LEUCEMIA MIELOIDE ACUTA. A.M. Carella U.O.C. Ematologia IRCCS AOU San Martino IST, Genova

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1 LEUCEMIA MIELOIDE ACUTA A.M. Carella U.O.C. Ematologia IRCCS AOU San Martino IST, Genova

2 Impact of mutational analysis in AML C. Thiede Optimal acute myeloid leukemia therapy in 2012 H. Dombret

3 Acquired mutations and epigenetic alterations accumulate in progressive way. Subclones of cells acquire new properties, giving cells advantages such as the ability to resist chemotherapy.

4 ü MDS clones contain hundreds of acquired mutations. ü Leukemias arose from at least one subclone that had gained new mutations. ü Sequential development of leukemia. Walter et al. NEJM 2012; 366:1979

5 Do they have prognostic value? Poor Survival: FLT3 + or MLL and in those with point mutations of ASXL1 or PHF6. Favorable Survival: CEBPA or IDH2 mutations; NPM1 mutations with concurrent IDH1 or IDH2 mutations.

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7 In a recent comprehensive analysis of mutations in a cohort of almost 400 pts with AML treated in the ECOG, reported for the first time a simultaneous mutational analysis of 18 genes, covering most abnormalities currently discussed as relevant for AML prognosis. (Patel et al., NEJM 2012)

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15 ü These data indicate: a. more detailed genetic analysis may lead to improved risk stratification and identification of patients who can benefit from more intensive induction chemotherapy. b. the challenge is to provide genetic information in a timely and affordable way and show that this information could prospectively influence treatment decisions.

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17 AML Therapy in 2012 Younger AML

18 ELN Guidelines Induction years ü Standard AraC Dauno 60+, Ida 10-12, Mtx HiDAC too toxic - Phase 3 studies: SWOG 2 g x12, ALSG 3 g x 8 - Phase 2 studies: ECOG 3 g x 6, SWOG 7+3 fw by 2 g x 6 (7+3+3) ü Promising options - CSF priming - G-CSF: HOVON-SAKK study - GM-CSF: ALFA study - Gemtuzumab ozogamicin (GO) - British AML15 study

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32 Lestaurtinib / Sorafenib Inhibition of constitutively activated FLT3, lestaurtinib in relapsed AML and sorafenib in newly diagnosed older AML, have failed to demonstrated significant benefit when combined to intensive chemotherapy.

33 Midostaurin /Quizartinib Phase III randomized study of midostaurin restricted to FLT3 mutated pts younger than 60 yrs is ongoing. Phase II study of quizartinib or AC220, the most selective FLT3 inhibitor available, in relapsed AML have confirmed that clonal responses could be observed with monotherapy.

34 Dasatinib KIT mutation, associated with unfavorable prognosis in CBF-AML, may be targeted with dasatinib. A frontline study of dasatinib combined to intensive chemotherapy is ongoing by the AMLSG. No responses were observed with dasatinib alone in the French DASA-CBF study.

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37 Plerixafor, a CXCR4 antagonist blocking the CXCR4/SDF-1 interaction has been developed as an agent capable to mobilize hematopoietic progenitors from the hematopoietic niche to the peripheral blood.

38 Evaluating its safety and potential when used alone or combined with G-CSF as a chemosensitizing agent in AML pts are ongoing.

39 ALLOGRAFTING

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41 ü Intent to treat donor versus no-donor comparisons is not well suited to evaluate the real effect of HSCT in very high-risk pts. ü Transplant versus no-transplant comparison should be preferred (as a significant proportion of these pts will never be transplanted in 1 st CR despite an identified donor).

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43 ü The value of allogeneic HSCT needs to be reassessed based on: - the identification of AML genetic heterogeneity. - the availability of different transplant sources and donor types. - The use of reduced-intensity conditioning (RIC). It is important to consider TRM that may vary between less than 15% and up to 50%. It is essential to assess whether the benefit of the reduced relapse rate outweighs TRM or will be offset by a high TRM.

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50 AML Therapy in 2012 Older AML

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52 Standard therapy in older AML pts Older age per se, however, should not be a reason to withhold intensive therapy. Remission induction chemotherapy provides better quality of life and longer survival than supportive care only. Intensive chemotherapy should thus remain the standard in pts capable to tolerate it. The 3+7 remains the most frequently used chemotherapy induction regimen.

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57 Hypomethylating Agents Azacitidine and Decitabine: significant benefit in HR-MDS (and pts with 20-30% marrow blasts), compared with conventional care including LDAC.

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59 Azacitidine has also shown interesting results in retrospective AML studies.

60 Azaci&dine followed by lenalidomide in pa&ents with higher- risk MDS or AML; ongoing AZALE study: results Patients Median 2 cycles (range 1 6) administered within all dose cohorts To date, 20 pa=ents enrolled: cohort 1 and 2: 4 pa=ents each cohort 3 and 4: 6 pa=ents each Safety MTD of lenalidomide: 20mg Therapy-induced grade 3/4 neutropenia or thrombocytopenia, n (%): 12 (60) DLTs, n: infectious complications: 2 thrombosis: 1 incomplete haematological recovery: 1 Sequential azacitidine and lenalidomide is feasible and appears effective in patients with higher-risk MDS/AML and del(5q) Patients, n Patients, n Response (n=19) CR CRi PR HI 2 0 Overall = 6 (32%) 13 (68%) patients had SD Cytogenetic response (n=19) 4 Overall = 7 (37%) 4 3 CR PR ORR in previously untreated patients: 5/9 (56%) Response in patients with p53 mutations: 5/7 (71%) Platzbecker U, et al. Poster presentation at ASH Abstract 3799

61 Addic&on of AZA to standard induc&on therapy in older pa&ents with AML Ulz Krug et al., Blood. 2010;[ASH 2010 Abstract 2180]

62 Pollyea, et al. abstract 3288 ASH 2010

63 Novel Agents which may have role in trea&ng elderly AML Hedgehog inhibitors. PARP inhibitors. Aminopep=dase inhibitors: Tosedostat Rigoser=b: ON HDM2 inhibitors

64 CONCLUSIONS ü In 2012, the ELN guidelines published in 2010 by an international expert panel remain valid. ü Addition of GO might become a new standard, at least in some patient subsets. ü Most recent and current investigations concern: conventional drug dose intensification new agent incorporation allograft stratification on patient-, AML- and stem cell source-related factors.

65 It is exciting to think that the goal of personalized medicine is quickly approaching, but it will require careful thought to implement genomic-based clinical evaluation in a way that is meaninful for patients. Lucy A. Godley. Profiles in Leukemia. NEJM 2012:366;1152

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67 Rilevanza prognostica del profilo genetico integrato. Associazione di target therapy e chemioterapia nei pazienti FLT3 mutati. Trapianto autologo: nuovi protocolli ad alte dosi.