Clinical Oncology: Cancer Clinical Trials; VOL: 28 (2); p. 165-

168 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0277-3732 CO: AJCOD Corporate Source:

Dr. J.W. Lynch Jr., Box J-100277 JHMHC, Division of Hematology/Oncology, Department of Medicine, Gainesville, FL 32610-0277 United States

COU: United States DT: Journal RN: 0010 TE: gemcitabine/103882-84-4; fludarabine/21679-14-1; cytarabine/147-94-4;

cytarabine/69-74-9; cladribine/4291-63-8 CR: 103882-84-4; 21679-14-1; 147-94-4; 69-74-9; 4291-63-8 AB: Purpose: The purpose of this study was to determine the tolerability, clinical

response rate, and time to disease progression of gemcitabine treatment in patients with low-grade non-Hodgkin lymphoma. (NHL) Patients and Methods: Twenty patients with low-grade NHL and progression of disease after at least 1 prior treatment regimen were prospectively enrolled. The treatment regimen consisted of 1200 mg/mxb2 gemcitabine intravenously administered weekly for 7 weeks followed by a 1-week rest. Subsequent treatment was given weekly for 3 weeks followed by a 1-week rest and repeated for a maximal treatment of 6 cycles until disease progression or unacceptable toxicity. Results: The predominant histologic subtypes among our patients were small lymphocytic (8 of 20) and follicular (7 of 20). Grade III/IV hematologic toxicity was observed in 15 of 20 patients and dose reductions or treatment delays occurred in 19 of 20 patients. Fatigue and asthenia were treatment-limiting in many patients. There were no complete or partial responses observed and only 2 patients had stable disease after 12 weeks of treatment. The average time to progression or off-study status was 2.3 months (95% confidence interval, 1.7-2.9) with 8 patients showing progression of disease. Twelve patients were taken off the study as a result of unacceptable toxicity before observed progression of disease. No patient completed the planned course of therapy. With a median follow up of 10.2 months, 10 of 20 patients remained alive. Conclusion: Gemcitabine as a single agent, in this dosage and schedule, has minimal clinical activity in relapsed or refractory low-grade lymphomas and was associated with considerable toxicity. Therefore, further study of gemcitabine in this setting is not justified. Copyright ©

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2005 by Lippincott Williams & Wilkins. CNOTE: Copyright 2005 Elsevier B.V., All rights reserved. ET: Cancer

Drug Literature Index Adverse Reactions Titles

3 3/31 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005148404 AU: Foussard C; Colombat P; Maisonneuve H; Berthou C; Gressin R; Rousselet M-C;

Rachieru P; Pignon B; Mahé B; Ghandour C; Desablens B; Casassus P; Lamy T; Delwail V; Deconinck E; Françoise S; Gardembas M; Brion A; Voillat L; Vuillier J; Abrgrall JF; Berthou C; Escoffre-Barbe M; Andrieu JM; Le Maignan C; Audhuy B; Cartron G; Delain M; Dugay J; Guilhot F; Jaubert J; Le Mevel A; Dauriac C; Bernard M; Maisonneuve H; Milpied N; Mahe B; Rossi JF; Quittet P; Vilque JP; Blaise AM; Himberlin C

Titel: Long-term follow-up of a randomized trial of fludarabine-mitoxantrone, compared with cyclophosphamide, doxorubicin, vindesine, prednisone (CHVP), as first-line treatment of lederly patients with advanced, low-grade non-Hodgkin's lymphoma beofre the era of monoclonal antibodies

Quelle: Annals of Oncology; VOL: 16 (3); p. 466-472 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 0923-7534 CO: ANONE Corporate Source:

Dr. E. Deconinck, Service d'Hématologie, CHU Besançon, 25 030 Besançon Cedex France [email protected]

COU: France DT: Journal RN: 0030 TE: aciclovir/59277-89-3; cotrimoxazole/8064-90-2; cyclophosphamide/50-18-0;

doxorubicin/23214-92-8; doxorubicin/25316-40-9; fludarabine/21679-14-1; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; pentamidine/100-33-4; prednisone/53-03-2; vindesine/53643-48-4

CR: 59277-89-3; 8064-90-2; 50-18-0; 23214-92-8; 25316-40-9; 21679-14-1; 65271-80-9; 70476-82-3; 100-33-4; 53-03-2; 53643-48-4

AB: Background: This randomized study compared the efficacy and safety of fludarabine-mitoxantrone (FM) with mini-CHVP (cyclophosphamide, doxorubicin, vindesine, prednisone) in elderly patients with advanced, low-grade non-Hodgkin's lymphoma. Patients and methods: End points were remission rates [overall response (OR) and complete response (CR)], failure-free survival (FFS), survival and toxicity. One hundred and fifty-five patients were randomized, 144 were evaluable for safety and 142 for response. Each treatment arm was given as six monthly cycles, followed by three bimonthly cycles. FM comprised fludarabine (20 mg/m² i.v.), days 1-5, plus mitoxantrone (10 mg/m² i.v.), day 1. CHVP cycles comprised cyclophosphamide (750 mg/m² i.V. infusion), doxorubicin (25 mg/m² i.v.) and vindesine (3 mg/m² i.v.) on day 1, and prednisone (50 mg/m²) on days 1-5. Results: FM therapy resulted in superior

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remission rates (OR 81% versus 64%, CR 49% versus 17%; P=0.0004). Median FFS for FM patients was 36 months, compared with 19 months for CHVP patients, and has not yet been reached for early CR patients at 53 months. Treatment arm was the major risk factor influencing survival. Both treatments were well tolerated, with only few infectious complications. Conclusion: FM was more effective than CHVP in achieving OR and CR, and favorably affected the outcome. © 2005 European Society for Medical Oncology.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

1 3/32 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004532699 AU: Morris GJ; Millenson MM; Padavic-Shaller K; Wang H; Rogatko A; Clyde J; Boyd RL;

Yeslow G; Halbherr T; Schilder RJ; Smith MR Titel: Phase II study of fludarabine and alpha-interferon in patients with low-grade non-

Hodgkin's lymphoma Quelle: Haematologica; VOL: 89 (12); p. 1484-1491 /2004/ Sprache: ENGLISH AL: ENGLISH CY: Italy ISSN: 0390-6078 CO: HAEMA Corporate Source:

Dr. M.R. Smith, Lymphoma Service, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111 United States [email protected]

COU: United States DT: Journal RN: 0045 DN: roferon/Hoffmann La Roche,United States MN: Hoffmann La Roche,United States; Hoffmann La Roche TE: doxorubicin/23214-92-8; doxorubicin/25316-40-9; fludarabine/21679-14-1;

rituximab/174722-31-7 CR: 23214-92-8; 25316-40-9; 21679-14-1; 174722-31-7 AB: Background and Objectives. Low-grade non-Hodgkin's lymphoma (NHL) remains

incurable with standard dose chemotherapy. Nucleoside analogs such as fludarabine are effective, but even when used as initial therapy, the median duration of remission ranges from only 16 to 24 months. Interferon (IFN) is also active and has been investigated both by incorporating it into the chemotherapy regimen and/or as maintenance therapy, where it may prolong remission. We designed a phase II trial of alternating fludarabine and IFNalpha2a to determine response rate, time to progression and toxicity of this regimen in patients with advanced stage low-grade NHL or mantle cell lymphoma. Design and Methods. Patients had received 0-2 prior regimens that did not include nucleoside analogs or IFN and had adequate organ

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function. Fludarabine was administered intravenously at 25 mg/m²/day for 5 days once every 6 weeks with IFN in weeks 4 and 5 at 3×10(sup(6)) U/m² subcutaneously three times weekly for 6 doses. Treatment continued in responders for 2 cycles past maximal response (minimum 6 cycles). No maintenance was given. Results. Between 1994 and 1999, 31 patients were accrued and were evaluable for toxicity, with 29 eligible for evaluation of response. Toxicity was primarily myelosuppression, with grade 3 neutropenia in 12 patients and grade 4 thrombocytopenia in one patient. The overall response rate was 51.7% (15/29), including 6 complete and 9 partial responses. With a median follow-up of 35.6 months, the median overall survival was 60.8 months, and the median time to disease progression (TTP) was 12.6 months. Of the 15 responding patients, treatment-naieve patients had a median response duration of 39.6 months with a median TTP of 42.1 months, while the median response duration was 5.2 months with a median TTP of 14.5 months in patients who had received prior treatment (p=0.0065 and 0.0374, respectively). Interpretation and Conclusions. This schedule of alternating fludarabine with IFN does not seem to increase response rate appreciably, but there are some prolonged responses, particularly in previously untreated patients. Given the non-overlapping toxicities of IFN with those of chemotherapy and antibody-based therapeutics, there may be a role for combination therapies, especially if the biological basis of response to IFN can be elucidated.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Drug Literature Index Adverse Reactions Titles

1 3/33 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004471339 AU: Haddad N; Rowe JM Titel: Current indications for reduced-intensity allogeneic stem cell transplantation Quelle: Best Practice and Research in Clinical Haematology; VOL: 17 (3); p. 377-386 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1521-6926 CO: BPRCA PII: S1521692604000489 Corporate Source:

Dr. N. Haddad, Dept. Haematol./Bone Marrow Transpl., Rambam Medical Center and Technion, Israel Institute of Technology, Haifa 31096 Israel

COU: Israel DT: Journal RN: 0038 DN: campath 1 h; revimid; velcade TE: busulfan/55-98-1; carmustine/154-93-8; etoposide/33419-42-0; cytarabine/147-94-4;

cytarabine/69-74-9; melphalan/148-82-3; fludarabine/21679-14-1; cladribine/4291-63-8; alemtuzumab/216503-57-0; imatinib/152459-95-5; imatinib/220127-57-1; thalidomide/50-35-1; 3 (4 amino 1,3 dihydro 1 oxo 2h isoindol 2 yl)glutarimide/191732-72-6; bortezomib/179324-69-7; bortezomib/197730-97-5;

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interleukin 2/85898-30-2 CR: 55-98-1; 154-93-8; 33419-42-0; 147-94-4; 69-74-9; 148-82-3; 21679-14-1; 4291-63-

8; 216503-57-0; 152459-95-5; 220127-57-1; 50-35-1; 191732-72-6; 179324-69-7; 197730-97-5; 85898-30-2

AB: Stem cell transplantation preceded by reduced-intensity conditioning (RIC) is based on the use of immunosuppressive agents as the sine qua non to ensure donor cell engraftment. It is a curative option for select patients suffering from haematological and non-haematological malignancies. The most beneficial results are observed when a full donor engraftment is achieved with 'tolerable' graft-vs-host disease (GVHD). To date, a vast amount of clinical data has been published, but in an uncontrolled manner. This review summarizes the currently known outcome of allogeneic transplants with RIC, with every disease category analysed separately. Unresolved problems include the optimal combination of immunosuppressive agxents, the degree of infectious complications, and GVHD that may appear in some patients. Directions to overcome these complications are discussed. Despite the paucity of controlled clinical data, the current indications for RIC allogeneic transplantation are summarized based on the best-available phase II data. © 2004 Elsevier Ltd. All rights reserved.

CNOTE: Copyright 2004 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Drug Literature Index Adverse Reactions Titles

» Volltext »3, 5 3/34 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004445336 AU: Gordon LI; Witzig T; Molina A; Czuczman M; Emmanouilides C; Joyce R; Vo K;

Theuer C; Pohlman B; Bartlett N; Wiseman G; Darif M; White C Titel: Yttrium 90-labeled ibritumomab tiuxetan radioimmunotherapy produces high

response rates and durable remissions in patients with previously treated B-cell lymphoma

Quelle: Clinical Lymphoma; VOL: 5 (2); p. 98-101 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1526-9655 CO: CLLYA Corporate Source:

Dr. L.I. Gordon, Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, 676 N St. Clair, Chicago, IL 60611 United States [email protected]

COU: United States DT: Journal RN: 0011 TE: cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9;

fludarabine/21679-14-1; ibritumomab tiuxetan/206181-63-7; prednisone/53-03-2;

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rituximab/174722-31-7; vincristine/57-22-7 CR: 50-18-0; 23214-92-8; 25316-40-9; 21679-14-1; 206181-63-7; 53-03-2; 174722-31-7;

57-22-7 AB: We report updated time-to-event variables of a phase III randomized study

comparing yttrium 90-labeled ibritumomab with rituximab standard therapy in 143 rituximab-naive patients with relapsed or refractory low-grade, follicular, or transformed CD20(sup(+)) non-Hodgkin's lymphoma (NHL). Most patients (79%) had follicular lymphoma. Patients were randomized to receive a single intravenous (I.V. dose of (sup(90))Y ibritumomab tiuxetan 0.4 mCi/kg (n = 73) or rituximab 375 mg/m² I.V. weekly for 4 doses (n = 70). The radioimmunotherapy group was pretreated with 2 rituximab doses (250 mg/m²) to improve biodistribution and one dose of Indium 111-labeled ibritumomab tiuxetan for imaging. The overall response rate was 80% versus 56% (P = 0.002) and complete response (CR)/CR unconfirmed (CRu) rates were 34% for (sup(90))Y ibritumomab tiuxetan versus 20% for rituximab. With a median follow-up of 44 months, the data are mature as all ongoing patients in both groups exceeded the median Kaplan-Meier estimated time to progression (TTP), duration of response (DR), and time to next therapy. Although this study was not powered to detect differences in time-to-event variables, the results from this randomized trial demonstrate trends toward longer median TTP (15 vs. 10.2 months; P = 0.07), DR (16.7 vs. 11.2 months; P = 0.44) and time to next therapy (21.1 vs. 13.8 months; P = 0.27) in follicular NHL patients treated with (sup(90))Y ibritumomab tiuxetan compared with the rituximab control arm. In patients achieving a CR/CRu, the median TTP was 24.7 months for patients treated with (sup(90))Y ibritumomab tiuxetan compared with 13.2 months for rituximab-treated patients (P = 0.41), and ongoing responses of >5 years have been observed. These results confirm that (sup(90))Y ibritumomab tiuxetan produces high response rates and durable remissions in patients with previously treated low-grade, follicular, and transformed NHL.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Drug Literature Index

3 3/35 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004415939 AU: Rao S; Watkins D; Cunningham D; Dunlop D; Johnson P; Selby P; Hancock BW;

Fegan C; Culligan D; Schey S; Morris TCM; Lissitchkov T; Oliver JW; Holmlund JT Titel: Phase II study of ISIS 3521, an antisense oligodeoxynucleotide to protein kinase C

alpha, in patients with previously treated low-grade non-Hodgkin's lymphoma Quelle: Annals of Oncology; VOL: 15 (9); p. 1413-1418 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 0923-7534 CO: ANONE Corporate Source:

Prof. D. Cunningham, Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT United Kingdom [email protected]

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COU: United Kingdom DT: Journal RN: 0024 DN: adriamycin; isis 3521 TE: anthraquinone/84-65-1; chlorambucil/305-03-3; cyclophosphamide/50-18-0;

doxorubicin/23214-92-8; doxorubicin/25316-40-9; fludarabine/21679-14-1; gentamicin/1392-48-9; gentamicin/1403-66-3; gentamicin/1405-41-0; isis 3521/151879-73-1; prednisolone/50-24-8; rituximab/174722-31-7; vincristine/57-22-7; warfarin/129-06-6; warfarin/2610-86-8; warfarin/3324-63-8; warfarin/5543-58-8; warfarin/81-81-2

CR: 84-65-1; 305-03-3; 50-18-0; 23214-92-8; 25316-40-9; 21679-14-1; 1392-48-9; 1403-66-3; 1405-41-0; 151879-73-1; 50-24-8; 174722-31-7; 57-22-7; 129-06-6; 2610-86-8; 3324-63-8; 5543-58-8; 81-81-2

AB: Background: The purpose of this study was to assess the efficacy and safety of ISIS 3521, an anti-sense phosphorothioate oligonucleotide to protein kinase C alpha in patients with relapsed low-grade non-Hodgkin's lymphoma (NHL). Patients and methods: Twenty-six patients received ISIS 3521 (2 mg/kg/day) as a continuous infusion over 21 days of each 28-day cycle. Results: The median age of the patients was 53 years (range 37-77). Histological subtypes were low-grade follicular lymphoma (n = 22) and B-cell small lymphocytic lymphoma (n = 4). Twenty-one (81%) had stage III/IV disease. The median number of previous lines of chemotherapy was two (range one to six). A total of 87 cycles of ISIS 3521 were administered. Twenty-three patients were assessable for response. Three patients achieved a partial response. No complete responses were observed. Ten patients had stable disease. Grade 3-4 toxicity was as follows: neutropenia (3.8%) and thrombocytopenia (26.9%). Conclusions: ISIS 3521 has demonstrated anti-tumour activity in patients with relapsed low-grade NHL. There may be a potential role for this agent in combination with conventional chemotherapy for advanced low-grade lymphoma, and further trials are warranted. © 2004 European Society for Medical Oncology.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

3 3/36 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004185248 AU: Goy A; Gilles F Titel: Update on the proteasome inhibitor bortezomib in hematologic malignancies Quelle: Clinical Lymphoma; VOL: 4 (4); p. 230-237 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1526-9655 CO: CLLYA Corporate Source:

Dr. A. Goy, Department of Lymphoma/Myeloma, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030

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United States [email protected]

COU: United States DT: Journal RN: 0097 DN: ps 341 TE: bortezomib/179324-69-7; bortezomib/197730-97-5; ubiquitin/60267-61-0;

dexamethasone/50-02-2; thalidomide/50-35-1; melphalan/148-82-3; doxorubicin/23214-92-8; doxorubicin/25316-40-9; rituximab/174722-31-7; gemcitabine/103882-84-4; protein bcl 2/219306-68-0; fludarabine/21679-14-1; imatinib/152459-95-5; imatinib/220127-57-1; flavopiridol/146426-40-6; protein Bak/166801-28-1; protein bcl xl/151033-38-4; X linked inhibitor of apoptosis/391965-84-7; caspase 3/169592-56-7

CR: 179324-69-7; 197730-97-5; 60267-61-0; 50-02-2; 50-35-1; 148-82-3; 23214-92-8; 25316-40-9; 174722-31-7; 103882-84-4; 219306-68-0; 21679-14-1; 152459-95-5; 220127-57-1; 146426-40-6; 166801-28-1; 151033-38-4; 391965-84-7; 169592-56-7

AB: The ubiquitin-proteasome system plays a crucial role in eukaryotic cells in maintaining protein homeostasis. Through the disruption of a variety of pathways and cell cycle checkpoints, proteasome inhibition leads to apoptosis and in experimental models can overcome chemoresistance. Bortezomib is the first of its class of proteasome inhibitors tested in humans that showed promising activity in several tumor types, and especially in hematologic malignancies, in phase I studies. The remarkable results obtained in phase II studies in multiple myeloma (MM) led to its fast-track approval by the US Food and Drug Administration in May 2003 for relapsed MM. More recent observation also revealed promising activity in non-Hodgkin's lymphoma. This review will explore the rationale for the use of bortezomib in hematologic malignancies as well as provide an update on the results of ongoing studies and future directions for the use of this new agent in hematologic malignancies. The mechanism of action of bortezomib and its nonoverlapping toxicity profile make it a very appealing drug for combination with other chemotherapeutic or biologic agents. Bortezomib represents an excellent example of how progress in understanding the biology of cancer cells can impact clinical practice and lead toward a new era of rational therapeutics.

