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AML and MDS: Highlights from 2012 William Blum, MD The Ohio State University and James Cancer Hospital.

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Presentation on theme: "AML and MDS: Highlights from 2012 William Blum, MD The Ohio State University and James Cancer Hospital."— Presentation transcript:

1 AML and MDS: Highlights from 2012 William Blum, MD The Ohio State University and James Cancer Hospital

2 Our agenda- Highlights from 2012 Risk stratification and treatment decisions in AML Novel treatment strategies for AML Low and intermediate-1 risk MDS Intermediate-2 and high risk MDS

3 ELN Standardized Reporting System for correlation of cytogenetic and molecular genetic data with clinical data in AML* Genetic GroupSubsets Favorablet(8;21)(q22;q22); RUNX1-RUNX1T1 inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11 Mutated NPM1 without FLT3-ITD (normal karyotype) Mutated CEBPA (normal karyotype) Intermediate-IMutated NPM1 and FLT3-ITD (normal karyotype) Wild-type NPM1 and FLT3-ITD (normal karyotype) Wild-type NPM1 without FLT3-ITD (normal karyotype) Intermediate-IIt(9;11)(p22;q23); MLLT3-MLL; Cytogenetic abnormalities not classified as favorable or adverse Adverseinv(3)(q21q26.2) or t(3;3)(q21;q26.2); RPN1-EVI1 t(6;9)(p23;q34); DEK-NUP214 t(v;11q23); MLL rearranged –5 or del(5q); –7; abn(17p); complex karyotype (≥3 abn) * International expert panel recommendations on behalf of ELN (Blood 115:453-74, 2010)

4 Overall survival (OS) Favorable (n=339) Intermediate-II (n=156) < 60 yrs Intermediate-I (n=144) Adverse (n=179) Overall Survival Years P <.001 ≥ 60 yrs Intermediate-II (n=222) Intermediate-I (n=136) Adverse (n=229) Years Favorable (n=145) P <.001 ELN classification, slide courtesy Mrozek, K

5 Levine, ASH education book 2012, from Patel NEJM 2012

6 Intensified Induction in AML Patients < 60 ECOG E1900 Observation Gemtuzumab Ozogamicin 6 mg/m 2 IV day 1(DISCONTINUED) Sibling Allogeneic HCT InductionPost -Remission + Cytarabine 100 mg/m 2 x 7 days 1-2 course to CR High-dose Cytarabine x 2 Auto- HCT DNR 45 mg/m 2 x 3 days DNR 90 mg/m 2 x 3 days Fernandez HF, et al. N Engl J Med. 2009;361(13): Untreated AML, N=657, median age 47

7 ECOG E1900: Overall Survival ECOG E1900: Overall Survival Induction Treatment DNR 45 mg/m 2 /day DNR 90 mg/m 2 /day Probability Month Favorable and Intermediate Cytogenetics Probability Month Unfavorable Cytogenetics Fernandez HF, et al. N Engl J Med. 2009;361(13): Log Rank P = Probability Month All Patients (N = 647) N = 327 N = 330 N = 178 N = 180 N = 63 N = 59 Log Rank P=0.004 Log Rank P = 0.45 DNR 45DNR 90P Induction Deaths4.5%5.5%0.60

8 APL: ATO in induction chemotherapy Randomized, Phase III trial comparing ATRA+ arsenic trioxide (ATO) vs. ATRA+ standard chemotherapy in non-high risk APL (WBC <10K) Primary objective: EFS at 2 years; non-inferiority trial (at least 80% of pts alive and free from events at 2 years) ATRA+ATO vs. AIDA Lo-Coco et al. Abstract No. 6 Plenary abstract

9 ATRA+ATO N=75 AIDA N=79 CR75 (100)75 (95) 2 yr EFS97%86.7% Death in CR13 Death during induction04 Relapse25 Fevers, prolonged neutropenia, and thrombocytopenia more common in chemotherapy arm Hyperleukocytosis more frequent in ATO arm Other events such as differentiation syndrome and increased LFTs similar in both arms One patient in ATO arm discontinued therapy due to prolonged QTc Lo-Coco et al. Abstract No. 6

10 Median follow up 31 months ( ) For patients with newly diagnosed, non-high risk APL, ATO+ATRA induction was at least not inferior for 2 year EFS when compared to standard chemotherapy based regimen Lo-Coco et al. Abstract No. 6

