INTERNISTI ED EMATOLOGI A CONFRONTO:
EVIDENCE-BASED MEDICINE NELLA GESTIONE MULTIDISCIPLINARE
DELLA LEUCEMIA LINFATICA CRONICA
STRUMENTI DIAGNOSTICO-TERAPEUTICI NELLA LLC
NELLA REALTA’ AMBULATORIALE QUOTIDIANA:
PRATICA CLINICA, POTENZIALITA’ REALI E TRANSITO VERSO IL FUTURO
Roberta Murru
WHAT HAS CHANGED IN CLL OVER THE LAST 10 YEARS?
1. Better understanding of the biology of the disease; future clinical
implications, maybe actual…
2. Improved prognostic stratification
3. More and more active drugs (new combinations, new drugs)
4. New concepts (definition of molecular responses and MRD - minimal
residual disease - consolidation and maintenance)
5. Impact on survival
CLL is not curable with standard therapies…. ALL PATIENTS PROGRESS AND DIE
BECAUSE OF THE DISEASE OR TREATMENT-RELATED COMPLICATIONS
PATIENT
OVERALL
RESPONSE
OVERALL
SURVIVAL
PROGRESSION
FREE
SURVIVAL
IMPACT OF
PROFESSIONAL
SKILLS
PATIENT
COMPLIANCE
QUALITY OF
LIFE
…..THE SITUATION IN CLL NOW
CLL: MAJOR CAUSE OF DEATH
…even with comorbidities
0
20
40
60
80
100
NO COMORBIDITY COMORBIDITY
Therapy-related
CLL-unrelated
CLL-related
CAUSE OF DEATH
Patients
(%
)
69% 70%
Cramer P, et al. Blood 2006; 108: Abstract 2840.
J Gribben. EHA 2014, oral presentation.
PROGNOSTIC MARKERS IN CLL
J Gribben. EHA 2014, oral presentation.
PRACTICAL USE OF
PROGNOSTIC MARKER AND DIAGNOSTIC TOOLS IN CLL
Rossi D et alii, Blood 2013, 121 (8): 1403-1412.
Integrated mutational and Cytogenetics Analysis identifies Prognostic subgroups in CLL
E’ possibile ottimizzare la
terapia dei pazienti affetti
da LLC?
BACKGROUND
STRUMENTI
DIAGNOSTICI
OUTCOMES
COMPLIANCE
PAZIENTI
REALTA’ LOCALI
INTERVENTI
TERAPEUTICI
ENDPOINT
CANCER is a disease of aging and the population
of older people in the US is growing rapidly…. 35
million people > 65 yrs old….expected to double by
2030 according to the US Census Bureau.
…Oncologists who have cared for older adults
understand that their treatment needs are different
than those of young counterparts….
…they can experience secondary cancers or
memory problems following treatment…..
…As a result, GERIATRIC ONCOLOGY
has become an emerging area of focus.
ASCO News and Forum, 2006
FRA GLI ULTRA65ENNI A LIVELLO NAZIONALE:
- oltre il 8% è confinato in casa
- oltre il 12% presenta limitazioni nello svolgimento di attività quotidiane
- oltre il 18% risulta disabile
- oltre il 40% è affetto da almeno una malattia cronica
- oltre il 68% delle persone disabili presenta almeno 3 malattie croniche
ALCUNI DATI RECENTI….
Fonte: Condizioni di salute, fattori di rischio e ricorso ai servizi sanitari. ISTAT, 2007.
LE PRINCIPALI PAURE DELLE PERSONE ANZIANE
Fonte CENSIS
ETA’
SINDROMI GERIATRICHE
- malnutrizione
- incontinenza
- sordità, riduzione del visus, alterazioni della deambulazione
- assunzione di farmaci
- fragilità
- alterazioni cognitive
- disturbi depressivi
DISABILITA’ - limitazioni nelle attività quotidiane
- autostima
COMORBIDITA’ - patologie cardiovascolari, respiratorie, metaboliche, neurologiche
PROBLEMATICHE NEL PAZIENTE ANZIANO CON MALATTIA EMATO-ONCOLOGICA
LOSS OF ORGAN RESERVE CHRONOLOGIC AGE
FUNCTIONAL STATUS:
PERFORMANCE STATUS,
ADL SCALE, IADL SCALE
COMORBIDITIES
IMMUNE SYSTEM
DEFECTION
BONE MARROW
RESERVE
CAREFUL ASSESSMENT OF THE RISK OF THERAPY
Chronic lymphocytic leukemia in the elderly: who should be treated.