CNOTE: Copyright 2004 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3 3/37 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004121389 AU: Seymour JF Titel: New Treatment Approaches to Indolent Non-Hodgkin's Lymphoma Quelle: Seminars in Oncology; VOL: 31 (1); p. 27-32 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United States

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ISSN: 0093-7754 CO: SOLGA Corporate Source:

Dr. J.F. Seymour, Peter MacCallum Cancer Institute, Department of Hematology, St Andrews Place, East Melbourne, Vic. 3002 Australia

COU: Australia DT: Journal RN: 0026 TE: rituximab/174722-31-7; cyclophosphamide/50-18-0; doxorubicin/23214-92-8;

doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2; fludarabine/21679-14-1; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; dexamethasone/50-02-2

CR: 174722-31-7; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2; 21679-14-1; 65271-80-9; 70476-82-3; 50-02-2

AB: Disseminated indolent non-Hodgkin's lymphoma (NHL) is considered incurable with conventional chemotherapy regimens, and more than 50% of patients die within 5 years of their first relapse. Therefore, newer treatment approaches have been used to try to improve survival and ultimately provide a cure for patients with disseminated indolent NHL. The anti-CD20 monoclonal antibody rituximab has been extensively evaluated and is now an integral component of many treatment strategies. The activity of rituximab was first shown in the pivotal trial in patients with relapsed and refractory low-grade and follicular lymphoma. More recent studies have shown somewhat higher activity of rituximab when used first-line, with further improvements with maintenance therapy. Rituximab in combination with chemotherapy has been shown to achieve high response rates, and two prospective randomized studies from the German Low-grade Lymphoma Study Group have shown significantly higher response rates and longer survival for patients receiving rituximab concurrently with chemotherapy compared with those receiving chemotherapy alone. Further data from ongoing phase III studies are still needed to determine whether rituximab can help alter the natural history of indolent NHL, and longer follow-up of these patients will help determine the optimal role for rituximab in treatment of indolent NHL. © 2004 Elsevier Inc. All rights reserved.

CNOTE: Copyright 2004 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3, 6 3/38 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004121388 AU: Hillmen P Titel: Advancing Therapy for Chronic Lymphocytic Leukemia - The Role of Rituximab Quelle: Seminars in Oncology; VOL: 31 (1 SUPPL. 2); p. 22-26 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0093-7754 CO: SOLGA

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Corporate Source:

Dr. P. Hillmen, Pinderfields General Hospital, Aberford Road, Wakefield WF1 4DG United Kingdom

COU: United Kingdom DT: Journal RN: 0034 TE: cyclophosphamide/50-18-0; fludarabine/21679-14-1; rituximab/174722-31-7 CR: 50-18-0; 21679-14-1; 174722-31-7 AB: Chronic lymphocytic leukemia (CLL) remains incurable despite decades of clinical

trials. Some patients survive for long periods without requiring definitive therapy, while others die rapidly despite intensive treatment. Because most patients with CLL express CD20 on their malignant cells, the chimeric anti-CD20 monoclonal antibody rituximab has been incorporated into treatment regimens in efforts to improve outcome. Rituximab monotherapy has limited activity in previously untreated and refractory/relapsed CLL patients with response rates that are generally lower than those seen in non-Hodgkin's lymphoma. Although increased dosing intensity and frequency leads to higher response rates than seen in patients treated with standard dose rituximab, responses are almost always partial remissions and the doses used are not feasible in routine clinical practice. On the other hand, combining rituximab with chemotherapy has proved to be feasible and appears to be synergistic with fludarabine-based chemotherapy in the treatment of CLL on the basis of recent phase II trials. In these studies, response rates (including complete remissions) to rituximab in combination with fludarabine-containing regimens are higher than those reported in similar phase II studies with any other treatment regime. The highest response rates reported are for the combination of rituximab, fludarabine, and cyclophosphamide. A randomized phase III trial has been initiated to evaluate the addition of rituximab to fludarabine and cyclophosphamide in patients with relapsed CLL. The combination of rituximab with other agents is also being investigated, and these ongoing trials will help define the role of rituximab in CLL. © 2004 Elsevier Inc. All rights reserved.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

2, 6 3/39 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2003249604 AU: Economopoulos T; Fountzilas G; Pavlidis N; Kalantzis D; Papageorgiou E;

Christodoulou C; Hamilos G; Nicolaides C; Dimopoulos M Titel: Rituximab in combination with CNOP chemotherapy in patients withn previously

untreated indolent non-Hodgkin's lymphoma Quelle: Hematology Journal; VOL: 4 (2); p. 110-115 /2003/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1466-4860 CO: HJEOB

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Corporate Source:

T. Economopoulos, Evangelismos Hospital, Second Department of Internal Med., Athens 106 76 Greece [email protected]

COU: Greece DT: Journal RN: 0026 TE: rituximab/174722-31-7; cyclophosphamide/50-18-0; mitoxantrone/65271-80-9;

mitoxantrone/70476-82-3; vincristine/57-22-7; prednisone/53-03-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5; bleomycin/11056-06-7; folinic acid/58-05-9; folinic acid/68538-85-2; fludarabine/21679-14-1

CR: 174722-31-7; 50-18-0; 65271-80-9; 70476-82-3; 57-22-7; 53-03-2; 23214-92-8; 25316-40-9; 15475-56-6; 59-05-2; 7413-34-5; 11056-06-7; 58-05-9; 68538-85-2; 21679-14-1

AB: Rituximab, a chimeric monoclonal antibody, produces response rates of up to 73% in patients with previously untreated indolent non-Hodgkin's lymphoma (NHL), and has high activity when combined with chemotherapy. The purpose of this phase II study was to determine the efficacy and safety of rituximab plus cyclophosphamide, mitoxantrone, vincristine and prednisone (CNOP) chemotherapy in patients with indolent NHL. In all, 42 patients (median age 67 years) with previously untreated follicular, marginal zone or small lymphocytic/lymphoplasmacytic NHL received six infusions of rituximab (375 mg/m²) in combination with six cycles of CNOP. The overall response rate was 90% comprising 30 complete (71%) and eight partial (19%) responses. Although patients with marginal zone lymphoma or International Prognostic Index (IPI) score 3 had lower complete response rates, no significant difference in overall response rate was observed between the histological groups (P = 0.24) or between patients stratified according to IPI score (P>0.05). Median overall survival, time-to-progression and response duration had not been reached after a median 19.5-month follow-up. In all, 31 patients (74%) are currently free from progression and 38 (90%) remain alive. Treatment was well tolerated. One patient (2% experienced grade 3/4 infusion-related toxicity; 13 (31%) grade 3/4 leukopenia and 18 (43%) grade 3/4 neutropenia. Infection was observed in nine patients: eight (19%) grade 1/2 and one (2.4%) grade 3. This study demonstrates that combining rituximab with CNOP achieves high remission rates without significant additional toxicity in patients with previously untreated indolent NHL. Further follow-up will determine response duration and survival.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3 3/40 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2003234983 AU: Herold M; Dölken G; Fiedler F; Franke A; Freund M; Helbig W; Pasold R Titel: Randomized phase III study for the treatment of advanced indolent non-Hodgkin's

lymphomas (NHL) and mantle cell lymphoma: Chemotherapy versus chemotherapy

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plus rituximab Quelle: Annals of Hematology; VOL: 82 (2); p. 77-79 /01 FEB 2003/ Sprache: ENGLISH CY: Germany ISSN: 0939-5555 CO: ANHEE Corporate Source:

M. Herold, HELIOS - Klinikum Erfurt, 2. Medizinische Klinik, Dept. of Hematology and Oncology, Nordhäuserstrasse 74, 99089 Erfurt Germany [email protected]

COU: Germany DT: Journal RN: 0004 TE: rituximab/174722-31-7; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3;

chlorambucil/305-03-3; prednisolone/50-24-8; paracetamol/103-90-2; dimetindene/3614-69-5; dimetindene/5636-83-9; cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; prednisone/53-03-2; vincristine/57-22-7; fludarabine/21679-14-1

CR: 174722-31-7; 65271-80-9; 70476-82-3; 305-03-3; 50-24-8; 103-90-2; 3614-69-5; 5636-83-9; 50-18-0; 23214-92-8; 25316-40-9; 53-03-2; 57-22-7; 21679-14-1

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

» Volltext »3 (Phase 3 Studie R-MCP vs. MCP nach Volltext) 3/41 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2003124267 AU: Abbasi MR; Sparano JA; Sarta C; Wiernik PH Titel: Phase I trial of fludarabine and paclitaxel in non-Hodgkin's lymphoma Quelle: Medical Oncology; VOL: 20 (1); p. 53-58 /2003/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1357-0560 CO: MONCE Corporate Source:

Dr. M.R. Abbasi, Jacobi Medical Center, Department of Medicine, 1400 Pelham Parkway South, Bronx, NY 10461 United States [email protected]

COU: United States DT: Journal RN: 0033

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TE: fludarabine/21679-14-1; paclitaxel/33069-62-4; dexamethasone/50-02-2; cimetidine/51481-61-9; cimetidine/70059-30-2; diphenhydramine/147-24-0; diphenhydramine/58-73-1

CR: 21679-14-1; 33069-62-4; 50-02-2; 51481-61-9; 70059-30-2; 147-24-0; 58-73-1 AB: Fludarabine is an active agent in low-grade non-Hodgkin's lymphoma and chronic

lymphocytic leukemia. Paclitaxel is also active in patients with refractory lymphoma, and preclinical data suggest an additive effect with fludarabine in vitro. We performed a phase I trial of fludarabine (25 mg/m² d 1-3) plus a 3-h infusion of paclitaxel (125,150, or 175 mg/m²) on d 3 every 28 d in 13 patients with non-Hodgkin's lymphoma. The paclitaxel dose was escalated in cohorts of 3-4 patients using standard phase I design schema. Dose-limiting toxicity was defined as febrile neutropenia, platelet nadir less than 50,000/µL, or grade 3-4 nonhematologic toxicity. Thirteen patients were accrued to the study, 8 of these 13 patients (62%) had received prior chemotherapy. At the 125-, 150-, and 175-mg/m² dose levels of paclitaxel, dose-limiting toxicity occurred in 1/4, 0/4, and 0/4 patients, respectively. The single patient with dose-limiting toxicity had febrile neutropenia. Partial response occurred in two of eight patients with low-grade lymphoma and none of five patients with other types of lymphoma. A paclitaxel dose of 175 mg/m² given as a 3-h infusion on d 3 in conjunction with fludarabine (25 mg/m² d 1-3 every 4 wk) is a well-tolerated regimen for non-Hodgkin's lymphoma. Further study will be required in order to determine whether the fludarabine-paclitaxel is more active than fludarabine alone in patients with low-grade lymphoma and chronic lymphocytic leukemia.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

1 3/42 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2003034688 AU: van Oers MHJ; Hagenbeck A; Van Glabbeke M; Teodorovic I Titel: Chimeric anti-CD20 monoclonal antibody (Mabthera) in remission induction and

maintenance treatment of relapsed follicular non-Hodgkin's lymphoma: A phase III randomized clinical trial - Intergroup Collaborative Study

Quelle: Annals of Hematology; VOL: 81 (10); p. 553-557 /2002/ Sprache: ENGLISH CY: Germany ISSN: 0939-5555 CO: ANHEE Corporate Source:

M.H.J. van Oers, Department of Hematology, Academic Medical Centre Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam Netherlands

COU: Netherlands DT: Journal RN: 0021 DN: mabthera TE: rituximab/174722-31-7; cyclophosphamide/50-18-0; doxorubicin/23214-92-8;

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doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2; chlorambucil/305-03-3; fludarabine/21679-14-1; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3

CR: 174722-31-7; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2; 305-03-3; 21679-14-1; 65271-80-9; 70476-82-3

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Pharmacology Drug Literature Index Adverse Reactions Titles

» Volltext »3 (Phase 3 Studie R-CHOP vs. CHOP nach Volltext) 3/43 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2003009645 AU: Klasa RJ; Meyer RM; Shustik C; Sawka CA; Smith A; Guéin R; Maksymiuk A;

Rubinger M; Samosh M; Laplante S; Grenier J-F Titel: Randomized phase III study of fludarabine phosphate versus cyclophosphamide,

vincristine, and prednisone in patients with recurrent low-grade non-Hodgkin's lymphoma previously treated with an alkylating agent or alkylator-containing regimen

Quelle: Journal of Clinical Oncology; VOL: 20 (24); p. 4649-4654 /15 DEC 2002/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND Corporate Source:

R.J. Klasa, Division of Medical Oncology, British Columbia Cancer Agency, 600 W 10th Ave, Vancouver, BC V5Z 4E6 Canada [email protected]

COU: Canada DT: Journal RN: 0033 TE: fludarabine/21679-14-1; cyclophosphamide/50-18-0; vincristine/57-22-7;

prednisone/53-03-2 CR: 21679-14-1; 50-18-0; 57-22-7; 53-03-2 AB: Purpose: To compare in a phase III study the safety and efficacy of fludarabine to

that of cyclophosphamide, vincristine, and prednisone (CVP) in recurrent, low-grade, non-Hodgkin's lymphoma after previous response to systemic treatment. Patients and Methods: Patients were randomized to fludarabine (25 mg/m² intravenously on days 1 to 5, every 28 days) or CVP (cyclophosphamide 750 mg/m² and vincristine 1.2 mg/m² both intravenously on day 1 and prednisone 40 mg/m² orally on days 1 to 5, every 21 days). The primary outcome assessed was progression-free survival (PFS); secondary outcomes included treatment-free survival (TFS), overall survival (OS), treatment-related toxicity, and quality of life (QoL) according to the European Organization for Research and Treatment of Cancer's Quality of Life Questionnaire C-30 version 1.0 instrument. Results: Ninety-one patients were randomized, 47 to fludarabine and 44 to CVP. There was no difference in response rates, with 64%

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(complete response [CR], 9%) for fludarabine versus 52% (CR, 7%) for CVP (P = .72). With a median follow-up of 42 months, median PFS (11 months v 9.1 months; P = .03) and TFS (15 months v 11 months; P = .02) were superior in patients receiving fludarabine. No difference in median overall survival was detected (57 months for fludarabine v 44 months for CVP; P = .95). Three patients receiving fludarabine died of treatment-related toxicity compared with none of the patients receiving CVP. Peripheral neuropathy and alopecia were more common with CVP. Patients receiving fludarabine had higher scores for social function (P = .008); no other differences in QoL were detected. Conclusion: In recurrent low-grade lymphoma, fludarabine improves PFS, TFS, and social function scores in comparison with CVP but does not improve OS. © 2002 by American Society of Clinical Oncology.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

1 3/44 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2002446657 AU: Bremer K Titel: High rates of long-lasting remissions after 5-day bendamustine chemotherapy cycles

in pre-treated low-grade non-Hodgkin's-lymphomas Quelle: Journal of Cancer Research and Clinical Oncology; VOL: 128 (11); p. 603-609 /2002/Sprache: ENGLISH AL: ENGLISH CY: Germany ISSN: 0171-5216 CO: JCROD Corporate Source:

K. Bremer, Klinik fur Hamatologie und Onkologie, Augusta-Kranken-Anstalt, Bergstrasse 26, 44791 Bochum Germany

COU: Germany DT: Journal RN: 0036 TE: bendamustine/16506-27-7; bendamustine/3543-75-7; chlorambucil/305-03-3;

prednisone/53-03-2; melphalan/148-82-3; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; prednimustine/29069-24-7; bleomycin/11056-06-7; fludarabine/21679-14-1; cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; dexamethasone/50-02-2

CR: 16506-27-7; 3543-75-7; 305-03-3; 53-03-2; 148-82-3; 65271-80-9; 70476-82-3; 29069-24-7; 11056-06-7; 21679-14-1; 50-18-0; 23214-92-8; 25316-40-9; 50-02-2

AB: Purpose: Since continuous relapse rates are characteristic for advanced low-grade non-Hodgkin's lymphomas (NHL), their treatment remains a problem. Previous phase II studies showed that bendamustine induced high remission rates in pre-treated low-grade NHL. To further examine its efficacy and side effects, bendamustine has been studied in a large number of patients with pre-treated low-grade NHL. Follow-up time was 3-8 years. Methods: From 1993 to 1998, 102 patients with pre-treated low-grade NHL [histologic subtypes: CLL n=15, immunocytic n=46, multiple myeloma (MM)

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n=25, others n=16] received a median of four (range 1-11) 5-day cycles of daily 60 mg/m² bendamustine as salvage chemotherapy. Bendamustine was given in short i.v. infusions mainly at intervals of 4-6 weeks. Results: Partial and complete remissions were observed in 76.5% and disease stabilization in 19.6% of the patients. Only 3.9% showed progressive disease. Median duration of response was 39 months for the NHL patients and 17 months for the MM patients. Median survival time was 32 months for the CLL patients, 31.5 months for the NHL patients and 17.5 months for the MM patients. Non-haematological side effects consisted mainly in reversible reduction of performance status, loss of appetite, and nausea/vomiting and diarrhoea, which were of WHO grade III/IV in less than 5% of patients. Haematological toxicities of WHO grade III/IV have been observed in 6.9%, 11.8%, and 24.5% of patients for hemoglobin, thrombocytes, and leukocytes, respectively. Alopecia did not occur. Febrile episodes or bacterial as well as viral, particularly opportunistic, infections were not observed, although bendamustine induced profound and long-lasting lymphocytopenias, including CD4+-, CD8+-, CD19+-, B-lymphocytes, and NK-cells. Conclusions: Bendamustine proved to be very effective in pretreated low-grade NHL patients by inducing high rates of long-lasting remissions. Bendamustine combines the pharmacological properties of an alkylating agent with those of a purine analogue and showed no cross-resistance to chlorambucil, melphalan, cyclophosphamide, mitoxantrone, and other anthracyclines. The myelosuppressive toxicities were dose limiting, and the non-haematological side effects were moderate.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

3 3/45 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2002432224 AU: Eucker J; Schille C; Schmid P; Jakob C; Schetelig J; Kingreen D; Mergenthaler H-G;

Huhn D; Possinger K; Sezer O Titel: The combination of fludarabine and cyclophosphamide results in a high remission

rate with moderate toxicity in low-grade non-Hodgkin's lymphomas Quelle: Anti-Cancer Drugs; VOL: 13 (9); p. 907-913 /01 OCT 2002/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 0959-4973 CO: ANTDE Corporate Source:

O. Sezer, Department of Hematology, Universitätsklinikum Charite, 10098 Berlin Germany [email protected]

COU: Germany DT: Journal RN: 0023 TE: fludarabine/21679-14-1; cyclophosphamide/50-18-0 CR: 21679-14-1; 50-18-0

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AB: We undertook a prospective study to evaluate the role of the combination of fludarabine and cyclophosphamide in patients with low-grade non-Hodgkin's lymphoma. Twenty-seven patients with low-grade non-Hodgkin's lymphoma were treated with i.v. fludarabine (30 mg/m²) and cyclophosphamide (250 mg/m²) on days 1-3. Cycles were given at 4-week intervals for a maximum of six courses. Fourteen patients (52%) were previously untreated, 13 patients (48%) had been treated with at least one chemotherapy regimen before. Of the 27 patients, 11 (41%) obtained a complete and 13 (48%) a partial remission, thus the overall response rate was 89%. The remission rate in untreated patients was slightly higher than in pretreated patients (93 versus 85%). The toxicity was mild, no treatment-related mortality occurred. Neutropenia was the most common side effect, grade 4 neutropenia of rather short duration was observed in less than 7% of the cycles. At the end of the treatment, the mean CD4(sup(÷)) count was 155/µl and the mean CD8(sup(÷)) count 204/µl. Severe infections did not occur. These results show that the combination of fludarabine and cyclophosphamide in the doses used in this study is an effective regimen with manageable toxicity in low-grade non-Hodgkin's lymphoma. © 2002 Lippincott Williams & Wilkins.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

1 3/46 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2002425983 AU: Cowan RA; Murby B; Gunton D; Owens SE; Hoyes KP; Sharma HL; Smith A-M;

Chang J; Van Kessel B; Nuttall PM; Crowther D Titel: Autologous lymphocytes as vectors to target therapeutic radiation, using indium-

114m, in patients with lymphoid cell malignancy Quelle: British Journal of Haematology; VOL: 119 (2); p. 459-466 /2002/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 0007-1048 CO: BJHEA Corporate Source:

R.A. Cowan, Department of Clinical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX United Kingdom [email protected]

COU: United Kingdom DT: Journal RN: 0023 TE: indium 114m/13981-55-0; indium/7440-74-6; chlorambucil/305-03-3;

cyclophosphamide/50-18-0; vincristine/57-22-7; prednisone/53-03-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; fludarabine/21679-14-1

CR: 13981-55-0; 7440-74-6; 305-03-3; 50-18-0; 57-22-7; 53-03-2; 23214-92-8; 25316-40-9; 21679-14-1

AB: Autologous lymphocytes provide a potential vector for the delivery of a cytotoxic