11 Maintenance Therapy with Decitabine in Younger Adults with Acute Myeloid Leukemia (AML) in First Remission: a Phase II Cancer and Leukemia Group B Study (Alliance 10503) William Blum, Ben Sanford, Rebecca Klisovic, Daniel J. DeAngelo, Geoffrey Uy, Bayard L. Powell, Wendy Stock, Maria R. Baer, Jonathan E. Kolitz, Meir Wetzler, Eva Hoke, Clara D. Bloomfield, Susan Geyer, Guido Marcucci, Richard M. Stone, and Richard A. Larson on behalf of the Alliance for Clinical Trials in Oncology

12 Maintenance in AML No compelling data for cytotoxic chemotherapy – Not better than intensive therapy; Cassileth, Blood 1992 – Studied, but abandoned; Mayer, NEJM 1994 – Low dose ara-c q6 weeks showed modest benefit for DFS but not OS in older patients; Lowenberg, JCO 1998 Gemtuzumab ozogamicin, no benefit – 3 courses ineffective in younger patients; Petersdorf, ASH 2009 (S0106) – Ineffective in older patients; Lowenberg, Blood 2010 Immunotherapy – Allogeneic transplantation… – Vaccine therapy (WT1, PR1, hTERT, CD168, etc) promising? – IL-2/ histamine dihydrochloride improved LFS compared to observation; Brune, Blood 2006 – IL-2 efficacious but did not meet survival endpoint; Kolitz, CALGB 19808

13 CALGB newly diagnosed, untreated AML<60 years ADE Core binding factor (CBF) + AML Non-CBF AML High dose Ara-c (HIDAC) x 3 HIDAC/VP chemomob Bu/VP autologous PBSCT (or HIDAC x2) IL-2 maintenance randomization Decitabine maintenance therapy Kolitz, et al, manuscript in review CALGB newly diagnosed, untreated *AML<60 years *including t-AML

14 Primary Endpoint Decitabine given for 1 year following intensive induction and consolidation – DFS – Feasibility, tolerability/ toxicities Detect DFS difference of 15% (at one year) in non-CBF patients – Historical control of previous CALGB trials, identical induction and risk-adapted consolidation therapies

15 Treatment plan: Decitabine Eligible if adequate count recovery within days of last consolidation/autoPBSCT Decitabine 20mg/m 2 /day IV over 1 hour for 5 days * Cycles repeated every 6 weeks Total of 8 cycles (≈1 year post-consolidation) * Dose modifications based on hematologic toxicity

16 Patient characteristics, decitabine Received decitabine, N134 CBF AML, N46 (34%) Non-CBF AML, N88 73 auto + 15 HIDAC Time from induction to maintenance, months 6.3 Median age, years45 (range, 18-60) Median presenting WBC count, x10 9 /L 13.5 (range, )

17 Decitabine administration data, N=132 Total number of cycles given, N770 Median number of cycles given/patient, N7 Treatment duration – Patients who received all 8 cycles, %46 – Patients who received at least 4 cycles, %75 Reasons that < 8 cycles were given – Relapse, %53 – Patient refusal, %25 – Adverse events, %7 – Other, including unknown, %15

18 Myelosuppression and infection, per cycle Adverse EventCycle U Total cycles Grade >3 Neutrophil, N /770 59% Any Grade Infection, N % Infection with Grade >3 Neutrophil, N % Grade >3 Platelets, N % N, Number of patients with adverse event in each cycle U, Unknown cycle number

19 DFS for (and historical control, 19808), based on CBF status DFS, vs , CBF AMLDFS, vs , non-CBF AML

20 DFS for (and historical control, 19808), based on CBF status DFS, vs , CBF AMLDFS, vs , non-CBF AML 10503Historical control, observation/IL-2 1 year OS, %96 3 year OS, %6661/68 1 year DFS, %80 3 year DFS, %5345/56

21 Conclusions For younger patients in CR after induction and consolidation, decitabine maintenance did not improve clinical outcome relative to the historical control For your practice – Maintenance therapy with azanucleosides remains investigational…