Zent C. ASCO 2010.
BIOLOGICAL
PROGNOSTIC FACTORS
COGNITIVE IMPAIRMENT
DEPRESSIVE DISORDERS
Journal of Clinical Oncology 2013, 31 (29): 3711-3718.
Adapted from: Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers.
Hematology 2013.
SELECTED STANDARDIZED TOOLS TO EVALUATE VARIOUS DIMENSIONS OF PATIENT FITNESS
METODO DI DETERMINAZIONE DEL “FITNESS STATUS”
Prevalenza di una valutazione soggettiva basata sull’esperienza
Comportamento sovrapponibile per i 2 target
Le scale CIRS, ECOG e WHO sono i riferimenti più citati fra i criteri definiti utilizzati
MEASUREMENT OF COMORBIDITY:
Cumulative illness rating scale (CIRS)
Linn B, et al. J Am Geriatr Soc 1968; 16:622–626.
Parmelee P, et al. J Am Geriatr Soc 1995; 43:130–137.
CUMULATIVE ILLNESS RATING SCALE (CIRS)
Total Score:
Organ system Score If illness/impairment present, please specify:
Heart
Vascular
Blood pressure
Respiratory
Endocrine/metabolic
Ear/nose/throat
Upper gastrointestinal
Lower gastrointestinal
Liver
Renal
Genitourinary
Musculoskeletal
Neurological
Psychiatric
0: ASSENTE (nessuna compromissione d’organo)
1: LIEVE (compromissione d’organo; non interferisce
con la normale attività; trattamento opzionale; prognosi
eccellente)
2: MODERATO (compromissione d’organo; interferisce
con la normale attività; trattamento necessario; prognosi
buona)
3: GRAVE (compromissione d’organo; produce disabilità;
trattamento non dilazionabile; prognosi non sempre
favorevole)
4: MOLTO GRAVE (compromissione d’organo; mette a
repentaglio la sopravvivenza; trattamento urgente;
prognosi grave)
LE SCALE CITATE DA CHI UTILIZZA CRITERI DEFINITI
CIRS consolidato nella letteratura ematologica e maggiormente utilizzato nella pratica clinica anche per altre patologie (linfomi)
FIT / UNFIT
FIRST-LINE TREATMENT CHOICE FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS:
WHAT DO CLINICIANS CARE ABOUT?
THE CLL FITNESS STUDY
Investigator-driven multicenter retrospective observational non-interventional study
Data collection on the criteria applied in the clinical practice when selecting first-line treatment for CLL
patients and on the outcome in terms of tolerance and toxicities to the initial therapy.
Primary objective: define the most relevant parameters influencing physician’s choice and their
correlation with treatment tolerance “Fitness score” (to be validated in clinical practice)
CLL patients requiring first-line treatment between January 1st, 2009 and December 31, 2010.
Study target population of 700 subjects…. 104 patient records were reported
36 Italian sites with long-standing experience in CLL patient management
MAIN REQUESTED CLINICAL INFORMATION:
anthropologic parameters
global health status
disease information
biological parameters
treatment
follow-up data Scarfò L. et alii. EHA 2014
FIRST-LINE TREATMENT CHOICE FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS:
WHAT DO CLINICIANS CARE ABOUT?
THE CLL FITNESS STUDY
35% of patients enrolled in clinical trials.
Treatment choice based on:
99% age
98% comorbidities
82% functional
80% performance status
79% mental status
68% need for caregiver
65% polypharmacy
39% biological factors (IgVH, FISH and CD38)
From: Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia: key
questions and current answers. Hematology 2013.
THE TIGHT LINK BETWEEN EFFICACY AND TOXICITY WITH HISTORICAL CLL THERAPY
DETERMINING THE GOALS OF TREATMENT FOR OLDER PATIENTS WITH CLL
From: Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia: key questions and current answers. Hematology 2013.