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agent in patients with lymphoid cell malignancy. This report describes a phase I-II study using autologous lymphocytes to target the radionuclide indium-114m ((sup(114m))In) in patients with refractory chronic lymphocytic leukaemia or small lymphocytic non-Hodgkin's lymphoma. Nineteen patients, the majority of whom had been heavily pretreated with conventional chemotherapy and radiotherapy, received between 69 and 211 MBq (sup(114m))In-labelled autologous lymphocytes. Approximately 80% of the administered activity was localized in the liver and spleen, with around 5% accumulating in the bone marrow. Ten patients (53%) responded (one complete response and nine partial responses). The median duration of response was 7 months. The median survival for the responders was 14 months and for the non-responders was 3 months. The first notable response in every patient was a fall in peripheral lymphocyte count. The indium treatment was not associated with any subjective toxicity, although all patients suffered from myelosuppression, with thrombocytopenia being the dose-limiting factor. This study has demonstrated a significant anti-tumour effect in a group of patients with late-stage highly resistant disease.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Nuclear Medicine Hematology Drug Literature Index Adverse Reactions Titles

3 3/47 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2002285313 AU: Lynch JW; Hei DL; Braylan RC; Rimzsa LM; Staab EV; Bewsher CJ; Mendenhall NP;

Hudson JK Titel: Phase II study of fludarabine combined with interferon-alpha-2a followed by

maintenance therapy with interferon-alpha-2a in patients with low-grade non-Hodgkin's lymphoma

Quelle: American Journal of Clinical Oncology: Cancer Clinical Trials; VOL: 25 (4); p. 391-397 /2002/

Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0277-3732 CO: AJCOD Corporate Source:

Dr. J.W. Lynch, Division of and Oncology, Department of Medicine, Univ. of Florida College of Medicine, P.O. Box 100277, Gainesville, FL 32610 United States

COU: United States DT: Journal RN: 0027 DN: fludara/Berlex,United States; roferon a/Hoffmann La Roche,United States MN: Berlex,United States; Berlex; Hoffmann La Roche,United States; Hoffmann La RocheTE: fludarabine/21679-14-1; alpha2a interferon/76543-88-9; fludarabine

phosphate/75607-67-9 CR: 21679-14-1; 76543-88-9; 75607-67-9

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AB: Randomized trials suggest improved disease-free survival in low-grade non-Hodgkin's lymphoma (LGNHL) when interferon is combined with multiagent chemotherapy. This phase II trial was conducted to investigate the feasibility of combining fludarabine monophosphate (fludarabine) and IFN in a regimen for treatment of LGNHL. Twenty-one patients were evaluable. Median age was 55 years, and patients had been treated with an average of 1.7 chemotherapy regimens before enrollment. Patients received 25 mg/m² of fludarabine intravenously on days 1 through 5 followed by 2 × 10(sup(6)) U/m² of interferon-alpha-2a subcutaneously on days 22 through 26. Cycles were repeated every 4 weeks with delays and dose modifications for significant cytopenias. Patients were restaged after cycles 4 and 8, and those with at least a partial response to therapy were given maintenance therapy consisting of 2 × 10(sup(6)) U/m² interferon-alpha-2a subcutaneously three times per week for 6 months. The overall response rate was 76% with a 25% complete response (CR) rate. Overall response rates were 75% (3/4 with 2 CR's) for chemotherapy-naive patients and 76% (13/17 with 3 CR's) for previously treated patients. Median time to progression was 12 months, and currently two patients are without evidence of progression at a median follow-up of 55 months. Grade III or greater toxicities included neutropenia (39%), anemia (17%), thrombocytopenia (5%), fevers/chills (5%), and fatigue (5%). Fludarabine and interferon can be effectively and safely combined in a regimen with significant activity against LGNHL. A modification of this regimen may be suitable for further study.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

1 3/48 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2002149464 AU: Tsimberidou AM; O'Brien SM; Cortes JE; Faderl S; Andreeff M; Kantarjian HM;

Keating MJ; Giles FJ Titel: Phase II study of fludarabine, cytarabine (ara-C), cyclophosphamide, cisplatin and

GM-CSF (FACPGM) in patients with Richter's syndrome or refractory lymphoproliferative disorders

Quelle: Leukemia and Lymphoma; VOL: 43 (4); p. 767-772 /2002/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 CO: LELYE Corporate Source:

F.J. Giles, Department of Leukemia, University of Texas, M.D. Anderson Cancer Center, 1400 Holcombe Boulevard, Houston, TX 77030 United States [email protected]

COU: United States DT: Journal RN: 0036 TE: fludarabine/21679-14-1; cytarabine/147-94-4; cytarabine/69-74-9;

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cyclophosphamide/50-18-0; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; fluconazole/86386-73-4; aciclovir/59277-89-3; cotrimoxazole/8064-90-2

CR: 21679-14-1; 147-94-4; 69-74-9; 50-18-0; 15663-27-1; 26035-31-4; 96081-74-2; 86386-73-4; 59277-89-3; 8064-90-2

AB: A phase II study was conducted to evaluate the safety and efficacy of fludarabine, cytarabine (ara-C), cyclophosphamide, cisplatin and GM-CSF (FACPGM) treatment in patients with Richter's syndrome (RS), refractory prolymphocytic leukemia (PLL) or refractory non-Hodgkin's lymphoma (NHL). Twenty-two patients with RS, refractory PLL, or refractory NHL were entered into this trial between March 1997 and February 2001. Median age was 62 years (42-74); 77% were over 60 years of age. Histologic diagnosis was large cell NHL transformation in 15 patients with CLL, immunoblastic transformation of CLL in one, refractory PLL in three, and refractory NHL in three patients. Treatment consisted of fludarabine 30 mg/m² (days 1-3), ara-C 0.5 g/m² (days 3-4), cyclophosphamide 250 mg/m² (days 2-4), cisplatin 15 mg/m² IV CI (days 1-4) with GM-CSF 250 µg/m² from day 5 to recovery of neutrophils and antibiotic prophylaxis. Patients with response were to receive a maximum of six cycles of therapy. Eighteen patients were evaluable for response; one patient achieved a complete remission (5%), 12 stable disease/no response (67%) and five patients had progressive disease (28%). The median survival was 2.2 months (range, 1-19); the median failure-free survival was 1.5 months (range, 0.5-18.6). Grade III/IV toxicities were as follows: anemia in 62% of cycles; leucopoenia in 66%; granulocytopenia in 90%; thrombocytopenia in 83%; hyperbilirubinemia in 14%; hyperuricemia in 17%; hyponatremia in 17%; hypokalemia in 14%; hypophosphatemia in 10%; hypoalbulinemia in 14%; hypocalcemia in 7%; and hypercalcemia in 3%. One (3%) patient developed cardiac failure. Forty-one percent of the cycles were complicated with fever, 34% with non-neutropenic fever, and 55% cycles with infections (fungal 31%; bacterial 57%; HSV 6%; VZV 6%). FACPGM had very limited activity and significant toxicity in a cohort of patients with heavily pretreated refractory lymphoproliferative disorders.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

1 3/49 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2002139565 AU: Wilder DD; Ogden JL; Jain VK Titel: Efficacy of fludarabine/mitoxantrone/dexamethasone alternating with CHOP in bulky

follicular non-Hodgkin's lymphoma Quelle: Clinical Lymphoma; VOL: 2 (4); p. 229-237 /2002/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1526-9655 CO: CLLYA Corporate Source:

Dr. V.K. Jain, Baylor-Charles A. Sammons Cancer Ctr, Baylor University Medical Center, 3535 Worth Street, Dallas, TX 75246

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United States [email protected]

COU: United States DT: Journal RN: 0025 DN: filgrastim; roferon TE: fludarabine/21679-14-1; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3;

dexamethasone/50-02-2; cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2; beta 2 microglobulin/9066-69-7; teniposide/29767-20-2; cotrimoxazole/8064-90-2; recombinant granulocyte colony stimulating factor/121181-53-1; etoposide/33419-42-0; chlormethine/51-75-2; chlormethine/55-86-7; chlormethine/82905-71-3; procarbazine/366-70-1; procarbazine/671-16-9; rituximab/174722-31-7; ibritumomab tiuxetan/206181-63-7

CR: 21679-14-1; 65271-80-9; 70476-82-3; 50-02-2; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2; 9066-69-7; 29767-20-2; 8064-90-2; 121181-53-1; 33419-42-0; 51-75-2; 55-86-7; 82905-71-3; 366-70-1; 671-16-9; 174722-31-7; 206181-63-7

AB: This phase II study investigated the efficacy of alternating fludarabine/mitoxantrone/dexamethasone (FMD) with cyclophosphamide/doxorubicin/ vincristine/prednisone (CHOP) chemotherapy for patients with high tumor burden, follicular non-Hodgkin's lymphoma. Maintenance interferon was given in a nonrandomized fashion, and a retrospective analysis of its impact was performed. A total of 87 patients were included (44 females and 43 males). The median age of patients was 56 years (range, 25-86 years). All patients had high tumor burden as defined by the Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria. Eighty-four percent of patients (73/87) had stage III/IV disease and 99% of patients (86/87) had good performance status. The majority of patients had not been previously treated, with only 3 patients receiving prior oral alkylators or cyclophosphamide/vincristine/prednisone (COP). A total of 637 cycles of FMD/CHOP were administered and were well tolerated during this trial, the majority on an outpatient basis. The overall response rate was 95% (79 complete response/unconfirmed complete response/partial response) in the 83 evaluable patients. Event-free survival (EFS) was 28.7 months, with time to progression (TTP) at 29 months and time to treatment failure at 41 months. Overall survival was not reached. Patients had similar EFS and TTP as patients in the French GELF trial with a shorter duration of chemotherapy. Patients with a lower International Prognostic Index (IPI) score had better EFS when compared to those with a higher IPI score (median EFS not reached versus 22.6 months). Serum beta(sub(2))-microglobulin levels were not a significant predictive factor. An informal analysis of interferon maintenance therapy suggests that patients who tolerated the immune modifier did better than those who did not. Alternating FMD/CHOP is a feasible and effective therapeutic option for patients with high tumor burden, low-grade non-Hodgkin's lymphoma. While this regimen may not offer dramatic benefit over FMD alone, it is beneficial in those patients for whom a prompt treatment response is needed.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

1

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3/50 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2002058606 AU: Seymour JF; Grigg AP; Szer J; Fox RM Titel: Cisplatin, fludarabine, and cytarabine: A novel, pharmacologically designed salvage

therapy for patients with refractory, histologically aggressive or mantle cell non-Hodgkin lymphoma

Quelle: Cancer; VOL: 94 (3); p. 585-593 /01 FEB 2002/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0008-543X CO: CANCA Corporate Source:

J.F. Seymour, Leukemia/Lymphoma Service, Department of Hematology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett Street, East Melbourne, Vic. 8006 Australia [email protected]

COU: Australia DT: Journal RN: 0051 TE: cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; fludarabine/21679-

14-1; cytarabine/147-94-4; cytarabine/69-74-9 CR: 15663-27-1; 26035-31-4; 96081-74-2; 21679-14-1; 147-94-4; 69-74-9 AB: BACKGROUND. Based on in vitro synergism, the combination of cytarabine (ara-C)

and cisplatin is the basis of many salvage regimens for patients with aggressive non-Hodgkin lymphoma (NHL). However, patients with previously refractory disease are significantly less likely to respond, stimulating the search for novel salvage regimens. In vitro, fludarabine enhances the cytotoxicity of both ara-C and cisplatin, increasing ara-C incorporation into DNA and inhibiting repair of platinum/DNA adducts, suggesting that the combination of cisplatin, fludarabine, and ara-C (PFA) may have clinical utility. METHODS. A Phase-II study of a 96-hour continuous infusion of cisplatin with two timed-sequential couplets of fludarabine and ara-C together with granulocytecolony stimulating factor was performed in 45 patients with previously refractory, histologically aggressive or mantle cell NHL. RESULTS. Patients had predominantly diffuse large cell and/or immunoblastic NHL or its variants (80%), or they had mantle cell lymphoma (18%). Overall, 93% of patients had previously refractory disease, with a median International Prognostic Index score of 3. A median of 2 cycles per patient were delivered (range, 1-4 cycles) with significant myelosuppression; there were medians of 2 days of neutropenia < 0.5 × 10(sup(9))/L (range, 0-12 days) and 3 days of thrombocytopenia < 20 × 10(sup(9))/L (range, 0-24 days). This was more severe in older patients and was cumulative with successive cycles. Thirty-five percent of cycles were complicated by infections, nausea and emesis were prominent, but other nonhematologic toxicity was mild. Peripheral blood progenitor cells were mobilized adequately after the first cycle, but collections were impaired after more prolonged therapy. The overall response rate was 48% (7% of patients had complete responses, and 41% of patients had partial responses), with one toxic death due to tumor-lysis syndrome. Patients with mantle cell lymphoma were more likely to respond than patients with other histologies (88% vs. 39%, respectively; P = 0.019), although three of eight patients had relapsed rather than refractory disease. The median remission duration was 4 months, with 28% of

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potentially eligible patients able to proceed to subsequent high-dose therapy. The actuarial 2-year survival rates were 20% ± 6% overall and 50 ± 18% for patients with mantle cell lymphoma. CONCLUSIONS. Given the adverse outlook for these patients, the results are promising, particularly for patients with mantle cell lymphoma, and suggest that the addition of fludarabine as a potential biochemical modulator may enhance the activity of cisplatin and ara-C. This is associated with significant cumulative (but manageable) myelosuppression. This paradigm, in which a nuceloside analogue is used to inhibit the repair of platinum/DNA adducts, also may be applicable for the treatment of patients with other types of platinum-sensitive tumors. © 2002 American Cancer Society.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

1 3/51 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2001382514 AU: McCune SL; Gockerman JP; Rizzieri DA Titel: Monoclonal antibody therapy in the treatment of non-hodgkin lymphoma Quelle: Journal of the American Medical Association; VOL: 286 (10); p. 1149-1152 /12 SEP

2001/ Sprache: ENGLISH CY: United States ISSN: 0098-7484 CO: JAMAA Corporate Source:

Dr. D.A. Rizzieri, Division of Oncology, Duke University Medical Center, Box 3961 North Pavilion, 2400 Pratt St, Durham, NC 27710 United States [email protected]

COU: United States DT: Journal RN: 0031 TE: rituximab/174722-31-7; alemtuzumab/216503-57-0; yttrium 90/10098-91-6;

ibritumomab tiuxetan/206181-63-7; tositumomab/208921-02-2; iodine 131/10043-66-0; iodine 131/15124-39-7; abciximab/143653-53-6; interleukin 2 receptor antibody/179045-86-4; OKT 3/140608-64-6; palivizumab/188039-54-5; infliximab/170277-31-3; trastuzumab/180288-69-1; fludarabine/21679-14-1; cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2

CR: 174722-31-7; 216503-57-0; 10098-91-6; 206181-63-7; 208921-02-2; 10043-66-0; 15124-39-7; 143653-53-6; 179045-86-4; 140608-64-6; 188039-54-5; 170277-31-3; 180288-69-1; 21679-14-1; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Internal Medicine

Cancer Hematology Drug Literature Index

Page 270: Fludara i.v. (2nd line NHL)

Adverse Reactions Titles 3, 6 3/52 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2001344888 AU: Kaminski MS; Zelenetz AD; Press OW; Saleh M; Leonard J; Fehrenbacher L; Lister

TA; Stagg RJ; Tidmarsh GF; Kroll S; Wahl RL; Knox SJ; Vose JM Titel: Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or

transformed low-grade B-cell non-Hodgkin's lymphomas Quelle: Journal of Clinical Oncology; VOL: 19 (19); p. 3918-3928 /01 OCT 2001/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND Corporate Source:

Dr. M.S. Kaminski, University of Michigan Cancer Center, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0936 United States [email protected]

COU: United States DT: Journal RN: 0031 DN: bexxar/Corixa,United States; bexxar/Glaxo,United States; bexxar/Smith Kline and

French,United States MN: Corixa,United States; Corixa; Glaxo,United States; Glaxo; Smith Kline and

French,United States; Smith Kline and French; Pharmacia Upjohn,United States; Pharmacia Upjohn

TE: tositumomab i 131/192391-48-3; doxorubicin/23214-92-8; doxorubicin/25316-40-9; cyclophosphamide/50-18-0; fludarabine/21679-14-1; chlorambucil/305-03-3

CR: 192391-48-3; 23214-92-8; 25316-40-9; 50-18-0; 21679-14-1; 305-03-3 AB: Purpose: To evaluate the efficacy and safety of tositumomab and iodine I 131

tositumomab (Bexxar; Corixa Corp, Seattle, WA, and GlaxoSmithKline, Philadelphia, PA) in patients with chemotherapy-refractory low-grade or transformed low-grade non-Hodgkin's lymphoma (NHL) and to compare its efficacy to the patients' last qualifying chemotherapy (LQC) regimens. Patients and Methods: Sixty patients who had been treated with at least two protocol-specified qualifying chemotherapy regimens and had not responded or progressed within 6 months after their LQC were treated with a single course of iodine I 131 tositumomab. Results: Patients had received a median of four prior chemotherapy regimens. A partial or complete response (CR) was observed in 39 patients (65%) after iodine I 131 tositumomab, compared with 17 patients (28%) after their LQC (P < .001). The median duration of response (MDR) was 6.5 months after iodine I 131 tositumomab, compared with 3.4 months after the LQC (P < .001). Two patients (3%) had a CR after their LQC, compared with 12 (20%) after iodine I 131 tositumomab (P < .001). The MDR for CR was 6.1 months after the LQC and had not been reached with follow-up of more than 47 months after iodine I 131 tositumomab. An independent review panel verified that 32 (74%) of the 43 patients with nonequivalent durations of response (> 30 days difference) had a longer duration of response after iodine I 131 tositumomab (P < .001). Only one patient was hospitalized for neutropenic fever. Five patients (8%)

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developed human antimurine antibodies, and one (2%) developed an elevated TSH level after treatment. Myelodysplasia was diagnosed in four patients in follow-up. Conclusion: A single course of iodine I 131 tositumomab was significantly more efficacious than the LQC received by extensively pretreated patients with chemotherapy-refractory, low-grade, or transformed low-grade NHL and had an acceptable safety profile. © 2001 by American Society of Clinical Oncology.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Drug Literature Index Adverse Reactions Titles

3 3/53 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2001140182 AU: Khorana A; Bunn P; McLaughlin P; Vose J; Stewart C; Czuczman MS Titel: A phase II multicenter study of CAMPATH-1H antibody in previously treated patients

with nonbulky non-Hodgkin's lymphoma Quelle: Leukemia and Lymphoma; VOL: 41 (1-2); p. 77-87 /2001/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 CO: LELYE Corporate Source:

Dr. M.S. Czuczman, Lymphoma Sec. Div. Hematol. Oncol., Bone Marrow Transplantation, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263 United States

COU: United States DT: Journal RN: 0025 DN: cytoxan; ara C; vp 16; novantrone TE: methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5;

bleomycin/11056-06-7; doxorubicin/23214-92-8; doxorubicin/25316-40-9; cyclophosphamide/50-18-0; vincristine/57-22-7; dexamethasone/50-02-2; prednisone/53-03-2; chlorambucil/305-03-3; fludarabine/21679-14-1; etoposide/33419-42-0; cytarabine/147-94-4; cytarabine/69-74-9; lomustine/13010-47-4; ifosfamide/3778-73-2; mesna/19767-45-4; mesna/3375-50-6; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; 5,6 dihydroazacitidine/62402-31-7; 5,6 dihydroazacitidine/62488-57-7

CR: 15475-56-6; 59-05-2; 7413-34-5; 11056-06-7; 23214-92-8; 25316-40-9; 50-18-0; 57-22-7; 50-02-2; 53-03-2; 305-03-3; 21679-14-1; 33419-42-0; 147-94-4; 69-74-9; 13010-47-4; 3778-73-2; 19767-45-4; 3375-50-6; 65271-80-9; 70476-82-3; 62402-31-7; 62488-57-7

AB: CAMPATH-1H is a humanized antilymphocyte monoclonal antibody (mAb) directed against the CD52 antigen expressed on normal and malignant lymphocytes. We report the results of a multicenter phase II trial using intravenous CAMPATH-1H in previously treated patients with nonbulky non-Hodgkin's lymphoma (NHL) or minimal

