Risk-adapted therapy of AML in younger adults. Sergio Amadori Tor Vergata University Hospital Rome

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1 Risk-adapted therapy of AML in younger adults Sergio Amadori Tor Vergata University Hospital Rome Pescara 11/2010

2 AML: treatment outcome Age CR % ED % DFS % OS % < < > <20 <10 Better treatment strategies needed

3 Molecular-cytogenetic heterogeneity NPM1 mut/flt3 ITD neg/wt1 wt 18% CEBPA mut (biallelic)/flt3 ITD neg 3% inv(16)/t(16;16)/ CBFB MYH11 5% t(8;21)/runx1 RUNX1 T1 8% Other adverse 14% ADVERSE MLL PTD 5% inv(3)/t(3;3)/evi 1 3% FAVORABLE t(15;17)/pml RARA 11% FLT3 ITD/NPM1 wt 12% 21% INTERMEDIATE Grimwade & Hills, ASH 2009

4 AML: prognostic factors Factor Comment Age WBC Prior therapy or MDS? Extramedullary disease Day 14 blast count Major impact at diagnosis Continuous variable Karyotype may be more important Variable Higher percentage worse # cycles of induction One better than two Cytogenetic/molecular profile Gene expression profile MicroRNA expression Gene sequencing MRD detection at CR Major impact at diagnosis Can further subdivide patients Needs validation by other groups Future application Independent predictor of outcome

5 How do we treat younger patients with AML in 2010? ν Treatment stratification based on age and genotype Cytogenetics Molecular diagnostics

6 AML therapy: current standard ν ν Remission induction chemotherapy Anthracycline + Ara-C (3+7 or variants) Post-remission therapy ID/HD-Ara-C based consolidation (1 or more courses) Auto-SCT Allo-SCT Decision based on risk and doctor/patient preference

7 Strategies to improve current standard ν Add and/or intensify cytotoxic drugs ν Add new agents ν Add immunotherapy (IL-2) as maintenance

8 Add and/or intensify cytotoxic drugs ν Addition of VP-16 or 6-TG or HD-Ara-C produced no survival advantage ν Which anthracycline? ν Anthracycline dose ν How much treatment?

9 Which anthracycline? EORTC-GIMEMA AML-10 DNR 50x3 MXR 12x3 IDA 10x3 Mandelli et al, JCO 2009

10 Anthracycline dose Is DNR 90 better than 45/50? ECOG 1900

11 ECOG 1900: Outline Daunorubicin 45 mg/m 2 x 3 + SDAC Daunorubicin 90 mg/m 2 x 3 + SDAC CR High Risk Allogeneic SCT HiDAC x 2 PBSCH after 2nd course A B Autologous SCT GO 6 mg/m 2 (1 mo pre-sct)

12 ECOG 1900: Results ν Phase 3 ν 657 pts (median age 48y, range 17-60) ν CR%: 57.3 (SD) vs 70.6 (HD), (P = 0.001) ν ν ID%: 4.5 (SD) vs 5.5 (HD) OS (median/mos): 15.7 (SD) vs 23.7 (HD), (P=0.003) Age >50: no survival benefit (HD) Adverse cytogenetics: no survival benefit (HD) But Fernandez et al, NEJM 2009

13 ECOG 1900 vs MRC AML15 ν ECOG 1900 ν Overall CR rate 63.9% HD 70.6% SD 57.3% Median survival HD 23.7 mos SD 15.7 mos ν ν MRC AML15 DNR 50x3 Overall CR rate 79.8% Median survival Whole cohort 29.9 mos

14 SWOG 0106 vs ECOG 1900 Appelbaum F, EHA 2010

15 How much treatment? (MRC: 4 vs 5 courses) Burnett A, 2010

16 How much treatment? (MRC: 3 vs 4 courses) Overall Good Risk Int Risk Poor Risk Burnett A, 2010

17 Add new agents ν New cytotoxics Nucleoside analogs ν Targeted agents Gemtuzumab (GO) FLT3 inhibitors ATRA

18 Adding Cladribine ν 673 pts age 18 to 60 yrs randomized to DA + ara-c (DAA n=223), DA + fluda (DAF; n=219), DA + cladribine (DAC; n=210) ν Median follow up 34 m: Outcome DAC DAF DAA p (vs DAA) p (vs DAF) CR (%) CR post 1 (%) yr OS (%) yr LFS (%) NS NS ν Early death rates: 9-11% (NS) Holowiecki et al, ASH 2009

