SINDROMI MIELODISPLASTICHE.

TERAPIA DEMETILANTE

ED

IMMUNOMODULANTE.

Clinica Ematologica,Centro Trapianti e Terapie Cellulari

Azienda Ospedaliero-Universitaria, Udine

Incidence of MDS increases with ageIncidence of MDS increases with age

35

30

25

20

15

10

5

0< 30 30–40 40–50 50–60 60–70 70–80 80–90

Agecategory(years)

Yearlyincide

nce

per100,000individu

als

Germing U et al. 2004, Jädersten M, Helström-Lindberg E. 2009

Factors that determine treatmentoptions in elderly patients with MDS

Biological

Geriatr

ic

Psychological

Social

Dementia

Depression

Delirium

FallsNeglect or abuse

Presence andadequacy of caregiver

Access to transportation

Social support

MDS

Treatment

Comorbidity

Functional status

Coping

Cognition

Psychiatric symptoms

Adherence

PatientAge

Nutrition

Fried LP et al. 2001, Tinetti ME, Fried T. 2004, Slaets JP. 2006, Gobbens RJ et al. 2007, Ossenkoppele G.J. 2010.

MDS THERAPYMDS THERAPY

•• HIGH RISK MDS.HIGH RISK MDS.

• Therapy : ImproveSurvival.

•• HYPOMETHYLATINGHYPOMETHYLATINGAGENTS (Azacitidine,AGENTS (Azacitidine,Decitabine).Decitabine).

• INTENSIVE CHT (ICT).

• AlloSCT.

•• LOW RISK MDS.LOW RISK MDS.

• Therapy: ↓ trasfusions; ↓risk of transformation.

• OBSERVATION.

• GROWTH FACTORS.

•• LENALIDOMIDE.LENALIDOMIDE.

• (AlloSCT, Hypomethylatingagents, etc).

AGENTI DEMETILANTIAGENTI DEMETILANTI

•• VIDAZA (5-Azacitidina)VIDAZA (5-Azacitidina)

•• DACOGEN (Decitabina)DACOGEN (Decitabina)

Chronology of Azacitidine DevelopmentChronology of Azacitidine DevelopmentEventEvent

•• Synthesis (Czech scientists)Synthesis (Czech scientists)•• Initial Laboratory WorkInitial Laboratory Work•• Initial Phase I Trials and PK Work asInitial Phase I Trials and PK Work as

CytotoxicCytotoxic•• Development as a Cytoxic (Upjohn)Development as a Cytoxic (Upjohn)•• Submission to the FDA as CT AgentSubmission to the FDA as CT Agent

(Upjohn)(Upjohn)•• NCI/CALGB Phase II- Studies 8421 and 8921NCI/CALGB Phase II- Studies 8421 and 8921

(Silverman/Holland)(Silverman/Holland)•• NCI/CALGB Phase III- 9221 (1992)NCI/CALGB Phase III- 9221 (1992)•• Publication of CALGB 9221 (Silverman)Publication of CALGB 9221 (Silverman)•• Pharmion ResubmissionPharmion Resubmission•• Pharmion Confirmatory TrialPharmion Confirmatory Trial•• Vidaza ApprovalVidaza Approval

Silverman LR, et al. Silverman LR, et al. Leukemia Leukemia 1993. 7(S1): 21-29.1993. 7(S1): 21-29.Silverman LR, et al. Silverman LR, et al. Mol and Cell DiffMol and Cell Diff 1994: 505. 1994: 505.

DNA Hypomethylation in vivoDNA Hypomethylation in vivo

1)1)CALBG 9221CALBG 9221 (AZA VS BSC).(AZA VS BSC).

2)2)AZA-001AZA-001 (AZA VS STANDARD OF(AZA VS STANDARD OFCARE).CARE).

2 studi randomizzati con2 studi randomizzati conAZACITIDINA in HR-MDS.AZACITIDINA in HR-MDS.

N=191; median age = 68 y; male = 69%; all FAB subtypes; transfusion dependent =71%*N=191; median age = 68 y; male = 69%; all FAB subtypes; transfusion dependent =71%*

Treatment**Treatment** Response Response Time to LeukemiaTime to Leukemia Transformation to Transformation to or Deathor Death AML as 1st eventAML as 1st event

AzacitidineAzacitidine CR = 7%CR = 7% 21 months21 months 15%15%(n = 99)(n = 99) PR = 16%PR = 16%

Improved = 37%Improved = 37%(Overall = 60%)(Overall = 60%)

Supportive careSupportive care CR = 0%CR = 0% 13 months13 months 38%38%(n = 92)(n = 92) PR = 0%PR = 0%

Improved = 5%Improved = 5%(Overall = 5%)(Overall = 5%)

Quality of life significantly improved with treatment: fatigue (Quality of life significantly improved with treatment: fatigue (P P = .001), dyspnea= .001), dyspnea((P P = .0014), physical functioning (= .0014), physical functioning (P P = .002), positive affect (= .002), positive affect (P P = .0077), and psychological= .0077), and psychologicaldistress (distress (P P = .015).= .015).