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residual NHL. Sixteen previously treated patients with nonbulky NHL and two patients with minimal residual NHL, were treated with CAMPATH-1H. Changes in peripheral blood lymphocyte subsets were analyzed by multiparameter flow cytometric techniques in eleven patients. The 18 patients enrolled in the studies received CAMPATH-1H for a median duration of 6 weeks (range, 3 to 14 weeks), and a median cumulative dose of 470 mg (range, 180 to 1185 mg). Two of the sixteen patients with nonbulky NHL achieved a complete response (CR) and one patient achieved a partial response (PR). One of the two patients with minimal residual NHL achieved a molecular CR. Infusional complications were seen with the majority of patients but were more common with initial infusions. Significant hematologic toxicity was also observed with grade 3/4 thrombocytopenia (n=10), grade 3/4 neutropenia (n=4) and grade 3 anemia (n=3). Due to excessive infectious complications observed with the patients enrolled, the trials were terminated early. Anti-tumor activity was demonstrated in a small subset of previously treated low-grade lymphoma patients with nonbulky or minimal residual disease. Future studies evaluating the effect of different drug schedules, modes of mAb administration, and concurrent use of prophylactic antibiotics/antiviral/antifungal agents to optimize anti-tumor activity and limit infectious toxicities are planned.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Drug Literature Index Adverse Reactions Titles

3 3/54 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2001073331 AU: Grillo-López AJ Titel: Rituximab: An insider's historical perspective Quelle: Seminars in Oncology; VOL: 27 (6); p. 9-16 /2000/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0093-7754 CO: SOLGA Corporate Source:

Dr. A.J. Grillo-López, IDEC Pharmaceuticals, 3030 Callan Rd., San Diego, CA 92121United States

COU: United States DT: Journal RN: 0030 DN: orthoclone/Johnson and Johnson,United States; reopro/Centocor,United States;

rituxan/Genentech,United States; zevalin/Idec,United States; rituxan/Idec,United States; orthoclone/Ortho,United States; reopro/Lilly,United States; rituxan/Hoffmann La Roche,United States

MN: Johnson and Johnson,United States; Johnson and Johnson; Centocor,United States; Centocor; Genentech,United States; Genentech; Idec,United States; Idec; Ortho,United States; Ortho; Lilly,United States; Lilly; Hoffmann La Roche,United States; Hoffmann La Roche

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TE: rituximab/174722-31-7; ibritumomab tiuxetan/206181-63-7; yttrium 90/10098-91-6; cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9; prednisone/53-03-2; vincristine/57-22-7; fludarabine/21679-14-1; abciximab/143653-53-6

CR: 174722-31-7; 206181-63-7; 10098-91-6; 50-18-0; 23214-92-8; 25316-40-9; 53-03-2; 57-22-7; 21679-14-1; 143653-53-6

AB: Rituximab (Rituxan; Genentech, Inc, South San Francisco, CA and IDEC Pharmaceutical Corporation, San Diego, CA) is a unique monoclonal antibody for the treatment of non-Hodgkin's lymphoma. This chimeric mouse/human antibody was discovered in 1991 at IDEC Pharmaceuticals' laboratories, where the anti-body was genetically engineered and produced utilizing high-yield expression systems. It is a human IgGI kappa antibody with mouse variable regions isolated from a murine anti-CD20 antibody, IDEC-2B8, that binds with high affinity to cells expressing the CD20 antigen found on the surface of malignant and normal B cells, but not on other normal tissues. It mediates complement-dependent cell lysis in the presence of human complement, and antibody-dependent cellular cytotoxicity with human effector cells. Also, it has been shown to induce apoptosis and to sensitize chemoresistant human lymphoma cell lines in vitro. Clinical development was expedited (3 years) with the first patient entered in phase I trials in March 1993 and the last patient entered in the phase III study in March 1996. IDEC Pharmaceuticals began a collaboration with Genentech, Inc in March 1995 and with F. Hoffman-LaRoche (Nutley, NJ) shortly thereafter. Marketing approval was granted by the US Food and Drug Administration on November 26, 1997 (and by the European Union on June 2, 1998) for the indication of relapsed or refractory, CD20-positive, B-cell, low-grade or follicular non-Hodgkin's lymphoma. Rituximab is the first therapeutic monoclonal antibody approved for the treatment of cancer and the first single agent approved specifically for therapy for a lymphoma. Substantial research has been performed over the past 8 years to further the understanding of this novel therapeutic. Nevertheless, much remains to be accomplished in key areas such as mechanism of action and resistance, combinations with chemotherapy, biologics and radiotherapy/radioimmunotherapy, role within multimodality regimens, and nonmalignant applications. Research conducted in the coming years should be targeted toward resolving these important issues. Copyright © 2000 by W.B. Saunders Company.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Pharmacy

3 3/55 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2001073330 AU: Fisher RI Titel: Current therapeutic paradigm for the treatment of non-Hodgkin's lymphoma Quelle: Seminars in Oncology; VOL: 27 (6); p. 2-8 /2000/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0093-7754

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CO: SOLGA Corporate Source:

Dr. R.I. Fisher, Cardinal Bernardin Cancer Center, Loyola University Medical Center, 2160 S First Ave, Maywood, IL 60153 United States

COU: United States DT: Journal RN: 0035 DN: rituxan/Genentech,United States; zevalin/Idec,United States; rituxan/Idec,United

States MN: Genentech,United States; Genentech; Idec,United States; Idec TE: rituximab/174722-31-7; yttrium 90/10098-91-6; cyclophosphamide/50-18-0;

doxorubicin/23214-92-8; doxorubicin/25316-40-9; teniposide/29767-20-2; prednisone/53-03-2; alpha2b interferon/99210-65-8; vincristine/57-22-7; fludarabine/21679-14-1; dexamethasone/50-02-2; pentostatin/53910-25-1; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5; etoposide/33419-42-0; cytarabine/147-94-4; cytarabine/69-74-9; bleomycin/11056-06-7; folic acid/59-30-3; folic acid/6484-89-5; carmustine/154-93-8; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2

CR: 174722-31-7; 10098-91-6; 50-18-0; 23214-92-8; 25316-40-9; 29767-20-2; 53-03-2; 99210-65-8; 57-22-7; 21679-14-1; 50-02-2; 53910-25-1; 65271-80-9; 70476-82-3; 15475-56-6; 59-05-2; 7413-34-5; 33419-42-0; 147-94-4; 69-74-9; 11056-06-7; 59-30-3; 6484-89-5; 154-93-8; 15663-27-1; 26035-31-4; 96081-74-2

AB: Patients with indolent non-Hodgkin's lymphoma may be treated with various approaches ranging from deferred initial therapy (watch and wait) to single-agent alkylating agents, radiation therapy, or combination chemotherapy. None of these approaches have produced curative results. Clearly, innovative treatment strategies are needed. The use of interferon, monoclonal antibodies with or without radioisotopes, purine analogues, and even high-dose therapy with stem-cell rescue are under investigation. Based on the fact that fewer than 40% of advanced-stage, aggressive non-Hodgkin's lymphoma patients are cured with cyclophosphamide/doxorubicin/vincristine/prednisone chemotherapy, the best approach for any patient is an experimental one. Examples include: (1) increasing the dose intensity of drugs used in standard regimens; (2) preventing the development of drug resistance; (3) combining monoclonal antibodies with chemotherapy; or (4) autologous stem-cell transplantation as a rescue from marrow-ablative chemotherapy. If a patient is not eligible or does not wish to participate in a clinical trial, cyclophosphamide/doxorubicin/vincristine/prednisone, as inadequate as it is, remains the gold standard. Copyright © 2000 by W.B. Saunders Company.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Health Policy, Economics and Management Drug Literature Index Adverse Reactions Titles

6 3/56 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2001053265 AU: Wood AM

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Titel: Rituximab: An innovative therapy for non-Hodgkin's lymphoma Quelle: American Journal of Health-System Pharmacy; VOL: 58 (3); p. 215-232 /01 FEB

2001/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1079-2082 CO: AHSPE Corporate Source:

A.M. Wood, Clinical Specialist, Oncology, HealthAnswers, Inc., 3 Acadia Branch Place, Woodlands, TX 77382 United States [email protected]

COU: United States DT: Journal RN: 0081 TE: rituximab/174722-31-7; chlorambucil/305-03-3; cyclophosphamide/50-18-0;

prednisone/53-03-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; vincristine/57-22-7; fludarabine/21679-14-1

CR: 174722-31-7; 305-03-3; 50-18-0; 53-03-2; 23214-92-8; 25316-40-9; 57-22-7; 21679-14-1

AB: The epidemiology, etiology, classification, and treatment of non-Hodgkin's lymphoma (NHL) are reviewed, and rituximab, a newly available therapy, is discussed. NHL comprises a group of lymphoproliferative disorders the frequency of which continues to rise. Although many classification systems exist for identifying specific histological subtypes, NHL is generally divided into indolent (low-grade) and aggressive (intermediate- and high-grade) forms. Low-grade NHL is characterized by a slowly progressive, continually relapsing course, with eventual transformation to a more rapidly progressive form that is usually fatal. Several options are available for the management of indolent NHL; none is curative. Rituximab, a human-mouse monoclonal antibody that targets the CD20 antigen expressed in over 90% of B-cell NHLs, provides an alternative to conventional chemotherapy that is relatively safe and effective. In a Phase III trial involving 166 patients with relapsed or refractory low-grade B-cell NHL, rituximab produced an overall response of 48%, with 20 of 80 responders still in remission more than 36 months after treatment. Study results in patients with bulky disease and those requiring retreatment have also been encouraging. Most adverse effects associated with rituximab are mild to moderate. Infusion-related reactions occur more commonly during initial infusions and in patients with evidence of increased tumor burden but can be effectively managed with premedication, supportive care, and adjusted infusion rates. Hematologic effects are generally mild and transient, and adverse immune responses are rare. Rituximab is an alternative to conventional chemotherapy for the treatment of relapsed or refractory low-grade or follicular CD20-positive B-cell NHL.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Radiology

Cancer Hematology Drug Literature Index Adverse Reactions Titles

3, 6

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3/57 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2000210929 AU: Van Den Neste E; Louviaux I; Michaux JL; Delannoy A; Michaux L; Sonet A; Bosly A;

Doyen C; Mineur P; Andre M; Straetmans N; Coche E; Venet C; Duprez T; Ferrant A Titel: Phase I/II study of 2-chloro-2'-deoxyadenosine with cyclophosphamide in patients

with pretreated B cell chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma

Quelle: Leukemia; VOL: 14 (6); p. 1136-1142 /2000/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 0887-6924 CO: LEUKE Corporate Source:

E. Van Den Neste, Department of Hematology/Radiology, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, 10 Av. Hippocrate, 1200 Brussels Belgium

COU: Belgium DT: Journal RN: 0044 DN: vp 16 TE: cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9;

mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; vincristine/57-22-7; prednisone/53-03-2; etoposide/33419-42-0; dexamethasone/50-02-2; cytarabine/147-94-4; cytarabine/69-74-9; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; ifosfamide/3778-73-2; fludarabine/21679-14-1

CR: 50-18-0; 23214-92-8; 25316-40-9; 65271-80-9; 70476-82-3; 57-22-7; 53-03-2; 33419-42-0; 50-02-2; 147-94-4; 69-74-9; 15663-27-1; 26035-31-4; 96081-74-2; 3778-73-2; 21679-14-1

AB: Because of their substantial in vitro synergy, we conducted a dose-escalation study of cyclophosphamide (CP) added to 2-chloro-2'-deoxyadenosine (CdA) in patients with previously treated chronic lymphocytic leukemia and non-Hodgkin's lymphoma. CdA was given at a fixed dose (5.6 mg/m²/day) as a 2-h intravenous (i.v.) infusion, immediately followed by a 1-h i.v. infusion of CP, for 3 days. The initial daily CP dose was 200 mg/m², and was escalated by 100 mg/m² increments in successive cohorts of three to six patients to determine the maximum-tolerated dose (MTD). Additional patients were included at the MTD to extend toxicity and response analysis. Twenty-six patients received 68 cycles of chemotherapy. The MTD of CP after CdA 5.6 mg/m², was 300 mg/m². Acute neutropenia was the dose-limiting toxicity of this regimen, which was otherwise well tolerated. Delivery of repeated cycles was not feasible in eight patients (31%) because of prolonged thrombocytopenia. Severe infections were seen in three of 68 cycles (4%). The overall response rate was 58% (15 of 26; 95% Cl, 36-76%), with 15% complete responses and 42% partial responses. These data show the feasibility of the association of CdA with CP. Given the response rate observed, further studies of this regimen are warranted in untreated patients, in particular with chronic lymphocytic leukemia and with Waldenstrom macroglobulinemia.

CNOTE: Copyright 2004 Elsevier B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index

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Adverse Reactions Titles 3 3/58 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2000108831 AU: Child JA; Johnson SA; Rule S; Smith GM; Morgan GJ; Johnson PWM; Prentice AG;

Tollerfield SM; Wareham E Titel: FLUDAP: Salvage chemotherapy for relapsed/refractory aggressive non-Hodgkin's

lymphoma Quelle: Leukemia and Lymphoma; VOL: 37 (3-4); p. 309-317 /2000/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 CO: LELYE Corporate Source:

Dr. J.A. Child, Department of Haematology, The General Infirmary, Great George Street, Leeds LS1 3EX United Kingdom

COU: United Kingdom DT: Journal RN: 0013 DN: ara C; lenograstim; granocyte TE: cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; cytarabine/147-94-

4; cytarabine/69-74-9; dexamethasone/50-02-2; fludarabine phosphate/75607-67-9; recombinant granulocyte colony stimulating factor/121181-53-1

CR: 15663-27-1; 26035-31-4; 96081-74-2; 147-94-4; 69-74-9; 50-02-2; 75607-67-9; 121181-53-1

AB: The aim of this study was to investigate the combination of fludarabine phosphate, dexamethasone, cytosine arabinoside and cis-platinum (FLUDAP) in the treatment of patients with relapsed/refractory aggressive non-Hodgkin's lymphoma (NHL). This regimen comprises: dexamethasone 100 mg/d continuous infusion (cont. inf.) d1-3; cytosine arabinoside (ara-C) 1 g/m²/d cont. inf. d 2,3; fludarabine phosphate 30 mg/m² short inf. 4 hr prior to each 24 hr ara-C inf.; cis-platinum 50 mg/m² 4 hr inf. at the start of each 24 hr ara-C inf. G-CSF (lenograstim, Granocyte®) is given at 263 µg s.c. daily from day 7 until the neutrophil count reaches 1.0 x 10(sup(9))/l. The regimen repeats at 21 day intervals. A total of 33 patients were registered (median age 47 years; 24 males, 9 females); the majority (73%) were refractory to their previous treatment and most had advanced disease by Ann Arbor stage. Thirteen (39%) of the 33 enrolled patients (52% of the 25 fully evaluable patients who received at least 2 courses of FLUDAP) responded to treatment. A maximum response of complete remission was achieved in 5 patients, good partial remission in 3, and partial remission in 5. Twelve patients went on to successful stem cell supported intensification therapy. Median survival times were higher in the responding patients, and in those patients transplanted post-FLUDAP. The toxicity associated with the FLUDAP regimen was generally predictable; frequently reported severe events included haematological toxicity and infection. In conclusion, the FLUDAP regimen shows promise as a salvage regimen and increases the available therapeutic options in the treatment of recurrent/refractory aggressive NHL.

CNOTE: Copyright 2004 Elsevier B.V., Amsterdam. All rights reserved.

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ET: Cancer Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

1 3/59 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2000096128 AU: Gahn B; Brittinger G; Dolken G; Dohner H; Emmerich B; Franke A; Freund M; Huber

C; Kuse R; Scholten T; Hiddemann W Titel: Multicenter phase II study of oral idarubicin in treated and untreated patients with B-

chronic lymphocytic leukemia Quelle: Leukemia and Lymphoma; VOL: 37 (1-2); p. 169-173 /2000/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 CO: LELYE Corporate Source:

Dr. B. Gahn, Center for Cell and Gene Therapy, Texas Children's Hospital, 6621 Fannin Street, Houston, TX 77030 United States [email protected]

COU: United States DT: Journal RN: 0025 TE: idarubicin/57852-57-0; idarubicin/58957-92-9; chlorambucil/305-03-3;

fludarabine/21679-14-1 CR: 57852-57-0; 58957-92-9; 305-03-3; 21679-14-1 AB: Idarubicin is the first anthracycline that can be administered orally facilitating

antineoplastic chemotherapy at an improved quality of life. In different studies idarubicin has proved clinical effectiveness in patients with advanced low grade non Hodgkin's lymphoma. We performed a phase II study in 19 patients with untreated and pretreated B-CLL of Binet stage A-C. Idarubucin was administered orally at a dose of 15 mg/m² over 3 days every 4 weeks. Of 19 evaluable patients (m:f, 16:3, median age 64 years, range 41-80 years) 7 were previously untreated while 12 patients had received prior therapy with fludarabine, chlorambucil or similar non-anthracycline containing regimens. 12 pts had Binet stage C, 5 Binet stage B and 2 Binet stage A. Five patients achieved a partial remission (26%), 5 patients had stable disease (26%) and 9 patients showed progressive disease (47%), resulting in an overall response of 26% (5/19). There was no correlation of response rate with Binet stages or previous treatment regimens. Treatment associated side effects consisted predominantly of mild nausea and vomiting (26%) as well as minor infections (21%) and diarrhoea (16%). These data demonstrate that oral idarubicin as a single agent is well tolerated but of limited effectiveness in B-CLL. Further studies are needed to assess different doses and schedules of oral idarubucin and to test it in combination with other chemotherapeutic agents.

CNOTE: Copyright 2004 Elsevier B.V., Amsterdam. All rights reserved. ET: Cancer

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Hematology Drug Literature Index Adverse Reactions Titles

3 3/60 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2000078070 AU: Imrie K; Esmail R; Buckstein R; Berinstein N; Meyer R; Zahra HA; Chin- Yee I;

Costello B; Crump M; De Metz C; Dhaliwal D; Gospodarowicz M; Huebsch L; Kacsor M; Kaizer L; Kouroukis T; Matthews J; Meharchand J; Messner H; Sawka C; Smith A; Walker I

Titel: Use of rituximab in the treatment of lymphoma: An evidence summary Quelle: Current Oncology; VOL: 6 (4); p. 228-235 /1999/ Sprache: ENGLISH AL: ENGLISH CY: Canada ISSN: 1198-0052 CO: CUONF Corporate Source:

R. Meyer, Haematology Disease Site Group, Hamilton Regional Cancer Centre, 699 Concession Street, Hamilton, Ont. L8V 5C2 Canada [email protected]

COU: Canada DT: Journal RN: 0036 TE: rituximab/174722-31-7; cyclophosphamide/50-18-0; doxorubicin/23214-92-8;

doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2; etoposide/33419-42-0; bleomycin/11056-06-7; fludarabine/21679-14-1

CR: 174722-31-7; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2; 33419-42-0; 11056-06-7; 21679-14-1

AB: Questions: 1. In what groups of lymphoma patients has rituximab been studied? 2. What beneficial treatment outcomes are associated with the use of rituximab in patients with lymphoma? 3. What is the toxicity of rituximab? 4. What patients are more-or-less likely to benefit from treatment with rituximab?. Perspective: Evidence was selected and reviewed by 2 people, one of whom is a member of the Cancer Care Ontario Practice Guidelines Initiatives Haematology Disease Site Group (DSG). This evidence summary has been reviewed, discussed, and approved by the DSG, which comprises haematologists, medical oncologists, radiation oncologists, methodologists, and community representatives. Methodology: Sources of Evidence: Relevant evidence was identified by a systematic search of the MEDLINE, CANCERLIT, HealthSTAR, CINAHL, PUBMED databases, and the Cochrane Library (using the text words 'rituxan,' 'rituximab,' 'ritux:,' and 'IDEC C2B8'). Also searched were the American Society of Hematology, the American Society of Clinical Oncology, and the Lugano meeting conference proceedings; the European Organisation for Research and Treatment of Cancer and the Physician Data Query databases; and reference lists from selected articles. Patient Population: Patients with non-Hodgkin's lymphoma. Outcomes of Interest: Survival, quality of life, time-to-progression, response duration, response rate, and toxicity were the primary outcomes of interest. Results: Search Results: Twenty-eight studies were identified: 1

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randomised trial of 2 different dosing strategies for rituximab in intermediate-grade lymphoma; 11 reports of single-arm studies of rituximab in follicular, low-grade lymphoma, or mantle-cell lymphoma; 1 abstract of a published paper; 8 abstracts of single-arm studies of rituximab in low- and intermediate-grade lymphoma, Waldenstrom's macroglobulinaemia, and post-transplant lymphoproliferative disorders; 3 abstracts of single-arm studies of rituximab in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or interferon alpha in follicular, low- or intermediate-grade lymphoma; 1 paper of a single-arm study of rituximab in combination with CHOP in follicular or low- grade lymphoma; 1 abstract of a single-arm study of rituximab in combination with fludarabine; 1 abstract of rituximab in combination with cyclophosphamide; and 1 abstract of rituximab in combination with carmustine (BCNU), cyclophosphamide and etoposide in low-grade or follicular non- Hodgkin's lymphoma. Benefits: The response rates were highest in patients with follicular lymphoma (60%; 95% Confidence Interval (CI): 52-68%) and lowest for those with small lymphocytic lymphoma (18%; 95% CI: 8-28%). Response rates were higher for patients still sensitive to conventional chemotherapy. Data on 1-year survival for mantle-cell lymphoma patients was 80% with a median duration of response of 14.4 months. Data on quality of life were not available. Harms: Detailed toxicity data were provided in the published phase II study. The majority of patients (84%) treated with rituximab in this study had adverse events. The most common of these were: fever (43%), chills (28%), nausea (18%), headache (14%), and allergic symptoms (43%) including angio-oedema (14%). Severe (grade 3 or 4) toxicity was uncommon. Little haematologic toxicity was noted and there did not appear to be any increase in infections up to 1 year after therapy. The majority of adverse events occurred with the first infusion. A 'Dear Doctor' letter was issued indicating that following approval of the drug in the United States (November 1997) and in Europe (June 1998), there were reports of 8 fatalities resulting from cytokine-release syndrome in an estimated 12 000-14 000 treated patients. These reactions occurred early in the first infusion. This appears more common in patients with high tumour burden or who have more than 50 x 10(sup(9)) circulating malignant cells per litre. Future Steps: Rituximab alone, or in combination with chemotherapy, is being compared with conventional chemotherapy in patients with relapsed, as well as those with newly diagnosed, low-grade or follicular lymphoma. It is also being evaluated as part of initial therapy for intermediate-grade lymphoma. At present, the evidence does not allow a firm clinical recommendation on this topic. Please see the full report for a more detailed discussion of the evidence, an interpretive summary, and a description of the opinions of the Disease Site Group members.