19 Adding Clofarabine EORTC-GIMEMA AML-14A Clofarabine in combination with a standard remission induction regimen in patients years old with previously untreated intermediate and poor risk acute myelogenous leukemia (AML) or high risk myelodysplasia (MDS): a phase 1-2 study

20 EORTC-GIMEMA AML-14A (phase 1) Study design (2) ν ν Remission induction Idarubicin: 10 mg/m2/d, on d1, d3, d5 Ara-C: 100 mg/m2/d ci on d1-d10 Clofarabine (1 hrs inf./push injection): test dose on d2, d4, d6, d8, d10 if PR after 1 st induction: 2nd induction if CR: start consolidation Consolidation Ara-C (c.i.): 500 mg/m2/12h (2-hr infusion) on d1-6 Idarubicin (i.v): 10 mg/m2/d on d4-6 Step TD Clofarabine (mg/m 2 ) dose/day (mg/m 2 ) Arm A: Arm B: Nr of pts dose/day (mg/m 2 ) Nr of pts

21 Adding GO: MRC AML15 Course 1 Course 2 Course 3 Course 4 Course 5 ADE /- GO R I S K ADE MACE +/- GO MidAc No further Treatment R DA /- GO FLAG-Ida +/- GO A S S E S S M E N T DA 3+8 FLAG -Ida R AC 1.5g/m 2 +/- GO AC 3g/m 2 +/- GO AC 1.5g/m 2 AC 3g/m 2 R AC 1g/m 2

22 GO: MRC AML15 Burnett A, 2010

23 GO: MRC AML15

24 GO: SWOG 0106 R A N D O M I Z A T I O N DNR+Ara-C +GO (6 mg/m 2 ) DNR+Ara-C HiDAC 3 courses R A N D O M I Z A T I O N GO x 3 (5 mg/m 2 monthly) No therapy

25 GO: SWOG 0106 ν ν ν ν No improvement in CR rate, RFS or OS Higher fatal AE rate during induction in GO arm No improvement in DFS on GO maintenance GO may improve RFS and OS in pts with favorable cytogenetics Petersdorf et al, ASH 2009

26 Adding FLT3 inhibitors Stone et al, ASH 2009

27 PKC412

28 PKC412

29 Adding ATRA Age 61+ Schlenk et al, Leukemia 2004

30 Adding ATRA Age 61+ Schlenk et al, Haematologica 2009

31 Adding ATRA: MRC AML12

32 MRC AML12 Burnett et al, Blood 2010

33 MRC AML12 Burnett et al, Blood 2010

34 Add IL-2 immunotherapy as maintenance ν ν ν ν IL-2 activates T and NK cells Rationale for efficacy in preventing relapse based on preclinical data No benefit in any of 6 large randomized trials using IL-2 monotherapy Histamine (HDC) protects T and NK cells from inactivation by myeloid cells (induced by ROS production)

35 How HDC may improve IL-2 efficacy Romero et al, Scand. Reference: J. Immunol. Hellstrand et 2009 al., J. Immunol. 153: (1994)

36 IL-2/HDC maintenance in AML Brune et al, Blood 2006

37 Strategies to improve current standard ν Refine pre-therapy risk stratification through incorporation of MRD data Buccisano et al, Blood 2010

38 allosct > autosct for High-risk AML Low-Risk Good K / MRD- Int K / MRD- High-Risk Adverse K FLT3+ Good K / MRD+ Int K / MRD+ ausct allosct Total L-risk H-risk Total Buccisano et al, Blood 2010

39 GIMEMA AML1310: a study of riskadapted and MRD-directed therapy for adult AML MRD marker Risk stratif MRD assess LAIP CG, molecular LAIP Low-risk Diagnosis Int-risk Induction (1 or 2 courses) CR Consolidation 1 MRD- MRD+ autosct allosct High-risk No CR FLA-I salvage CR Low-risk: CBF/Kit wt ; NPM1+/FLT3- Int-risk: all others High-risk: Adverse K; FLT3+ allosct: MRD, MUD, UCB, HRD

40 AML: personalized therapy