* Transfusion-dependent patients in azacitidine arm only2

**16-week course of treatment with azacitidine 75 mg/m2/d SC for 7 d in 28-d cycles x 4 or supportive care

1. Silverman LR, et al. J Clin Oncol. 2002;20:2429. 2. Kaminskas E. Oncologist. 2005;10:176.

CALGB TrialCALGB Trial: Azacitidine vs Supportive Care

AZA 001AZA 001

AZA 001AZA 001

Fenaux et al. 2009.

Hematological AEsa occur early during azacitidinetreatment in higher-risk patients

aAll grades.

Patie

nts,

%

The majority of skin and subcutaneousThe majority of skin and subcutaneousAEs are local injection site reactionsAEs are local injection site reactions

Side-effect management: lessons learnedSide-effect management: lessons learnedfrom AZA-001 and CALGB 9221from AZA-001 and CALGB 9221

• The majority of AEs were transient, non-serious andwere managed by

– Dose delays for hematological events– Supportive care measures

• Most hematological events occurred during thefirst 1–2 cycles

Santini V et al. 2008.

Silverman LR, et al. Further analysis of trials with azacitidine in patients with myelodysplastic syndrome: studies 8421,8921, and 9221 by the Cancer and Leukemia Group B. J Clin Oncol 2006.

Fenaux P, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-riskmyelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009.

AZACITIDINEAZACITIDINE

Almeno 4-6 CicliAlmeno 4-6 Cicli

Continued azacitidine therapy beyondContinued azacitidine therapy beyondtime of first response improves quality oftime of first response improves quality of

response in patients with higher-riskresponse in patients with higher-riskmyelodysplastic syndromes.myelodysplastic syndromes.

Silverman LR, Fenaux P, Mufti GJ, Santini V,Hellström-Lindberg E, Gattermann N, Sanz G,

List AF, Gore SD, Seymour JF.[Cancer. 2011 Jun 15;117(12):2697-702].

AzacitidineAzacitidine

•• CASESCASES. MDS IPSS INT-2 or HIGH RISK GROUP andnot eligible to AlloSCT, or eligible to AlloSCT butlacking an immediately available donor (Grade A).

•• DOSE and SCHEDULEDOSE and SCHEDULE. The recommended startingdose for the first treatment cycle is 75 mg/m2 s.c.for 7 days q.28d. for all patients regardless ofbaseline hematology laboratory values (Grade A).

• It is recommended that patients should be treatedfor at least 6 cycles (Grade A).

• Patients should be monitored for hematologicalresponse/toxicity and renal toxicities

Clinical management of MDS update of SIE,Clinical management of MDS update of SIE,SIES, GITMO practice guidelines, 2010.SIES, GITMO practice guidelines, 2010.

AZACITIDINEAZACITIDINEAREAS REQUIRING FURTHER INVESTIGATIONAREAS REQUIRING FURTHER INVESTIGATION

•• 1)COMBINATIONS (Lenalidomide; Low dose CHT; Histone1)COMBINATIONS (Lenalidomide; Low dose CHT; HistoneDeacetylase Inihbitors).Deacetylase Inihbitors).

•• 2)Bridge to Allo SCT.2)Bridge to Allo SCT.

•• 3)Maintenance Therapy after intensive CHT.3)Maintenance Therapy after intensive CHT.

•• 4)Aza in Low-INT-1 Risk MDS that are resistant or not suitable4)Aza in Low-INT-1 Risk MDS that are resistant or not suitablefor other treatments.for other treatments.

•• 5)In AML with more than 30% marrow blasts.5)In AML with more than 30% marrow blasts.

TERAPIATERAPIA

IMMUNOMODULANTEIMMUNOMODULANTE

Immunomodulatory drugs (IMiDsImmunomodulatory drugs (IMiDs®®))

CC-5013 = lenalidomideCC-4047 = pomalidomide

Microglia

Monocytes

T cells

B cells

Haemopoieticstem cells

Endothelial cells

Bone marrow stroma

IMiDs®

Haemopoietic tumours

IMiDs®® are multifunctional agents

IMiD® is a registered trademark of Celgene Corporation. IMiDs® are small-molecule immunomodulatory compounds.Chanan-Khan A, et al. Lancet Oncol. 2006;7:480-8. List A, et al. N Engl J Med. 2005;352:549-57.