CNOTE: Copyright 2004 Elsevier B.V., Amsterdam. All rights reserved. ET: Internal Medicine

Cancer Hematology Drug Literature Index Adverse Reactions Titles

3, 6 3/61 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM1999118403 AU: Younes A Titel: Paclitaxei-based treatment of lymphoma Quelle: Seminars in Oncology; VOL: 26 (1); p. 123-128 /1999/ Sprache: ENGLISH AL: ENGLISH

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CY: United States ISSN: 0093-7754 CO: SOLGA Corporate Source:

Dr. A. Younes, Department of Lymphoma, Box 68, Texas Univ. M.D. Anderson Can. Ctr., 1515 Holcombe Blvd, Houston, TX 77030 United States

COU: United States DT: Journal RN: 0022 DN: paclitaxel/Bristol Myers Squibb,United States MN: Bristol Myers Squibb,United States; Bristol Myers Squibb TE: cyclosporin/79217-60-0; verapamil/152-11-4; verapamil/52-53-9;

cyclophosphamide/50-18-0; mesna/19767-45-4; mesna/3375-50-6; ifosfamide/3778-73-2; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; etoposide/33419-42-0; cytarabine/147-94-4; cytarabine/69-74-9; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; methylprednisolone/6923-42-8; methylprednisolone/83-43-2; fludarabine/21679-14-1; topotecan/119413-54-6; topotecan/123948-87-8

CR: 79217-60-0; 152-11-4; 52-53-9; 50-18-0; 19767-45-4; 3375-50-6; 3778-73-2; 65271-80-9; 70476-82-3; 33419-42-0; 147-94-4; 69-74-9; 15663-27-1; 26035-31-4; 96081-74-2; 6923-42-8; 83-43-2; 21679-14-1; 119413-54-6; 123948-87-8

AB: The activity of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) recently was evaluated in patients with relapsed and refractory non-Hodgkin's lymphoma in three phase II clinical trials using different doses and infusion schedules. The largest trial, conducted at M.D. Anderson Cancer Center, used the most intensive dose (200 mg/mxb2 infused over 3 hours every 3 weeks) in 96 patients. As expected, the response rate was low in patients with primary refractory disease. In contrast, patients with intermediate-grade lymphoma and no primary refractory disease had a response rate of 50% and those with low-grade lymphoma had a response rate of 31%. Lower response rates were reported in clinical trials conducted by the National Cancer Institute, which used paclitaxel 140 mg/mxb2 infused over 96 hours, and by the Southwest Oncology Group, which used paclitaxel 175 mg/mxb2 infused over 24 hours. Paclitaxel-based combination programs currently are being evaluated at M.D. Anderson Cancer Center and other institutions in patients with relapsed non-Hodgkin's lymphoma. Early results are encouraging.

CNOTE: Copyright 2004 Elsevier B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

3, 6 3/62 von 62 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM1999090154 AU: Lossos IS; Paltiel O; Polliack A Titel: Salvage chemotherapy using a combination of fludarabine and cyclophosphamide for

refractory or relapsing indolent and aggressive non-Hodgkin's lymphomas Quelle: Leukemia and Lymphoma; VOL: 33 (1-2); p. 155-160 /1999/ Sprache: ENGLISH AL: ENGLISH

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CY: United Kingdom ISSN: 1042-8194 CO: LELYE Corporate Source:

Prof. A. Polliack, Lymphoma and Leukemia Unit, Department of Hematology, Hadassah University Hospital, POB 12000, Jerusalem Israel

COU: Israel DT: Journal RN: 0016 TE: fludarabine/21679-14-1; cyclophosphamide/50-18-0 CR: 21679-14-1; 50-18-0 AB: The prognosis of patients with refractory or relapsing non-Hodgkin's lymphoma (NHL)

after primary therapy is poor and multi-drug salvage treatments are associated with less than 60% response rates, usually of short duration. Here we report the results of a phase II study using a fludarabine-cyclophosphamide (FAMP-Cy) combination as a salvage failure regimen in refractory and relapsing low-grade (6) and intermediate-grade (9) NHL patients. Fifteen patients, who had received up to 4 regimens prior to therapy with FAMP-Cy were treated with fludarabine (25 mg/mlxb2) and cyclophosphamide (300 mg/mxb2) for 3 consecutive days followed by G-CSF (5 µg/kg). The overall response was 74%, 4 achieving complete responses (CR) and 7 partial responses (PR). All patients with low-grade NHL responded (4 CR, 2 PR); 5 patients with intermediate-grade NHL achieved PR lasting for a median of 5 months. The main toxicity encountered was moderate myelosuppression. Three patients had febrile neutropenia, one had drug-induced fever and a single patient developed severe neurotoxicity. Opportunistic infections due to lymphopenia were not seen. The combination of fludarabine and cyclophosphamide used as a salvage regimen showed an impressive response in a small group of heavily pretreated low-grade NHL patients who had previously received a large number of prior regimens. FAMP-Cy had limited effect in a similar group of intermediate-grade NHL patients. Results with this 'failure' regimen are encouraging, however further studies are needed in order to confirm these observations in a larger series of patients.

CNOTE: Copyright 2004 Elsevier B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

2 (n=15)

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Anlage 9 Anmerkungen zur Auswahl der Literatur

Ausgewählt und in die Bewertung eingeschlossen wurden nur Literaturbeiträge, die alle folgenden Kriterien erfüllten: 1. Nicht in Medlinerecherche vom 08.07.2008 (siehe Anlage 1) enthalten und

2. Auswertungen klinischer Studien der Phase 2 mit Einschluss von mindestens 20 Patienten in der Rezidivtherapie bzw. Therapie primär refraktärer NHL (bei Einschluss vorbehandelter und nicht vorbehandelter Patienten getrennte Auswertung für vorbehandelte Patienten und mindestens 20 Patienten in dieser Untergruppe) oder klinische Studie der Phase 3 / Metaanalyse unabhängig von der Therapielinie, in der Auswertung als Endpunkt(e) Ansprechrate und / oder progessionsfreies Überleben o. ä. und / oder Gesamtüberleben und / oder krankheitsbezogene Lebensqualität und/oder nach anerkannter Skalierung erfasste Toxizität, und

3. intravenöses Fludarabin als Prüfmedikament und

4. geprüfte Indikation niedrig- oder intermediär malignes B-NHL außer CLL oder multiples Myelom, bei verschiedenen Unterformen getrennte Auswertung für CLL, andere niedrig und intermediär maligne B-NHL (mindestens 20 Patienten) und hoch maligne B-NHL und

5. geprüftes Therapiekonzept ist konventionell dosierte Chemotherapie ohne Hochdosistherapie und / oder Stammzelltransplantation und

6. Publikationstyp: Auswertung einer Studie, keine Übersichtsarbeit, kein „letter“, kein „editorial“

Fett gedruckte Titel wurden eingeschlossen Bei den übrigen Publikationen wurde in der letzten Zeile mindestens eines der Auswahlkriterien genannt, weshalb diese Arbeit nicht berücksichtigt wurde (siehe auch Abschnitt 8 des Gutachtens), ggf. Erläuterung in Klammern, sofern der Ausschlussgrund nicht schon aufgrund von Überschrift oder Abstract erkennbar war: Im Ergebnis erfüllte keine der unten aufgelisteten Publikationen sämtliche Einschlusskriterien EMBASE-Recherche vom 29.10.2007 Suchkriterien: fludarabine, Non-Hodgkin’s lymphoma, clinical trial, not chronic lymphocytic leukaemia Erscheinungsjahr: 1999-2007 (Anzahl Treffer: 21) Dokumente Suchschritt : ((AU=NON ? OR (NON#)) AND (AU=HODGKIN ? OR (HODGKIN#)) AND ( (AU=S OR AU=S ?) OR (S)) AND (AU=TRIAL ? OR (TRIAL#)) AND (AU="NOT" ? OR ("NOT"#)) AND FLUDARABINE# AND LYMPHOMA# AND CLINIC### AND CHRON### AND LYMPHOCYT### AND LEUKE####) AND PY=1999 to 2007 3/1 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V.

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ND: EM2007077607 AU: Maloney DG Titel: Immunotherapy for non-Hodgkin's lymphoma: Monoclonal antibodies and

vaccines Quelle: Journal of Clinical Oncology; VOL: 23 (26); p. 6421-6428 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0732-183X CO: JCOND Corporate Source:

Dr. D.G. Maloney, Fred Hutchinson Cancer Research Center, Mail Stop: D1-100, 1100 Fairview Ave N, Seattle, WA 98109-1024 United States [email protected]

COU: United States DT: Journal RN: 0057 DN: cmc 544; favid/Favrille,United States; gtop 99/Genitope; myvax/Genitope,United

States MN: Favrille,United States; Favrille; Genitope,United States; Genitope TE: alemtuzumab/216503-57-0; carrier protein/80700-39-6; cyclophosphamide/50-18-

0; dexamethasone/50-02-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; fludarabine/21679-14-1; galiximab/357613-77-5; prednisone/53-03-2; rituximab/174722-31-7; thalidomide/50-35-1; vincristine/57-22-7

CR: 216503-57-0; 80700-39-6; 50-18-0; 50-02-2; 23214-92-8; 25316-40-9; 21679-14-1; 357613-77-5; 53-03-2; 174722-31-7; 50-35-1; 57-22-7

AB: Advances in the development of monoclonal antibodies have led to new agents rapidly incorporated into standard lymphoma therapy. The characteristics of the target antigen and the properties of the antibody including interaction with the host immune system have been found to correlate with outcome. Antibodies targeting the CD20 antigen on B cells have been most widely used, led by the chimeric antibody rituximab, now used in nearly all types of B-cell non-Hodgkin's lymphoma(NHL). New antibodies targeting CD20 with augmented complement or Fc receptor binding are now being evaluated and will eventually have to be compared with rituximab. Challenges to these new antibodies include the nearly universal use of rituximab early in NHL therapy, and its increasing use as maintenance therapy. It is not clear what the activity of these antibodies will be in rituximab-refractory patients. New antibodies targeting antigens such as CD40 and CD80 are also being tested alone and in combination with rituximab. Vaccine trials using patient-specific immunization with immunoglobulin idiotype (Ig-Id present on the surface of most B-cell NHL) isolated by molecular rescue or by cell hybridization techniques are also nearing completion. These approaches attempt to actively induce specific humoral or cellular immune responses to the Ig-Id by attaching the protein to a carrier protein and the use of an immunologic adjuvant such as granulocyte macrophage colony-stimulating factor. Prior rituximab appears to delay humoral responses to the idiotype but may still allow cellular responses. The incorporation of all these approaches into optimal NHL therapy remains a challenge. © 2005 by American Society of Clinical Oncology.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

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Public Health, Social Medicine and Epidemiology Hematology Drug Literature Index Pharmacy

3/2 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006579945 AU: Rao R; Shammo JM; Enschede SH; Porter C; Adler SS; Venugopal P; Gregory

SA Titel: The combination of fludarabine, cyclophosphamide, and granulocyte-macrophage

colony-stimulating factor in the treatment of patients with relapsed chronic lymphocytic leukemnia and low-grade non-Hodgkin's lymphoma

Quelle: Clinical Lymphoma and Myeloma; VOL: 6 (1); p. 26-30 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1557-9190 Corporate Source:

Dr. R. Rao, Department of Hematology and Oncology, Rush University Medical Center, 1725 W Harrison St, Chicago, IL 60612 United States [email protected]

COU: United States DT: Journal RN: 0021 TE: cyclophosphamide/50-18-0; fludarabine/21679-14-1 CR: 50-18-0; 21679-14-1 AB: Purpose: The goal of this study was to evaluate the efficacy of the

fludarabine/cyclophosphamide combination in patients with relapsed chronic lymphocytic lymphoma (CLL) and low-grade non-Hodgkin's Lymphoma (NHL) and to assess the impact of adding granulocyte-macrophage colony-stimulating factor (GM-CSF) to this regimen in a randomized fashion. Patients and methods: Thirty-four patients (CLL, n = 16; low-grade NHL, n = 18) were enrolled. The median number of previous treatments was 2. Patients received (less-than or equal to) 6 cycles of fludarabine at 30 mg/m² per day and cyclophosphamide at 300 mg/m² per day on days 1-3 of a 28-day cycle. Patients were randomized to supportive care or to receive GM-CSF at 250 µg/m² per day, starting 24 hours after completion of chemotherapy and continuing up to 48 hours before the next cycle. Those who had received > 6 months of previous therapy with an alkylating agent or had preexisting cytopenias received a 25% dose reduction. Twenty-two patients (65%) were randomized to receive GM-CSF. Patients completed a median of 5 cycles of treatment (range, 1-6 cycles). Twenty-seven patients (80%) received (greater-than or equal to) 3 cycles of treatment and were evaluated for response. Results: Seven patients (26%) exhibited a complete response; 6 of the 7 had low-grade NHL. Fourteen patients (52%) exhibited a partial response, and 6 patients (22%) had stable disease. Notably, 6 of the 7 patients who exhibited complete response and 9 of 14 patients with partial responses were randomized to the GM-CSF arm. The duration of response ranged from 4 months to 26 months. The toxicities were mainly hematologic. Nineteen patients (70%) experienced (greater-than or equal to) 1 episode of grade 3/4 neutropenia, but only 4 (15%) experienced febrile neutropenia; 3 of those patients were assigned to the GM-CSF arm. Conclusions: The combination of fludarabine and cyclophosphamide is a well-tolerated and effective treatment regimen for patients with relapsed CLL and

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low-grade NHL. A higher percentage of complete responses were noted in patients with low-grade NHL compared with patients with CLL. Granulocyte-macrophage colony-stimulating factor did not seem to decrease the incidence of febrile neutropenia. However, the higher number of complete and partial responses noted on the GM-CSF arm is intriguing and warrants further investigation.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

1 3/3 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006538043 AU: Robak T; Lech-Maranda E; Korycka A; Robak E Titel: Purine nucleoside analogs as immunosuppressive and antineoplastic agents:

Mechanism of action and clinical activity Quelle: Current Medicinal Chemistry; VOL: 13 (26); p. 3165-3189 /2006/

http://www.ingentaconnect.com/content/ben/cmc/2006/00000013/00000026/art00006Sprache: ENGLISH AL: ENGLISH CY: Netherlands ISSN: 0929-8673 CO: CMCHE Corporate Source:

T. Robak, Department of Hematology, Medical University of Lodz, Copernicus Memoral Hospital, Pabianicka 62 Str., 93-513 Lodz Poland [email protected]

COU: Poland DT: Journal RN: 0271 DN: mylinax/Serono; mylinax/Ivax; bch 1777 MN: Serono; Ivax TE: fludarabine/21679-14-1; cladribine/4291-63-8; pentostatin/53910-25-1;

clofarabine/123318-82-1; nelarabine/121032-29-9; 8 chloroadenosine/34408-14-5; DNA/9007-49-2; deoxyadenosine/958-09-8; deoxyadenosine triphosphate/1927-31-7; 2 aminopurine/452-06-2; guanine/69257-39-2; guanine/73-40-5; cyclophosphamide/50-18-0; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; doxorubicin/23214-92-8; doxorubicin/25316-40-9; vincristine/57-22-7; chlorambucil/305-03-3; prednisone/53-03-2; rituximab/174722-31-7; alemtuzumab/216503-57-0; cytarabine/147-94-4; cytarabine/69-74-9

CR: 21679-14-1; 4291-63-8; 53910-25-1; 123318-82-1; 121032-29-9; 34408-14-5; 9007-49-2; 958-09-8; 1927-31-7; 452-06-2; 69257-39-2; 73-40-5; 50-18-0; 65271-80-9; 70476-82-3; 23214-92-8; 25316-40-9; 57-22-7; 305-03-3; 53-03-2; 174722-31-7; 216503-57-0; 147-94-4; 69-74-9

AB: The purine nucleoside analogs (PNA) form an important group of cytotoxic drugs

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active in the treatment of neoplastic and autoimmune diseases. Three of them, fludarabine (FA), cladribine (2-chlorodeoxyadenosine, 2-CdA) and pentostatin (2'-deoxycoformycin, DCF) have established clinical activity in hematological malignancies and have been approved by FDA. These drugs are also investigated in some autoimmune diosorders. Recently four novel PNA: clofarabine (CAFdA), nelarabine, immucillin H (BCX-1777, forodesine) and 8-chloroadenosine (8-Cl-Ado) have been synthesized and introduced into clinical trials. All these drugs have chemical structure similar to adenosine or guanosine, however, the mechanism of their action is different. FA, 2-CdA and CAFdA mainly require phosphorylation by deoxynucleoside salvage pathways. The cytotoxic effect exerts the triphosphate metabolites, which are incorporated into DNA, and finally lead to programmed cell death. In contrast, DCF does not need to be phosphorylated and results in an increase of plasma deoxyadenosine (dAdo) levels and intracellular deoxyadenosine triphosphate (dATP). Nelarabine is an arabinosylguanine (ara-G) prodrug, which after conversion to ara-G is phosphorylated to ara-G triphosphate (ara-GTP). Accumulation of ara-GTP finally leads to apoptosis. Forodesine is a purine nucleoside phosphatase (PNP) inhibitor which blocks intracellular deoxyguanine (dGuo) cleaving to guanine (Guo), but instead converts it to deoxyguanosine triphosphate (dGTP), and similarly to other PNA resulting in apoptosis. 8-chloroadenosine (8-Cl-Ado) is a ribonucleoside analog. The mechanism of its action is quite different from other PNA and remains poorly understood. However, it is known that the drug inhibits RNA synthesis, but not DNA. These agents have significant cytotoxic activity against lymphoid and myeloid malignant cells. Moreover, they have deleterious effects on the normal resting lymphocytes. They result in prolonged lymphocyte depletion especially in the CD4 subset of T-cells. Several clinical trials have demonstrated that PNA used alone or in combination with other cytotoxic drugs or monoclonal antibodies shows good efficacy and acceptable toxicity profile in the treatment of lymphoid malignancies. 2-CdA and DCF are drugs of choice in the treatment of hairy cell leukemia. FA and 2-CdA have significant clinical activity in low-grade non-Hodgkin's lymphoma and chronic lymphocytic leukemia. 2-CdA exhibits some activity in progressive multiple sclerosis and other autoimmune disorders. This review will summarize current knowledge concerning the mechanism of action, pharmacological properties, clinical activity and toxicity of PNA accepted for use in clinical practice as well as new agents available for clinical trials. © 2006 Bentham Science Publishers Ltd.