COMORBIDITY
TOXICITY
COMPLIANCE
SOCIAL FACTORS
THERAPY OF LLC: CRITICISM IN ELDERLY
No unequivocal age cut-off
(treatment dependent)
DOSE REDUCTION
LESS EFFECTIVENESS
1724 studies found for CLL
413 open studies found for CLL therapy
41 studies found for ELDERLY CLL
1650 studies found for CLL therapy
21 open studies found for THERAPY
IN ELDERLY CLL
NEW THERAPEUTIC AGENTS AND THEIR TARGETS IN A CHRONIC LYMPHOCYTIC LEUKEMIA CELL
F1000Prime Reports 2014, 6: 65.
Adapted from: Hallek M. Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies.
Haematology 2013.
POTENTIAL FUTURE STRATEGIES TO ACHIEVE LONG-TERM CONTROL OF CLL
CLL: INCREASE IN CR RATE OVER THE YEARS
Montserrat et alii. Blood 2005, 106: 2226
Rai et al. 2000; Leporrier et al. 2001; Lundin et al. 2002; O’Brien et al. 2001; Bosch et al. 2008; Tam et al. 2008
0
20
40
60
80
Chlorambucil Fludarabine Alemtuzumab CAP CHOP FC FCM FCR
Pe
rce
nt o
f p
atie
nts
CR according to NCI criteria, 1996
INCREASING COMPLETE REMISSIONS...
Anti CD20 di nuova generazione;
inibitori tirosin kinasi, inibitori Bruton kinasi, ......
?
?
?
?
? ?
? ?
? ?
Hematol Oncol 2014, 15 (Epub ahead of print).
Frequency of first line treatment over time (n=620).
Others: regimens with frequency < 5%
Hematol Oncol 2014, 15 (Epub ahead of print).
Frequency of second line treatment
(n= 270)
Martin, et al. Blood. 2012;119:2590-2594.
BCR-Inhibition and Transient Lymphocytosis
Unexpected side effect of BCR inhibitors (SYK, BTK, and PI3K inhibitors):
• Rapid reduction of lymphadenopathy
• Transient lymphocytosis
IBRUTINIB (PCI-32765)
Inhibits BCR-controlled signaling and integrin-
mediated adhesion
Inhibits CXCL12-, CXCL13-, and CCL19-induced
signaling
Overcomes BCR and chemokine-controlled
integrin-mediated retention/homing of CLL cells
Deprives CLL cells of growth- and survival-
supporting lymph node and bone marrow
microenvironment
Particolare attenzione a:
- agenti antiaggreganti e anticoagulanti (intervento chirurgico)
- linfocitosi
- leucostasi
- infezioni
- neoplasie maligne
- interazioni farmacologiche (l’elenco completo degli inibitori, induttori e substrati del citocromo P450 è
disponibile all’indirizzo http://medicine.iupui.edu/clinpharm/ddis/table.aspx)
IBRUTINIB: AVVERTENZE E PRECAUZIONI SPECIALI PER L’USO
FINAL RESULS OF A PHASE I STUDY OF IDELALISIB (GS-1101) A SELECTIVE INHIBITOR OF PHOSPHATIDYLINOSITOL 3-
KINASE p110 Delta (PI3Kδ) IN PATIENTS WITH RELAPSED OR REFRACTORY CLL
Adverse events and selected lab abnormalities
FINAL RESULS OF A PHASE I STUDY OF IDELALISIB (GS-1101) A SELECTIVE INHIBITOR OF PHOSPHATIDYLINOSITOL 3-
KINASE p110 Delta (PI3Kδ) IN PATIENTS WITH RELAPSED OR REFRACTORY CLL
Serious adverse events, leading to study drug discontinuation
SKIN LESIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA
Cutaneous lesions in up to 25% of patients with chronic lymphocytic leukemia (cutaneous seeding by
leukemic cells - leukemia cutis, LC - and other malignant diseases or non malignant disorders.
Solitary, grouped, or generalized papules, plaques, nodules, or large tumors
Prognosis in CLL patients with LC is rather good and many authors claim that it does not
significantly affect patients' survival.
However, prognosis is poor in patients in whom LC shows blastic transformation (Richter's
syndrome) and when leukemic infiltrations in the skin appear after the diagnosis of CLL.