Meta-analysis of studies with Thalidomide as single agent in MDSMeta-analysis of studies with Thalidomide as single agent in MDS

AUTHOR N. PTS DOSE OVERALL RESPONSE DROP-OUT

(mg/d) (Intent-to-treat)

Raza, 2001 83 100-400 31 % (19 %) 38 %

Strupp, 2002 34 100-500 65 % (56 %) 15 %

Musto, 2002-2004 40 100-300 32 % (20 %) 37 %

Bowen, 2005 12 100-800 50% (16 %) 67 %

Bouscary, 2005 47 200-800 88 % (49 %) 64 %

Moreno-Aspitia, 2006 68 200-1000 16 % (9 %) 57 %

Kelaidi, 2008 120 32% (37% 24 del5q)

•• Erythroid improvements accounted for the majority of responses• Possibility of long term response• No significant changes in marrow morphology, rare cytogenetic remissions• Response mainly achieved within 8 weeks, no dose-response effect• High drop-out rate, improved tolerability with lower doses

Thalidomide + Darbepoetin in MDS

• Early conclusion of a trial due toa high number of thromboembolicevents

Steurer et al, Br J Haematol 2003; 121: 101Steurer et al, Br J Haematol 2003; 121: 101

0 20 40 60 80 100

Other

Normal

Del 5q31.1

Major Erythroid ResponseDuration by Cytogenetic Pattern

Median Response Duration [Weeks]

Overall RR 56%; Major RR 48%

List AF, et al. NEJM 2005; 352: 11-19List AF, et al. NEJM 2005; 352: 11-19

MDS 001MDS 001

NB. DVT and PE in < 0,5 % of 7500 MDS pts treated withLENALIDOMIDE- post marketing experience in USA.

LENALIDOMIDELENALIDOMIDE•• CASESCASES

• A)MDS IPSS LOW-INT1 RISK GROUP, transfusion dependent andwith 5q- deletion (isolated or with additional cytogeneticabnormalities) (Grade B).

• B)MDS IPSS INT2 or HIGH RISK GROUP, transfusion dependent andwith 5q- deletion (isolated or with additional cytogeneticabnormalities) without an immediately available donor for alloBMT(Grade C).

• C)MDS IPSS LOW-INT1, transfusion dependent, without 5q deletionand not candidate for ESAs therapy or who failed previous ESAstherapy (grade D- only clinical trials).

•• DOSE and SCHEDULEDOSE and SCHEDULE. The recommended starting dose forthe first treatment cycle is 5-10 mg/mg day orally for 21 daysevery month (Grade B).

• Patients should be treated for at least 4 cycles (Grade B).

Clinical management of MDS update of SIE, SIES, GITMO practice guidelines, 2010.

JCO, 2011

INDICAZIONI IN ITALIAINDICAZIONI IN ITALIAAZACITIDINA. Indicazioni:AZACITIDINA. Indicazioni:

Vidaza e' indicato per il trattamento di pazienti adulti non eleggibili altrapianto di cellule staminali emopoietiche con:

Sindromi mielodisplastiche (SMD) a rischio intermedio-2 e alto secondoSindromi mielodisplastiche (SMD) a rischio intermedio-2 e alto secondol'International Prognostic Scoring System (IPSS),l'International Prognostic Scoring System (IPSS),

• leucemia mielomonocitica cronica (LMMC) con il 10-29% di blasti midollarisenza disordine mieloproliferativo,

• leucemia mieloide acuta (LMA) con 20-30% di blasti e displasia multilineare.

LENALIDOMIDE. Indicazioni sottoposte a monitoraggio AIFA:LENALIDOMIDE. Indicazioni sottoposte a monitoraggio AIFA:

Trattamento di pazienti anemici trasfusione-dipendenti, con sindromeTrattamento di pazienti anemici trasfusione-dipendenti, con sindromemielodisplastica a rischio basso o intermedio-1, portatori di delezione 5q-mielodisplastica a rischio basso o intermedio-1, portatori di delezione 5q-associata o meno ad altre anomalie cromosomicheassociata o meno ad altre anomalie cromosomiche

TerapiaMDS

1- Controllodell’accumulo di ferrotrasfusionale conpossibilità di mantenereun buon livelloemoglobinico

2- Impiego della 5-Azanei p. intermedio II e altorischio

Lenalidomide: p. abasso rischio eintermedio I con 5q- eisolata o inserita in uncariotipo complesso

PROF. TURA, 2008

Duong V, 2012.Duong V, 2012.