CNOTE: Copyright 2006 Elsevier B.V., All rights reserved. ET: Cancer

Immunology, Serology and Transplantation Pharmacology Arthritis and Rheumatism Drug Literature Index Adverse Reactions Titles

6 3/4 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006523519 AU: Roberts JD; Smith MR; Feldman EJ; Cragg L; Millenson MM; Roboz GJ;

Honeycutt C; Thune R; Padavic-Shaller K; Carter WH; Ramakrishnan V; Murgo AJ; Grant S

Titel: Phase I study of bryostatin 1 and fludarabine in patients with chronic lymphocytic leukemia and indolent (non-Hodgkin's) lymphoma

Quelle: Clinical Cancer Research; VOL: 12 (19); p. 5809-5816 /01 OCT 2006/ Sprache: ENGLISH

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AL: ENGLISH CY: United States ISSN: 1078-0432 CO: CCREF Corporate Source:

S. Grant, Virginia Commonwealth University, P.O. Box 980230, Richmond, VA 23298-0230 United States [email protected]

COU: United States DT: Journal RN: 0050 DN: nsc 339555 TE: alanine aminotransferase/9000-86-6; alanine aminotransferase/9014-30-6;

aspartate aminotransferase/9000-97-9; bilirubin/18422-02-1; bilirubin/635-65-4; bryostatin 1/83314-01-6; cotrimoxazole/8064-90-2; fludarabine/21679-14-1; hemoglobin/9008-02-0; protein kinase C/141436-78-4

CR: 9000-86-6; 9014-30-6; 9000-97-9; 18422-02-1; 635-65-4; 83314-01-6; 8064-90-2; 21679-14-1; 9008-02-0; 141436-78-4

AB: Purpose: Preclinical studies suggested that bryostatin 1 might potentiate the therapeutic effects of fludarabine in the treatment of hematologic malignancies. We undertook a phase I study to identify appropriate schedules and doses of bryostatin 1 and fludarabine to be used in phase II studies. Experimental Design: Patients with chronic lymphocytic leukemia (CLL) or indolent lymphoma received fludarabine daily for 5 days and a single dose of bryostatin 1 via a 24-hour continuous infusion either before or after the fludarabine course. Doses were escalated in successive patients until recommended phase II doses for each sequence were identified on the basis of dose-limiting toxic events. Results: Bryostatin 1 can be administered safely and tolerably with full dose fludarabine (25 mg/m²/d × 5). The recommended bryostatin 1 phase II dose is 50 µg/m² for both sequences, bryostatin 1 (rightwards arrow) fludarabine and fludarabine (rightwards arrow) bryostatin 1. The combination is active against both CLL and indolent lymphomas with responses seen in patients who had been previously treated with fludarabine. Correlative studies do not support the hypothesis that bryostatin 1 potentiates fludarabine activity through down-regulation of protein kinase C in target cells. Conclusions: Bryostatin 1 can be administered with full dose fludarabine, and the combination is moderately active in patients with persistent disease following prior treatment. In view of the activity of monoclonal antibodies such as the anti-CD20 monoclonal antibody rituximab in the treatment of CLL and indolent lymphomas, the concept of combining bryostatin 1 and fludarabine with rituximab warrants future consideration. © 2006 American Association for Cancer Research.

CNOTE: Copyright 2007 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

1 3/5 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V.

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ND: EM2006488573 AU: Kreitman RJ; Pastan I Titel: Immunotoxins in the treatment of hematologic malignancies Quelle: Current Drug Targets; VOL: 7 (10); p. 1301-1311 /2006/

http://www.ingentaconnect.com/content/ben/cdt/2006/00000007/00000010/art00010Sprache: ENGLISH AL: ENGLISH CY: Netherlands ISSN: 1389-4501 CO: CDTUA Corporate Source:

R.J. Kreitman, Clinical Immunotherapy Section, Laboratory of Molecular Biology, 9000 Rockville Pike, Bethesda, MD 20892-4255 United States [email protected]

COU: United States DT: Journal RN: 0235 DN: ontak TE: denileukin diftitox/173146-27-5; aminotransferase/9031-66-7; trimetrexate/52128-

35-5; cladribine/4291-63-8; fludarabine/21679-14-1; retinoic acid/302-79-4; rituximab/174722-31-7

CR: 173146-27-5; 9031-66-7; 52128-35-5; 4291-63-8; 21679-14-1; 302-79-4; 174722-31-7

AB: Immunotoxins, composed of protein toxins connected to cell binding ligands including monoclonal antibodies and growth factors, have been developed for several decades to target hematologic malignancies. Protein toxins from either plants or bacteria are extremely potent based on their enzymatic inhibition of protein synthesis and induction of apoptosis. Plant toxins, particularly ricin, are useful for chemically conjugating to monoclonal antibodies, and have shown clinical activity in several types of lymphoma and leukemia. Their dose is generally limited by vascular leak syndrome. Bacterial toxins have been used to produce single chain fusions with either growth factors or recombinant antibody fragments. These agents are smaller in size (55-65 kDa) and exit the bloodstream much more rapidly than the chemical conjugates, and generally do not cause severe vascular leak syndrome. The only approved drug containing a protein toxin is denileukin diftitox, a fusion of human interleukin 2 with truncated diphtheria toxin. Denileukin diftitox has shown efficacy in cutaneous T-cell lymphoma, chronic lymphocytic leukemia, and non-Hodgkin's lymphoma. Recombinant immunotoxin BL22 is an anti-CD22 Fv fragment fused to truncated Pseudomonas exotoxin; it induces complete remissions in a high percentage of patients with chemoresistant hairy cell leukemia. The anti-CD25 recombinant immunotoxin LMB-2 is active in several CD25+ hematologic malignancies. Several other recombinant immunotoxins are undergoing preclinical development for other target antigens expressed on hematologic malignancies. © 2006 Bentham Science Publishers Ltd.

CNOTE: Copyright 2006 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Immunology, Serology and Transplantation Drug Literature Index Adverse Reactions Titles

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Toxicology 3, 6 3/6 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006314370 AU: Peichev D; Staneva M Titel: Fludarabine and Mabcampath in the treatment of malignant hemopathies Quelle: Clinical and Transfusion Haematology; VOL: 41 (1-2); p. 19-23 /2005/ Sprache: BULGARIAN AL: ENGLISH CY: Bulgaria ISSN: 0861-7880 CO: KTKLB Corporate Source:

D. Peichev, National Centre of Haematology and Transfusiology, Sofia Bulgaria

COU: Bulgaria DT: Journal RN: 0010 DN: mabcampath; fludara; campath ih; campath TE: fludarabine phosphate/75607-67-9; alemtuzumab/216503-57-0; protein kinase

ZAP 70/148047-34-1; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; cytarabine/147-94-4; cytarabine/69-74-9; idarubicin/57852-57-0; idarubicin/58957-92-9; cyclophosphamide/50-18-0; melphalan/148-82-3; busulfan/55-98-1; dexamethasone/50-02-2

CR: 75607-67-9; 216503-57-0; 148047-34-1; 65271-80-9; 70476-82-3; 147-94-4; 69-74-9; 57852-57-0; 58957-92-9; 50-18-0; 148-82-3; 55-98-1; 50-02-2

AB: Fludara® (fludarabine phosphate) is an active anticancer agent with significant efficacy as a second-line treatment in patients with B-cell chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma who have not responded to, or whose disease has progressed during or after treatment with, at least one standard alkylating-agent-containing regimen. Fludara® proved to be a highly effective agent for the monotherapy of CLL and indolent NHL. Fludara® has been evaluated in combination therapy for the treatment of CLL and indolent NHL as both a first- and a second-line treatment. The data suggest that Fludara® in combination with other agents offers another treatment strategy to patients. Recently in the treatment of CLL, there is evaluated efficacy of monoclonal antibody Alemtuzumab (MabCampath, CAMPATH), which binds to a surface antigen CD52.

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Hematology Immunology, Serology and Transplantation Drug Literature Index

6 3/7 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2006249274

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AU: Cvetkovic RS; Perry CM Titel: Rituximab: A review of its use in non-Hodgkin's lymphoma and chronic

lymphocytic leukaemia Quelle: Drugs; VOL: 66 (6); p. 791-820 /2006/

http://drugs.adisonline.com/pt/re/drugs/pdfhandler.00003495-200666060-00005.pdf;jsessionid=GykTLcWPBmSn1MLJFMfc2kZ4QyTpyLGJYN8clVNch8fpL YsskHbz!50530596!-949856144!8091!-1

Sprache: ENGLISH AL: ENGLISH CY: New Zealand ISSN: 0012-6667 EISSN: 0012-6667 CO: DRUGA Corporate Source:

R.S. Cvetkovic, Adis International Limited, 41 Centorian Drive, Mairangi Bay, Auckland 1311 New Zealand [email protected]

COU: New Zealand DT: Journal RN: 0108 DN: mabthera; rituxan TE: rituximab/174722-31-7; cyclophosphamide/50-18-0; doxorubicin/23214-92-8;

doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2 CR: 174722-31-7; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2 AB: Rituximab (MabThera®, Rituxan®) is an anti-CD20 monoclonal antibody that

induces lysis and apoptosis of normal and malignant human B cells, and sensitises malignant B cells to the cytotoxic effect of chemotherapy. In phase III trials in patients with indolent or aggressive B-cell non-Hodgkin's lymphoma (NHL), intravenous rituximab in combination with chemotherapy was more effective as first- or second-line therapy than chemotherapy alone in providing tumour remission and patient survival. Likewise, in patients with chronic lymphocytic leukaemia (CLL), rituximab in combination with chemotherapy appeared more effective than chemotherapy alone as either first- or second-line treatment. In addition, rituximab maintenance therapy was shown to significantly prolong tumour remission and patient survival in patients with indolent B-cell NHL or CLL. The combination of rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) was cost effective as first-line therapy for advanced-stage diffuse large B-cell NHL compared with CHOP alone. Rituximab, either alone or in combination with chemotherapy, was generally well tolerated in patients with NHL or CLL. Overall, rituximab in combination with chemotherapy, is a valuable option for first- and second-line therapy in patients with advanced-stage indolent or aggressive B-cell NHL, and possibly those with B-cell CLL, and is included in current treatment guidelines for these indications. The drug is also potentially useful as maintenance therapy in patients with indolent B-cell NHL or CLL. Pharmacological Properties: Rituximab is a chimaeric murine/human monoclonal antibody directed against the surface antigen CD20 expressed on all normal and >90% of NHL and 14% of CLL malignant B cells. It induces lysis and apoptosis of all CD20-positive B cells and also sensitises malignant B cells to the cytotoxic effect of chemotherapy. At the recommended dose, rituximab causes rapid and profound B-cell lymphopenia in the majority of patients that lasts for up to 6 months and recovers (from haematopoietic stem cells) within 9-12 months

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after treatment. As maintenance therapy, rituximab would continue suppression of the B-cell population, including the malignant variety. Following intravenous administration of rituximab in patients with B-cell NHL, drug serum concentrations increase in a dose-proportional manner (within clinically relevant dosage range), are positively correlated with clinical tumour responses (i.e. they are significantly higher in patients responding to rituximab monotherapy than in nonresponders) and are inversely correlated to the absolute level of circulating peripheral B cells and the tumour bulk measurements at baseline. The pharmacokinetics of rituximab are also characterised by accumulation of the drug with repeated administrations (reflecting the change in the population of CD20-positive B cells) and wide interindividual variability (caused by variable tumour responsiveness and burden between patients). Clinically relevant drug concentrations are present in the serum (less-than or equal to)6 months after, and were also found in the CNS during treatment with rituximab. The pharmacokinetics of rituximab appear to be similar in patients with follicular or diffuse large B-cell NHL, and are unaffected by the coadministration of CHOP. Significantly lower serum concentrations of rituximab were found in patients with a lymphomatous form of B-cell CLL, compared with values in patients with B-cell NHL. Therapeutic Efficacy: Indolent NHL: In phase III trials in patients with previously untreated advanced-stage follicular NHL, the addition of rituximab 375 mg/m ² (as an intravenous infusion) to 6-8 cycles of standard chemotherapy regimens was more effective in achieving tumour remission (i.e. complete response [CR]) and short-term (2.5-year) event-free survival (EFS) rates than chemotherapy alone. In combination with cyclophosphamide, vincristine and prednisone (CVP), rituximab also significantly prolonged the duration of tumour response (>2-fold), failure-free (4-fold) and disease-free survival (DFS) [>2-fold], and more than doubled the time to disease progression. At the estimated 3-year follow-up, these effects have not yet translated into a significantly greater overall survival (OS) rate compared with CVP alone (89% vs 81%), although both results are clinically relevant. Importantly, however, patients receiving rituximab in addition to CVP spent significantly longer time without disease symptoms or toxicity, and had a substantially improved quality-adjusted survival than patients receiving CVP alone. In patients with advanced follicular NHL, first-line therapy with rituximab in combination with mitoxantrone, chlorambucil and prednisone (MCP) also resulted in significantly longer progression-free survival (PFS) and OS rates than MCP alone. As a second-line therapy in patients with relapsed or refractory follicular NHL, the addition of a single dose of rituximab to each of six cycles of CHOP or four cycles of fludarabine, cyclophosphamide and mitoxantrone (FCM) regimens significantly improved CR and objective response (OR) rates and prolonged PFS compared with chemotherapy alone in two phase III trials. A significantly improved 4-year OS rate was also reported in a trial with FCM. The significant survival benefit of adding rituximab to first- or second-line chemotherapy regimens in patients with follicular NHL was confirmed in a meta-analysis of data from several randomised, phase III trials As monotherapy, four once-weekly intravenous infusions of rituximab 375 mg/m² produced clinically relevant CR and OR rates in two phase II trials in patients with mucosa-associated lymphoid tissue B-cell NHL. One of the trials showed 2-fold longer (p = 0.001) failure-free survival in chemotherapy-naive than in chemotherapy-experienced patients receiving rituximab monotherapy. Likewise, maintenance therapy with single-agent rituximab 375 mg/m² (four once-weekly doses repeated every 6 months or single infusion every 2-3 months, for up to 2 years or until relapse), significantly increased CR and/or OR rates, and prolonged duration of remission, EFS and/or PFS after induction therapy in patients with follicular NHL or CLL (lymphomatous form), compared with rituximab re-treatment (at disease progression) [in a phase II trial] or observation (i.e. no further treatment) [in three phase III trials]. Rituximab maintenance therapy provided significantly greater 3- and 4-year PFS and OS rates in both previously

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treated and untreated patients with follicular NHL, compared with no further treatment. The estimated 3-year OS rates were high with both the rituximab maintenance and re-treatment approach, but results were not statistically significantly different (72% vs 68%) in previously untreated patients. Aggressive NHL: The combination of rituximab 375 mg/m² intravenous infusions with a CHOP or a CHOP-like regimen, administered in 6-8 cycles, was more effective than chemotherapy alone as the first-line treatment in patients with advanced-stage, diffuse large B-cell NHL or mantle cell lymphoma (MCL), in several phase III trials. Irrespective of the age of patients with diffuse, large B-cell NHL, the addition of rituximab resulted in significantly greater CR, 2- to 3-year failure-free survival and 2- to 5-year OS rates (the latter effect was observed only in low-risk patients). A significantly greater 5-year PFS rate was also reported with rituximab plus CHOP in a trial in older patients (age (greater-than or equal to)60 years) irrespective of disease prognosis. In younger patients (age <60 years) with low-risk disease, rituximab plus CHOP or CHOP-like regimen significantly decreased the relative risk of treatment failure (by 64%) compared with chemotherapy alone. Significantly greater 1-year failure-free or 4-year OS rates were observed in patients with MCL receiving intravenous infusions of rituximab 375 mg/m ² in combination with first-line CHOP (six cycles) or second-line FCM (four cycles), than those receiving chemotherapy alone, in two randomised, phase III trials. Meta-analysis of data from both trials confirmed the OS benefit of adding rituximab to chemotherapy in patients with MCL, both previously untreated or those with relapsed or refractory MCL. Rituximab did not improve either tumour response or survival rates in patients with HIV-related, aggressive B-cell NHL, while increasing the risk of infectious death, in a randomised, phase III trial. By contrast, the findings of previous phase I and II trials suggested that rituximab therapy may be beneficial in this patient population. Rituximab maintenance therapy was effective in patients with diffuse large B-cell NHL, only when the drug was not part of an induction regimen, and was ineffective in patients with MCL. CLL: Standard rituximab monotherapy (i.e. four intravenous infusions of 375 mg/m² once weekly) was less effective than fludarabine monotherapy in phase II trials in patients with B-cell CLL. However, the addition of rituximab 375 or 500 mg/m² to six cycles of fludarabine (with or without cyclophosphamide) significantly improved response (CR and/or OR) and survival (2- to 4-year PFS and/or OS) rates in these patients, compared with chemotherapy alone in retrospective comparative analyses of several phase II and III trials. Tolerability: Rituximab, alone or in combination with various chemotherapy regimens, was generally well tolerated in clinical trials in patients with advanced-stage indolent or aggressive B-cell NHL or B-cell CLL. The most common types of adverse events in these trials were infusion-related reactions, haematological adverse events and infections. © 2006 Adis Data Information BV. All rights reserved.

CNOTE: Copyright 2006 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Pharmacology Health Policy, Economics and Management Drug Literature Index

6 3/8 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005582003 AU: Hotta T Titel: Treatment of T-cell lymphoma

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Quelle: Hematology; VOL: 10 (SUPPL. 1); p. 193-196 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1024-5332 EISSN: 1607-8454 CO: HMATF Corporate Source:

T. Hotta, Division of Hematology/Oncology, Department of Medicine, Tokai University School of Medicine, Boseidai, Isehara, Kanagawa 259-1193 Japan

COU: Japan DT: Journal RN: 0019 TE: carboplatin/41575-94-4; recombinant granulocyte colony stimulating

factor/121181-53-1; vincristine/57-22-7; cyclophosphamide/50-18-0; prednisolone/50-24-8; doxorubicin/23214-92-8; doxorubicin/25316-40-9; bleomycin/11056-06-7; vincristine sulfate/2068-78-2; pirarubicin/95343-20-7; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5; etoposide/33419-42-0; ranimustine/58994-96-0; pentostatin/53910-25-1; cladribine/4291-63-8; busulfan/55-98-1; fludarabine/21679-14-1

CR: 41575-94-4; 121181-53-1; 57-22-7; 50-18-0; 50-24-8; 23214-92-8; 25316-40-9; 11056-06-7; 2068-78-2; 95343-20-7; 15475-56-6; 59-05-2; 7413-34-5; 33419-42-0; 58994-96-0; 53910-25-1; 4291-63-8; 55-98-1; 21679-14-1

AB: T-cell lymphoma composes 25% of lymphoid malignancies in Japan. Peripheral T-cell lymphoma (PTCL) unspecified and adult T-cell leukemia/lymphoma (ATLL) are major subtypes of T-cell lymphoma. The Japan Clinical Oncology Group (JCOG) has conducted 7 clinical trials for aggressive non-Hodgkin's lymphoma (NHL) including T-cell lymphoma. JCOG trials revealed that patients with ATLL had an extremely poor prognosis as compared with other peripheral T-cell lymphomas. A second generation combination chemotherapy including pentostatin (JCOG9109) could not improve the prognosis of patients with aggressive ATLL with the median survival time (MST) of 7.4 months. Subsequently, JCOG developed a new alternating multi-agent chemotherapy including MCNU and carboplatin with prophyractic use of G-CSF, resulting 35% of CR rate and 31% of 2-year OS. Considering the poor prognosis of aggressive ATLL patients, allogeneic stem cell transplantation seems to be another promising approach for a cure of the disease. New active agents such as chimeric monoclonal anti-CCR antibody are under developing for PTCL and ATLL. © 2005 Taylor & Francis.