Secondary cutaneous malignancies are also frequent complications in patients with CLL.
Nonspecific, secondary cutaneous lesions are frequently observed in CLL patients (infectious or
hemorrhagic )
Other secondary lesions present as vasculitis, purpura, generalized pruritus, exfoliative erythroderma, and
paraneoplastic pemphigus
An exaggerated reaction to an insect bite and insect bite-like reactions have been also observed.
Leuk Lymphoma 2007, 48 (5): 855-865.
MANIFESTAZIONI AUTOIMMUNI NON EMATOLOGICHE NELLA LLC
Pemfigo paraneoplastico
Pioderma gangrenoso
Angioedema
Sindrome di Churg-Strauss
Tiroidite autoimmune
Glomerulonefrite
LES
Sindrome di Raynaud
Polineuropatia
Artrite reumatoide
Sindrome di Sjogren
Vasculite
Colite ulcerativa
DIAGNOSI CORRETTA
DIAGNOSI DIFFERENZIALE
SUPPORTIVE CARE CONSIDERATIONS FOR CLL PATIENTS
From: Shanafelt T. Treatment of older patients with chronic lymphocytic leukemia:
key questions and current answers. Hematology 2013.
Dipartimento di
Oncologia Medica
Struttura Complessa
Ematologia e Centro Trapianti
Programma Trapianti
Accreditato Presidio Ospedaliero
Armando Businco
Centro Riferimento Oncologico Regionale
TRIALS CLINICI IN CORSO
Studio di fase III, multicentrico randomizzato, a tre bracci di trattamento, di comparazione dell’efficacia e della sicurezza di
RO5072759 + chlorambucil (GClb), rituximab + chlorambucil (RClb) o chlorambucil (Clb) in monoterapia in pazienti affetti da
leucemia linfatica cronica non pretrattati, con comorbidità (CLL11 - BO21004).
Studio di fase III randomizzato, in doppio cieco, controllato con placebo, per valutare l’efficacia e la sicurezza di GS-1101
(CAL-101) in combinazione con bendamustina e rituximab per la leucemia linfocitica cronica precedentemente trattata (GS-
US-312-0115).
Studio di fase III MO28543 - multicentrico, in aperto, a braccio singolo, di fase IIIB, per valutare la sicurezza di
obinutuzumab in monoterapia o in associazione a chemioterapia in pazienti affetti da leucemia linfatica cronica non
pretrattata o recidivata/refrattaria.
Studio di fase III multicentrico randomizzato, controllato vs placebo, in doppio cieco, sull’efficacia e sicurezza di
lenalidomide come terapia di mantenimento dopo terapia di prima linea in pazienti ad alto rischio affetti da leucemia linfatica
cronica – CLLM1.
Named Patient Program – NPP - Ibrutinib
TRIALS CLINICI CONCLUSI
Studio di fase III sulla immunochemoterapia con Fludarabina, Ciclofosfamide e Rituximab (FC-R) in confronto
alla sola chemioterapia con Fludarabina e Ciclofosfamide (FC), in pazienti con leucemia linfatica cronica non trattata
in precedenza (CLL8 - ML1710).
Studio multicentrico a braccio singolo, di Bendamustina associata ad Ofatumumab (BendOfa) in pazienti con
leucemia linfatica cronica (LLC) refrattari o ricaduti.
PROSSIMA APERTURA
Studio di fase III multicentrico randomizzato per valutare l’efficacia e la sicurezza di GS-1101 (CAL-101) in
combinazione con bendamustina e rituximab per la leucemia linfocitica cronica in prima linea (GS-US-312-0123).
RICERCA CLINICA
Progetto di ricerca clinica “Rischio evolutivo in pazienti con leucemia linfatica cronica (LLC): ricerca di modello
predittivo”, finanziato dall’Assessorato della Programmazione,– Centro Regionale di Programmazione, Regione
Sardegna, annualità 2012.
Dipartimento di
Oncologia Medica
Struttura Complessa
Ematologia e Centro Trapianti
Programma Trapianti
Accreditato Presidio Ospedaliero
Armando Businco
Centro Riferimento Oncologico Regionale
Journal of Clinical Oncology 2007, 25 (14).