CNOTE: Copyright 2006 Elsevier B.V., All rights reserved. ET: Public Health, Social Medicine and Epidemiology

Hematology Pharmacology Drug Literature Index

6 3/9 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005559038 AU: Lissitchkov T; Arnaudov G; Peytchev D; Merkle Kh

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Titel: Phase-I/II study to evaluate dose limiting toxicity, maximum tolerated dose, and tolerability of bendamustine HCl in pre-treated patients with B-chronic lymphocytic leukaemia (Binet stages B and C) requiring therapy

Quelle: Journal of Cancer Research and Clinical Oncology; VOL: 132 (2); p. 99-104 /2006/

Sprache: ENGLISH AL: ENGLISH CY: Germany ISSN: 0171-5216 CO: JCROD Corporate Source:

T. Lissitchkov, National Center of Haematology and Transfusiology, 6 Plovdivsko Pole, 1746 Sofia Bulgaria [email protected]

COU: Bulgaria DT: Journal RN: 0013 TE: bendamustine/16506-27-7; bendamustine/3543-75-7; fludarabine/21679-14-1;

bilirubin/18422-02-1; bilirubin/635-65-4 CR: 16506-27-7; 3543-75-7; 21679-14-1; 18422-02-1; 635-65-4 AB: Purpose: Bendamustine hydrochloride, an antineoplastic agent with unique

mechanism of action, is known to cause impressive remissions in relapsed non-Hodgkin's lymphoma and chronic lymphocytic leukaemia (CLL). Optimal bendamustine dosing for CLL patients had not been finally established and a phase I/II study was conducted to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of bendamustine. Methods: The open-label, single-centre phase I/II study was conducted from March 2001 to September 2002 in Sofia, Bulgaria. The 15 study patients were extendedly pre-treated, but fludarabine-naive (3 female, 12 male, 47-72 years of age, 61 years on average). Bendamustine was given at a starting dose of 100 mg/m² on days 1 and 2 every 3 weeks based on the previous results in lymphoma. Results: Bendamustine was well tolerated in spite of heavy pre-treatment of the study participants. Toxicity corresponded to the known safety profile of bendamustine, with the exception of bilirubin elevation. The level of 110 mg/m² was established as MTD. A bendamustine dose of 100 mg/m² is the recommended dose for further clinical investigations. A 4-week interval is recommended to allow for sufficient recovery. Efficacy results confirmed powerful anti-neoplastic activity of bendamustine even in extendedly pretreated CLL patients. Based on the remission criteria, nine patients were defined as responders (four CRs, two PR, three NC) and two patients as nonresponders to therapy. Four patients were not evaluable for response, because they had received less than three courses bendamustine. After a follow-up period of 15 months, the four patients with CR were still in remission. One patient with PR had relapsed, the other had ongoing response. Conclusions: Bendamustine is a very active and well-tolerated drug in patients with pre-treated and refractory CLL. Fludarabine-naivity of patients appears to markedly improve their bendamustine tolerability. First-line use of bendamustine is a safe option for CLL-patients requiring treatment, because bendamustine - owing to its unique pharmacodynamics - (1) is highly effective, (2) reasonably safe, and (3) does hardly produce cross-resistance against other anti-neoplastic drugs effective in this indication. © Springer-Verlag 2005.

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ET: Cancer Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3 3/10 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005338386 AU: Rao R; Shammo JM; Enschede SH; Porter C; Adler SS; Venugopal P; Gregory

SA Titel: The combination of fludarabine, cyclophosphamide, and granulocyte-macrophage

colony-stimulating factor in the treatment of patients with relapsed chronic lymphocytic leukemia and low-grade non-Hodgkin's lymphoma

Quelle: Clinical Lymphoma; VOL: 6 (1); p. 26-30 /2005/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1526-9655 CO: CLLYA Corporate Source:

Dr. R. Rao, Section of Hematology and Oncology, Rush University Medical Center, 1725 W Harrison St., Chicago, IL 60612 United States [email protected]

COU: United States DT: Journal RN: 0021 TE: fludarabine/21679-14-1; cyclophosphamide/50-18-0; chlorambucil/305-03-3;

prednisone/53-03-2 CR: 21679-14-1; 50-18-0; 305-03-3; 53-03-2 AB: Purpose: The goal of this study was to evaluate the efficacy of the

fludarabine/cyclophosphamide combination in patients with relapsed chronic lymphocytic lymphoma (CLL) and low-grade non-Hodgkin's lymphoma (NHL) and to assess the impact of adding granulocyte-macrophage colony-stimulating factor (GM-CSF) to this regimen in a randomized fashion. Patients and methods: Thirty-four patients (CLL, n = 16; low-grade NHL, n = 18) were enrolled. The median number of previous treatments was 2. Patients received (less-than or equal to) 6 cycles of fludarabine at 30 mg/m² per day and cyclophosphamide at 300 mg/m² per day on days 1-3 of a 28-day cycle. Patients were randomized to supportive care or to receive GM-CSF at 250 µg/m² per day, starting 24 hours after completion of chemotherapy and continuing up to 48 hours before the next cycle. Those who had received > 6 months of previous therapy with an alkylating agent or had preexisting cytopenias received a 25% dose reduction. Twenty-two patients (65%) were randomized to receive GM-CSF Patients completed a median of 5 cycles of treatment (range, 1-6 cycles). Twenty-seven patients (80%) received 3 cycles of treatment and were evaluated for response. Results: Seven patients (26%) exhibited a complete response; 6 of the 7 had low-grade NHL. Fourteen patients (52%) exhibited a partial response, and 6 patients (22%) had stable disease. Notably, 6 of the 7 patients who exhibited complete response and 9 of 14

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patients with partial responses were randomized to the GM-CSF arm. The duration of response ranged from 4 months to 26 months. The toxicities were mainly hematologic. Nineteen patients (70%) experienced alpha 1 episode of grade 3/4 neutropenia, but only 4 (15%) experienced febrile neutropenia; 3 of those patients were assigned to the GM-CSF arm. Conclusions: The combination of fludarabine and cyclophosphamide is a well-tolerated and effective treatment regimen for patients with relapsed CLL and low-grade NHL. A higher percentage of complete responses were noted in patients with low-grade NHL compared with patients with CLL. Granulocyte-macrophage colony-stimulating factor did not seem to decrease the incidence of febrile neutropenia. However, the higher number of complete and partial responses noted on the GM-CSF arm is intriguing and warrants further investigation.

CNOTE: Copyright 2005 Elsevier B.V., All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

1 3/11 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2005132575 AU: Montillo M; Hamblin T; Hallek M; Montserrat E; Morra E Titel: Chronic lymphocytic leukemia: Novel prognostic factors and their relevance for

risk-adapted therapeutic strategies Quelle: Haematologica; VOL: 90 (3); p. 391-399 /2005/ Sprache: ENGLISH AL: ENGLISH CY: Italy ISSN: 0390-6078 CO: HAEMA Corporate Source:

M. Montillo, Divisione Ematologia, Ospedale Niguarda Ca' Granda, Piazza Ospedale Maggiore 3, 20162 Milan Italy [email protected]

COU: Italy DT: Journal RN: 0059 TE: cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9;

vincristine/57-22-7; prednisone/53-03-2; fludarabine phosphate/75607-67-9; cladribine/4291-63-8; pentostatin/53910-25-1; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; alemtuzumab/216503-57-0; chlorambucil/305-03-3; rituximab/174722-31-7; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2

CR: 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2; 75607-67-9; 4291-63-8; 53910-25-1; 65271-80-9; 70476-82-3; 216503-57-0; 305-03-3; 174722-31-7; 15663-27-1; 26035-31-4; 96081-74-2

AB: Background and Objectives. Many years ago it was established that prompt treatment of early stage chronic lymphocytic leukemia (CLL), the stage at which almost two-thirds of CLL patients present, has no benefit over a management of

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watching and waiting, then treating progression. However, this fact was based on series treated ineffectually with chlorambucil, which were not stratified according to prognostic markers. Design and Methods. The prognosis and clinical course of CLL are heterogeneous. While some patients may have a normal life expectancy without requiring treatment, others die of drug-resistant disease as early as within two years of presentation. However, unlike the situation in non-Hodgkin's lymphoma, there is no standard Prognostic Index that can be used to group patients with CLL according to likely outcome or to guide treatment. Results. A number of clinical and biological factors of prognostic relevance, which may add to the classical assessment provided by the staging systems, have been identified. These include clinical characteristics, such as age, gender and performance status, and laboratory parameters reflecting the tumor burden or disease activity, such as lymphocyte count, lactate dehydrogenase (LDH) increase, bone marrow infiltration pattern or lymphocyte doubling time. Recently more informative prognostic parameters have been identified: serum markers such as soluble CD23, beta2-microglobulin or thymidine kinase and genetic markers of tumor cells, such as genomic aberrations, gene abnormalities (p53, ATM), the mutation status of the variable segments of the immunoglobulin heavy chain genes (IGVH) or surrogate markers for these factors, such as CD38 and ZAP-70. Interpretations and Conclusions. From the clinician's perspective the importance of this new knowledge is how it affects treatment. It is now possible to produce molecular remissions even in advanced disease using combinations of purine analogs and monoclonal antibodies. Moreover, potentially curative therapeutic modalities such as autologous and allogeneic stem cell transplantation are becoming safer. Clinical trials of effective treatment stratified by more reliable prognostic markers are surely now warranted. ©2005 Ferrata Storti Foundation.

CNOTE: Copyright 2005 Elsevier B.V., All rights reserved. ET: Human Genetics

Hematology Pharmacology Drug Literature Index

6 3/12 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004248926 AU: Johnson SA Titel: Use of fludarabine in the treatment of mantle cell lymphoma, Waldenström's

macroglobulinemia and other uncommon B-cell and T-cell lymphoid malignancies Quelle: Hematology Journal; VOL: 5 (SUPPL.); p. S50-S61 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1466-4860 CO: HJEOB Corporate Source:

S.A. Johnson, Department of Haematology, Taunton and Somerset Hospital, Taunton, Somerset TA1 5DA United Kingdom [email protected]

COU: United Kingdom DT: Journal RN: 0108

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TE: fludarabine/21679-14-1; cyclophosphamide/50-18-0; vincristine/57-22-7;

prednisone/53-03-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; prednimustine/29069-24-7; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; teniposide/29767-20-2; bleomycin/11056-06-7; etoposide/33419-42-0; chlormethine/51-75-2; chlormethine/55-86-7; chlormethine/82905-71-3; procarbazine/366-70-1; procarbazine/671-16-9; idarubicin/57852-57-0; idarubicin/58957-92-9; bendamustine/16506-27-7; bendamustine/3543-75-7; rituximab/174722-31-7; immunoglobulin M/9007-85-6; chlorambucil/305-03-3; cladribine/4291-63-8; dexamethasone/50-02-2; thalidomide/50-35-1; pentostatin/53910-25-1; alpha2a interferon/76543-88-9; alemtuzumab/216503-57-0

CR: 21679-14-1; 50-18-0; 57-22-7; 53-03-2; 23214-92-8; 25316-40-9; 29069-24-7; 65271-80-9; 70476-82-3; 29767-20-2; 11056-06-7; 33419-42-0; 51-75-2; 55-86-7; 82905-71-3; 366-70-1; 671-16-9; 57852-57-0; 58957-92-9; 16506-27-7; 3543-75-7; 174722-31-7; 9007-85-6; 305-03-3; 4291-63-8; 50-02-2; 50-35-1; 53910-25-1; 76543-88-9; 216503-57-0

AB: After initial efforts using fludarabine as a single agent in the treatment of acute leukemia, its activity at lower and safer doses was demonstrated in chronic lymphocytic leukemia (CLL) patients who were refractory or had relapsed from traditional chemotherapies, representing a highly effective therapy for this condition. Fludarabine was also rapidly shown to be beneficial as first-line therapy in CLL. There is now considerable evidence that fludarabine is an effective agent in non-Hodgkin's lymphoma and in combination therapy for acute myeloid leukemia. Further, good responses are achieved when fludarabine-based approaches are used as conditioning regimens prior to transplantation procedures. The actions of fludarabine are not restricted to these settings and its potential role in the treatment of a range of uncommon T- and B-cell lymphoid malignancies is slowly emerging. This review will focus on the characteristics and treatment options for two B-cell disorders, mantle cell lymphoma and Waldenström's macroglobulinemia, with emphasis on the clinical activity of fludarabine. Additionally, the advantages of using fludarabine-containing regimens for a range of other lymphoproliferative conditions will also be discussed. These include B-cell neoplasms such as the CLL variant prolymphocytic leukemia, hairy cell leukemia and mucosa-associated lymphoid tissue-derived lymphomas; the T-cell disorders cutaneous T-cell lymphoma, angioimmunoblastic lymphadenopathy and other rarer T-cell diseases; and aggressive variants of non-Hodgkin's lymphoma including Richter's syndrome. © 2004 The European Hematology Association All rights reserved.

CNOTE: Copyright 2004 Elsevier B.V., All rights reserved. ET: Cancer

Public Health, Social Medicine and Epidemiology Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

3/13 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004248925 AU: Zinzani PL Titel: Clinical experience with fludarabine in indolent non-Hodgkin's lymphoma Quelle: Hematology Journal; VOL: 5 (SUPPL.); p. S38-S49 /2004/ Sprache: ENGLISH AL: ENGLISH

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CY: United Kingdom ISSN: 1466-4860 CO: HJEOB Corporate Source:

P.L. Zinzani, Ist. Ematol./Oncol. Med. Seragnoli, Università di Bologna, Via Massarenti 9, 40138 Bologna Italy [email protected]

COU: Italy DT: Journal RN: 0064 DN: filgrastim TE: fludarabine/21679-14-1; cyclophosphamide/50-18-0; vincristine/57-22-7;

prednisone/53-03-2; mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; rituximab/174722-31-7; cladribine/4291-63-8; chlorambucil/305-03-3; doxorubicin/23214-92-8; doxorubicin/25316-40-9; ibritumomab tiuxetan/206181-63-7; idarubicin/57852-57-0; idarubicin/58957-92-9; epirubicin/56390-09-1; epirubicin/56420-45-2; dexamethasone/50-02-2; vindesine/53643-48-4; recombinant granulocyte colony stimulating factor/121181-53-1; paclitaxel/33069-62-4

CR: 21679-14-1; 50-18-0; 57-22-7; 53-03-2; 65271-80-9; 70476-82-3; 174722-31-7; 4291-63-8; 305-03-3; 23214-92-8; 25316-40-9; 206181-63-7; 57852-57-0; 58957-92-9; 56390-09-1; 56420-45-2; 50-02-2; 53643-48-4; 121181-53-1; 33069-62-4

AB: Fludarabine, a purine nucleoside analog, is currently indicated for the first-line treatment of chronic lymphocytic leukemia and is also licensed for the management of indolent non-Hodgkin's lymphoma (NHL) in countries such as Switzerland and Canada. Clinical evidence from studies in patients with NHL suggests that fludarabine monotherapy is at least as effective, if not better, than conventional therapies such as cyclophosphamide, vincristine, prednisone (CVP) for the first- and second-line treatment of NHL, achieving objective response rates of 31-84%. The combination of fludarabine with other chemotherapeutic agents such as cyclophosphamide or mitoxantrone also provides the clinician with additional useful treatment options in this setting. Objective response rates of 70-100% have been reported with fludarabine-containing combination regimens, often exceeding those reported with CVP. Furthermore, beneficial effects on overall and progression-free survival have been reported with fludarabine or fludarabine-containing combination regimens in a number of studies, including a significant survival benefit with the combination of fludarabine, cyclophosphamide, mitoxantrone and rituximab. While adverse events such as granulocytopenia, neutropenia and anemia and, less frequently, infectious complications have been reported with fludarabine, its adverse event profile generally compares favorably with that of other available treatment options. Available clinical data therefore indicate that fludarabine has an important role to play in the treatment of patients with indolent NHL. Further, studies are warranted to identify the optimal fludarabine regimen for this patient group. © 2004 The European Hematology Association All rights reserved.

CNOTE: Copyright 2004 Elsevier B.V., All rights reserved. ET: Cancer

Public Health, Social Medicine and Epidemiology Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

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6 3/14 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004121388 AU: Hillmen P Titel: Advancing Therapy for Chronic Lymphocytic Leukemia - The Role of Rituximab Quelle: Seminars in Oncology; VOL: 31 (1 SUPPL. 2); p. 22-26 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 0093-7754 CO: SOLGA Corporate Source:

Dr. P. Hillmen, Pinderfields General Hospital, Aberford Road, Wakefield WF1 4DGUnited Kingdom

COU: United Kingdom DT: Journal RN: 0034 TE: cyclophosphamide/50-18-0; fludarabine/21679-14-1; rituximab/174722-31-7 CR: 50-18-0; 21679-14-1; 174722-31-7 AB: Chronic lymphocytic leukemia (CLL) remains incurable despite decades of clinical

trials. Some patients survive for long periods without requiring definitive therapy, while others die rapidly despite intensive treatment. Because most patients with CLL express CD20 on their malignant cells, the chimeric anti-CD20 monoclonal antibody rituximab has been incorporated into treatment regimens in efforts to improve outcome. Rituximab monotherapy has limited activity in previously untreated and refractory/relapsed CLL patients with response rates that are generally lower than those seen in non-Hodgkin's lymphoma. Although increased dosing intensity and frequency leads to higher response rates than seen in patients treated with standard dose rituximab, responses are almost always partial remissions and the doses used are not feasible in routine clinical practice. On the other hand, combining rituximab with chemotherapy has proved to be feasible and appears to be synergistic with fludarabine-based chemotherapy in the treatment of CLL on the basis of recent phase II trials. In these studies, response rates (including complete remissions) to rituximab in combination with fludarabine-containing regimens are higher than those reported in similar phase II studies with any other treatment regime. The highest response rates reported are for the combination of rituximab, fludarabine, and cyclophosphamide. A randomized phase III trial has been initiated to evaluate the addition of rituximab to fludarabine and cyclophosphamide in patients with relapsed CLL. The combination of rituximab with other agents is also being investigated, and these ongoing trials will help define the role of rituximab in CLL. © 2004 Elsevier Inc. All rights reserved.

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Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

2, 3, 6

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3/15 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2004067241 AU: Nicolle A; Proctor SJ; Summerfield GP Titel: High dose chlorambucil in the treatment of lymphoid malignancies Quelle: Leukemia and Lymphoma; VOL: 45 (2); p. 271-275 /2004/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 CO: LELYE Corporate Source:

G.P. Summerfield, Department of Haematology, Sheriff Hill, Gateshead NE9 6SX United Kingdom

COU: United Kingdom DT: Journal RN: 0025 TE: chlorambucil/305-03-3; fludarabine/21679-14-1; cyclophosphamide/50-18-0;

doxorubicin/23214-92-8; doxorubicin/25316-40-9; vincristine/57-22-7; prednisone/53-03-2; cladribine/4291-63-8; prednisolone/50-24-8; dexamethasone/50-02-2; idarubicin/57852-57-0; idarubicin/58957-92-9; etoposide/33419-42-0; lomustine/13010-47-4

CR: 305-03-3; 21679-14-1; 50-18-0; 23214-92-8; 25316-40-9; 57-22-7; 53-03-2; 4291-63-8; 50-24-8; 50-02-2; 57852-57-0; 58957-92-9; 33419-42-0; 13010-47-4

AB: High dose chlorambucil has been shown to be an effective single-agent treatment in chronic lymphocytic leukemia (CLL), and to be useful as part of combination chemotherapy in low-grade non-Hodgkin's (NHL) and Hodgkin's disease (HD). In general, it is well tolerated and can be used in an outpatient setting. The optimum dose of chlorambucil has not been defined and there are numerous different dosing schedules available. Pharmacokinetic studies suggest decreased bioavailability with successive cycles, probably due to accelerated metabolism. There is good evidence that regimens which use higher doses of chlorambucil have a better outcome than standard dose therapy. Most of the trials which have compared cblorambucil with fludarabine have not used a higher dose regimen of chlorambucil and cannot truly be described as comparative. There is an increase in the incidence of grade 3 and 4 neutropenia and also of sepsis with fludarabine treatment, compared to chlorambucil. Fludarabine produces a higher initial response rate in CLL but no statistical difference has been shown in long term survival between fludarabine and high dose chlorambucil. In the treatment of lymphoma, single agent chlorambucil does not confer a durable remission. There have been good results with combination chemotherapy regimens such as CID and PECC. The oral route of administration of these combinations makes them particularly useful as part of palliative chemotherapy. A further point to consider is that chlorambucil is very much cheaper than fludarabine and other newer agents. Chlorambucil should not automatically be overlooked in favor of more recently developed drugs such as fludarabine. There is good evidence that the drug is an effective treatment at a suitable dose, and there is a need for randomized trials to compare it fully with other current treatments.

CNOTE: Copyright 2004 Elsevier B.V., All rights reserved. ET: Cancer

Hematology

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Pharmacology Health Policy, Economics and Management Drug Literature Index Adverse Reactions Titles

2, 6 3/16 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2003197250 AU: Schriever F; Huhn D Titel: New directions in the diagnosis and treatment of chronic lymphocytic leukaemia Quelle: Drugs; VOL: 63 (10); p. 953-969 /2003/ Sprache: ENGLISH AL: ENGLISH CY: New Zealand ISSN: 0012-6667 CO: DRUGA Corporate Source:

Dr. F. Schriever, Gartenstr. 26, 85456 Wartenberg Germany [email protected]

COU: Germany DT: Journal RN: 0108 DN: fk 228; fr 901228 TE: rituximab/174722-31-7; alemtuzumab/216503-57-0; chlorambucil/305-03-3;

prednisone/53-03-2; cyclophosphamide/50-18-0; vincristine/57-22-7; doxorubicin/23214-92-8; doxorubicin/25316-40-9; fludarabine/21679-14-1; cladribine/4291-63-8; bendamustine/16506-27-7; bendamustine/3543-75-7; fr 901228/128517-07-7; bryostatin 1/83314-01-6; flavopiridol/146426-40-6; CD40 ligand/226713-27-5

CR: 174722-31-7; 216503-57-0; 305-03-3; 53-03-2; 50-18-0; 57-22-7; 23214-92-8; 25316-40-9; 21679-14-1; 4291-63-8; 16506-27-7; 3543-75-7; 128517-07-7; 83314-01-6; 146426-40-6; 226713-27-5

AB: Chronic lymphocytic leukaemia (CLL) is the most common leukaemia of adults in Western countries. It is a systemic haematological malignancy that originates from B cells (B-CLL) in 95% of patients, while only a minority are derived through malignant transformation of T cells (T-CLL). Although B-CLL is classified as a non-Hodgkin's lymphoma, several issues make this leukaemia a unique entity among malignant lymphoma. Inhibition of the programmed cell death (apoptosis) and upregulation of the anti-apoptotic protein Bcl-2 are key elements of the pathophysiology of B-CLL cells and define clinical prognosis. Furthermore, B-CLL cells are arrested in G0/G1 phase of the cell cycle. Dysfunctional apoptosis and cell cycle are the main reasons for the clinical enigma, that CLL can not yet be cured with conventional chemotherapy. However, the molecular pathways that are responsible for this characteristic feature of the B-CLL cells still need further definition. Recently, considerable progress has been made in defining the molecular basis for the pathogenesis of CLL and in finding new therapeutic options. Recent studies indicate that B-CLL cells may be delineated from two main groups of normal B cells, i.e. pre- and postgerminal B cells, and can be distinguished through lack of or existence of mutations of the V heavy chain gene.

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This differential mutational status of the Ig V gene has significant impact on patient survival. Modern cytogenetic methods such as fluorescence in situ hybridisation (FISH) have opened a new era in the molecular analysis of CLL cells. Determining the chromosomal aberration of the leukaemic cells has become a standard scientific programme for each clinical trial. The cytogenetic profile may soon help to define a clinical risk profile and guide the various treatment strategies. Further progress has been made in the therapy of CLL. Purine analogues such as fludarabine were able to induce significant improvement in remission rates; however, they did not lead to improved survival. Chimera of murine or rat monoclonal antibodies and human antibodies were designed to treat CLL. Antibodies such as rituximab and alemtuzumab (Campath-1H), directed against CD20 and CD52, respectively, appear as attractive alternatives to conventional chemotherapy because of their lack of significant myelotoxicity. Studies using myeloablative chemotherapy followed by autologous or allogeneic stem cell transplantation were initiated with the hope of finding a cure for CLL. In contrast to autologous stem cell transplantation, allogeneic transplants appear to display a plateau of relapse rates. In conclusion, for many years CLL was considered as a chronic haematological malignancy that required only few diagnostic tools and for whom no hope of cure could be offered. The current review focuses on recent improvements in diagnosis and treatment of CLL that have opened a new era in the management of patients with this systemic malignancy.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Pharmacology Drug Literature Index Adverse Reactions Titles

2, 6 3/17 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2002425983 AU: Cowan RA; Murby B; Gunton D; Owens SE; Hoyes KP; Sharma HL; Smith A-M;

Chang J; Van Kessel B; Nuttall PM; Crowther D Titel: Autologous lymphocytes as vectors to target therapeutic radiation, using indium-

114m, in patients with lymphoid cell malignancy Quelle: British Journal of Haematology; VOL: 119 (2); p. 459-466 /2002/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 0007-1048 CO: BJHEA Corporate Source:

R.A. Cowan, Department of Clinical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX United Kingdom [email protected]

COU: United Kingdom DT: Journal RN: 0023 TE: indium 114m/13981-55-0; indium/7440-74-6; chlorambucil/305-03-3;

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cyclophosphamide/50-18-0; vincristine/57-22-7; prednisone/53-03-2; doxorubicin/23214-92-8; doxorubicin/25316-40-9; fludarabine/21679-14-1

CR: 13981-55-0; 7440-74-6; 305-03-3; 50-18-0; 57-22-7; 53-03-2; 23214-92-8; 25316-40-9; 21679-14-1

AB: Autologous lymphocytes provide a potential vector for the delivery of a cytotoxic agent in patients with lymphoid cell malignancy. This report describes a phase I-II study using autologous lymphocytes to target the radionuclide indium-114m ((sup(114m))In) in patients with refractory chronic lymphocytic leukaemia or small lymphocytic non-Hodgkin's lymphoma. Nineteen patients, the majority of whom had been heavily pretreated with conventional chemotherapy and radiotherapy, received between 69 and 211 MBq (sup(114m))In-labelled autologous lymphocytes. Approximately 80% of the administered activity was localized in the liver and spleen, with around 5% accumulating in the bone marrow. Ten patients (53%) responded (one complete response and nine partial responses). The median duration of response was 7 months. The median survival for the responders was 14 months and for the non-responders was 3 months. The first notable response in every patient was a fall in peripheral lymphocyte count. The indium treatment was not associated with any subjective toxicity, although all patients suffered from myelosuppression, with thrombocytopenia being the dose-limiting factor. This study has demonstrated a significant anti-tumour effect in a group of patients with late-stage highly resistant disease.

CNOTE: Copyright 2003 Elsevier Science B.V., Amsterdam. All rights reserved. ET: Cancer

Nuclear Medicine Hematology Drug Literature Index Adverse Reactions Titles

3 3/18 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2001369667 AU: Oscier D; Orchard JA; Culligan D; Cunningham D; Johnson S; Parker A; Klein M;

Gieschen H Titel: The bioavailability of oral fludarabine phosphate is unaffected by food Quelle: Hematology Journal; VOL: 2 (5); p. 316-321 /2001/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1466-4860 CO: HJEOB Corporate Source:

D. Oscier, Clinical Haematology, Royal Bournemouth Hospital, Castle Lane East, Bournemouth, Dorset BH7 7DW United Kingdom [email protected]

COU: United Kingdom DT: Journal RN: 0021 TE: fludarabine phosphate/75607-67-9 CR: 75607-67-9

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AB: Introduction: A prospective, open and randomized, two-way crossover study was conducted to evaluate the pharmacokinetics and bioavailability of oral fludarabine phosphate when taken on a full versus an empty stomach. The effectiveness of therapy was also assessed after two cycles of treatment, four weeks apart. Materials and methods: Patients with chronic lymphocytic leukemia or low-grade non-Hodgkin's lymphoma were randomly assigned to two groups, both of which received two cycles of treatment with 90 mg of oral fludarabine phosphate administered when either fed or fasted. Patients in Group 1 (n = 8) received oral treatment on a full stomach for the first cycle then on a fasted stomach for the second, while those in Group 2 (n=10) received their treatment in the reverse sequence. Oral fludarabine phosphate was administered on the first day of the two study cycles and intravenous fludarabine phosphate was administered on days 3-6. Results and conclusion: Of 22 patients recruited, 18 (CLL n=10; NHL n=8) were eligible for efficacy and safety evaluation, and 16 for bioavailability and pharmacokinetic analyses. The response to oral 2-F-ara-AMP was rapid: by two treatment cycles, 12 out of 18 patients (66.7%) had achieved partial response. Of the six patients who did not respond, five patients (27.7%) had stable disease. There was no notable difference in the rate of response between patients with B-CLL and lg-NHL. There was a marginal increase in total systemic availability of fludarabine phosphate when administered orally on a fed stomach (2-F-ara-A AUC(sub((0-24h))) = 3.28 ± 1.48 µg·h/ml) compared to a fasted stomach (2-F-ara-A AUC(sub((0-24h))) = 3.05±1.56 µg·h/ml). Time to peak plasma concentration was slightly extended by the presence of food (2.2±1.0 versus 1.3±0.74h) but the terminal half-life was unaffected. The minor differences in the pharmacokinetics of oral fludarabine phosphate when taken after food were not statistically significantly different and seem unlikely to be clinically relevant. The efficacy and safety data closely paralleled previous experience with the intravenous formulation.

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Pharmacology Drug Literature Index Adverse Reactions Titles

3 3/19 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2001277548 AU: Dabaja BS; O'Brien SM; Kantarjian HM; Cortes JE; Thomas DA; Albitar M;

Schlette ES; Faderl S; Sarris A; Keating MJ; Giles FJ Titel: Fractionated cyclophosphamide, vincristine, liposomal daunorubicin (daunoxome),

and dexamethasone (hyperCVXD) regimen in Richter's syndrome Quelle: Leukemia and Lymphoma; VOL: 42 (3); p. 329-337 /2001/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 1042-8194 CO: LELYE Corporate Source:

Dr. F.J. Giles, Department of Leukemia, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 United States [email protected]

COU: United States

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DT: Journal RN: 0018 DN: adriamycin; bactrim; daunoxome TE: cyclophosphamide/50-18-0; vincristine/57-22-7; daunorubicin/12707-28-7;

daunorubicin/20830-81-3; daunorubicin/23541-50-6; dexamethasone/50-02-2; fludarabine/21679-14-1; doxorubicin/23214-92-8; doxorubicin/25316-40-9; methotrexate/15475-56-6; methotrexate/59-05-2; methotrexate/7413-34-5; cytarabine/147-94-4; cytarabine/69-74-9; recombinant granulocyte colony stimulating factor/121181-53-1; ciprofloxacin/85721-33-1; levofloxacin/100986-85-4; levofloxacin/138199-71-0; cotrimoxazole/8064-90-2; fluconazole/86386-73-4; aciclovir/59277-89-3; prednisone/53-03-2; platinum/7440-06-4; rituximab/174722-31-7; chlorambucil/305-03-3

CR: 50-18-0; 57-22-7; 12707-28-7; 20830-81-3; 23541-50-6; 50-02-2; 21679-14-1; 23214-92-8; 25316-40-9; 15475-56-6; 59-05-2; 7413-34-5; 147-94-4; 69-74-9; 121181-53-1; 85721-33-1; 100986-85-4; 138199-71-0; 8064-90-2; 86386-73-4; 59277-89-3; 53-03-2; 7440-06-4; 174722-31-7; 305-03-3

AB: Approximately 3 to 5% of patients with chronic lymphocytic leukemia (CLL) develop an aggressive large cell non Hodgkin's lymphoma (NHL) known as Richter's syndrome (RS). RS has a poor prognosis and a response rate of <10% with fludarabine-based or other cytotoxic combination regimens. The aim of this study was to evaluate the efficacy and toxicity of the hyperCVXD regimen in RS. Twenty-nine patients, median age 61 years (36-75) 23 males, were treated. Prior diagnosis was CLL in 26 patients, NHL in 2, and Prolymphocytic leukemia in 1. Treatment consisted of fractionated cyclophosphamide, vincristine, daunoXome and dexamethasone. Six patients (20%) died while receiving study therapy, 4 (14%) during the first cycle of whom 2 had started therapy with overt pneumonia. Grade 4 granulocytopenia occurred in all 95 cycles of therapy with a median time to recovery of 14 days. Twenty three (24%) cycles were complicated by fever, and 15 (15%) by pneumonia. Sepsis was documented in 8 (8%) cycles, and neuropathy in 5 (5%) of cycles. Twenty three patients had a platelet count < 100 × 10(sup(9))/1 prior to therapy: a greater than 50% decrease in platelet count over pre-therapy level occurred in 79% of first cycles, overt bleeding occurred in 4 (4%) of all cycles. Eleven of 29 (38%) patients achieved complete remission (CR), 4 of whom have relapsed after 5, 6, 9, and 12 months of remission. Two of 11 CR patients presented with RS without any prior CLL therapy. One patient had a partial remission. Thus the overall response rate was 12/29 (41%). Overall median survival was 10 months, 19 months in patients who achieved CR, 3 months in those who did not (p=0.0008). A landmark analysis performed at 2 months from start of therapy comparing patients alive in CR versus patients alive but not in CR showed a median survival of 19 months versus 6 months, respectively (p0.0017). In conclusion the hyper CVXD regimen has a relatively high response rate, significant toxicity and a moderate impact on survival in RS.

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Hematology Drug Literature Index Adverse Reactions Titles

3 3/20 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2000210929

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AU: Van Den Neste E; Louviaux I; Michaux JL; Delannoy A; Michaux L; Sonet A; Bosly A; Doyen C; Mineur P; Andre M; Straetmans N; Coche E; Venet C; Duprez T; Ferrant A

Titel: Phase I/II study of 2-chloro-2'-deoxyadenosine with cyclophosphamide in patients with pretreated B cell chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma

Quelle: Leukemia; VOL: 14 (6); p. 1136-1142 /2000/ Sprache: ENGLISH AL: ENGLISH CY: United Kingdom ISSN: 0887-6924 CO: LEUKE Corporate Source:

E. Van Den Neste, Department of Hematology/Radiology, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, 10 Av. Hippocrate, 1200 Brussels Belgium

COU: Belgium DT: Journal RN: 0044 DN: vp 16 TE: cyclophosphamide/50-18-0; doxorubicin/23214-92-8; doxorubicin/25316-40-9;

mitoxantrone/65271-80-9; mitoxantrone/70476-82-3; vincristine/57-22-7; prednisone/53-03-2; etoposide/33419-42-0; dexamethasone/50-02-2; cytarabine/147-94-4; cytarabine/69-74-9; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2; ifosfamide/3778-73-2; fludarabine/21679-14-1

CR: 50-18-0; 23214-92-8; 25316-40-9; 65271-80-9; 70476-82-3; 57-22-7; 53-03-2; 33419-42-0; 50-02-2; 147-94-4; 69-74-9; 15663-27-1; 26035-31-4; 96081-74-2; 3778-73-2; 21679-14-1

AB: Because of their substantial in vitro synergy, we conducted a dose-escalation study of cyclophosphamide (CP) added to 2-chloro-2'-deoxyadenosine (CdA) in patients with previously treated chronic lymphocytic leukemia and non-Hodgkin's lymphoma. CdA was given at a fixed dose (5.6 mg/m²/day) as a 2-h intravenous (i.v.) infusion, immediately followed by a 1-h i.v. infusion of CP, for 3 days. The initial daily CP dose was 200 mg/m², and was escalated by 100 mg/m² increments in successive cohorts of three to six patients to determine the maximum-tolerated dose (MTD). Additional patients were included at the MTD to extend toxicity and response analysis. Twenty-six patients received 68 cycles of chemotherapy. The MTD of CP after CdA 5.6 mg/m², was 300 mg/m². Acute neutropenia was the dose-limiting toxicity of this regimen, which was otherwise well tolerated. Delivery of repeated cycles was not feasible in eight patients (31%) because of prolonged thrombocytopenia. Severe infections were seen in three of 68 cycles (4%). The overall response rate was 58% (15 of 26; 95% Cl, 36-76%), with 15% complete responses and 42% partial responses. These data show the feasibility of the association of CdA with CP. Given the response rate observed, further studies of this regimen are warranted in untreated patients, in particular with chronic lymphocytic leukemia and with Waldenstrom macroglobulinemia.

CNOTE: Copyright 2004 Elsevier B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index Adverse Reactions Titles

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3 3/21 von 21 DIMDI: EMBASE (EM74) © 2007 Elsevier B.V. ND: EM2000075622 AU: Witzig TE; Timm M; Stenson M; Svingen PA; Kaufmann SH Titel: Induction of apoptosis in malignant B cells by phenylbutyrate or phenylacetate in

combination with chemotherapeutic agents Quelle: Clinical Cancer Research; VOL: 6 (2); p. 681-692 /2000/ Sprache: ENGLISH AL: ENGLISH CY: United States ISSN: 1078-0432 CO: CCREF Corporate Source:

T.E. Witzig, 920E Hilton Building, Mayo Clinic, Rochester, MN 55905 United States [email protected]

COU: United States DT: Journal RN: 0077 MN: SmithKline Beecham,United States; SmithKline Beecham; Sigma,United States;

Sigma; Elan,United States; Elan TE: phenylacetic acid/103-82-2; cytarabine/147-94-4; cytarabine/69-74-9;

topotecan/119413-54-6; topotecan/123948-87-8; doxorubicin/23214-92-8; doxorubicin/25316-40-9; etoposide/33419-42-0; chlorambucil/305-03-3; melphalan/148-82-3; fludarabine/21679-14-1; carboplatin/41575-94-4; cisplatin/15663-27-1; cisplatin/26035-31-4; cisplatin/96081-74-2

CR: 103-82-2; 147-94-4; 69-74-9; 119413-54-6; 123948-87-8; 23214-92-8; 25316-40-9; 33419-42-0; 305-03-3; 148-82-3; 21679-14-1; 41575-94-4; 15663-27-1; 26035-31-4; 96081-74-2

AB: Phenylacetate (PA) and phenylbutyrate (PB) are aromatic fatty acids that are presently undergoing evaluation as potential antineoplastic agents. In vitro, PA and PB cause differentiation or growth inhibition of malignant cells. Clinical trials of these drugs as single agents indicate that they are not myelosuppressive; therefore, combinations with other chemotherapy agents may be possible. The goals of this study were to determine whether PA and PB (a) are cytotoxic to malignant B cells from patients with non-Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia and (b) exhibit additive or synergistic induction of apoptosis when administered to myeloma cell lines in combination with conventional drugs. In the clinical specimens, cytotoxicity was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and percent apoptosis was measured using 7-aminoactinomycin D and flow cytometry. Viability was decreased by >50% in 7% (1/15) of non- Hodgkin's lymphoma samples treated with 5 mM PA, 27% treated with 1 mM PB, and 60% treated with 2 mM PB. Likewise, viability was decreased by >50% in 44% (4/9) of chronic lymphocytic leukemia samples treated with 5 mM PA, 67% treated with 1 mM PB, and 100% treated with 2 mM PB. Studies in the myeloma cell lines demonstrated that PB treatment induced activation of caspases 3, 7, and 9 accompanied by cleavage of their substrates and internucleosomal DNA degradation. Combinations of PA or PB with conventional drugs (cytarabine, topotecan, doxorubicin, etoposide,

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chlorambucil, melphalan, fludarabine, carboplatin, and cisplatin) were examined for synergism (combination index <1 in median effect analysis) in inducing apoptosis of both the MY5 and 8226 human myeloma cell lines. At concentrations that killed >50% of cells, most combinations were additive; however, PB was synergistic with cytarabine, etoposide, and topotecan, with the combination index <1 at each of the 50, 75, and 95% apoptosis levels. These observations indicate that PA and PB can induce apoptosis in malignant B cells and enhance the cytotoxicity of agents used in the treatment of these malignancies.

CNOTE: Copyright 2004 Elsevier B.V., Amsterdam. All rights reserved. ET: Cancer

Hematology Drug Literature Index

3