22 Relapsed/refractory AML – AC220 Single agent quizartinib (AC220) Phase 2 trials – FLT3 inhibitor – Age >60 years with AML relapsed in <1 yr or refractory to induction chemotherapy (n=134) – Age >18 years with AML relapsed or refractory after salvage chemotherapy or HSCT (n=137) – Both trials included FLT3-ITD positive and negative patients

23 Relapsed/refractory AML – AC220 Age >60 years with AML relapsed in <1 yr or refractory to induction chemotherapy (n=134) – Single agent – CR/CRi/CRp: 54% ITD+ vs. 32% ITD- – Median OS (weeks): 25.3 ITD+ vs ITD- – Most common Grade 3-4 toxicities myelosuppression and QTc prolongation Cortes JE et al. Abstract No. 48

24 Relapsed/refractory AML Age >18 years with AML relapsed or refractory after salvage chemotherapy or HSCT (n=137) – Single agent – CR/CRi/CRp: 44% ITD+ vs. 34% ITD- – Median OS (weeks): 23.1 ITD+ vs ITD- – Primary Grade 3-4 toxicities myelosuppression and QTc prolongation Levis MJ et al. Abstract No. 673 * FLT3 D835 mutations resistant to AC220; new inhibitor, crenolanib, appears to have activity in vitro (Smith CC et al. Abstract No. 141)

25 CALGB /BMT CTN 0502 A Phase II Study of Allogeneic Transplant for Older Patients with AML in First Morphologic Complete Remission Using a Reduced Intensity Preparative Regimen Steven M. Devine, Kouros Owzar, William Blum, Daniel DeAngelo, Richard M. Stone, Jack W Hsu, Richard E. Champlin, Yi-Bin A. Chen, Ravi Vij, James L Slack, Robert J. Soiffer, Richard A. Larson, Thomas C. Shea, Vera Hars, Elizabeth Bennett, Sada Spangle, Sergio A Giralt, Shelly L Carter, Mary M. Horowitz, Charles Linker, and Edwin P Alyea III on behalf of The Alliance and Blood and Marrow Transplant Clinical Trials Network

26 CALGB /BMT CTN 0502 AML CR1, age 60-74AML CR1, age Primary objective 2-year DFS > 35% 90% power to exclude historical DFS < 20% (based on CALGB and multiple cooperative group trials) Stopping rules for TRM Assume true TRM 20% Unacceptable TRM 40%

27 CALGB /BMT CTN 0502 Demographics Related: N=58; Unrelated N=65 Median age 65yrs (60-74); related: 64.5; unrelated: 66 M/F-- 76/47 Cytogenetic risk (CALGB criteria) –Favorable: 1 –Intermediate: 83 –Adverse: 25 –Missing: 14 Donor age (median; range) –Related: 63yrs (43-81); Unrelated: 30 (19-55)

28 CALGB /BMT CTN 0502 Disease free/Overall Survival Median follow up: 3.3 yrs (related: 3.9 yrs; unrelated: 2.9 yrs) DFS at 2 yrs: 39% (95% CI: 30-50%) OS at 2 yrs: 46% (95% CI: 36-57%)

29 MDS Kantarjian, et al--Update on randomized trial placebo vs romiplostim in low/ int-1 risk MDS – Trial had been closed prematurely due to DSM concern of increased transformation to AML in romiplostim arm – Updated data show statistically similar rates of OS and transformation to AML (median f/u 18mo) – Romiplostim showed some evidence of (very modest) efficacy in terms of reducing bleeding complications Kantarjian HM et al. Abstract No. 421

30 MDS Garcia-Manero, et al---Extended dosing of oral azacitidine appears to be safe and effective in lower risk MDS – Response rates 39 or 30% in 14 or 21 day dosing (respectively) – Transfusion independence achieved in 47 or 33% Garcia-Manero et al. Abstract No. 424

31 Relapsed/refractory AML/MDS SGI-110 (n=78 included AML and higher risk MDS) – Single agent, dinucleotide of decitabine/guanosine designed to provide extended exposure with subcutaneous administration – Phase 1-2 PK/PD guided dose-escalation study – Two regimens: daily x 5 doses OR weekly x 3; both with 28 day courses – AML responses (n=44): 2 CRs, 1 CRp, 1 CRi – Dose related hypomethylation observed – Decitabine exposure increased in dose-proportional manner Kantarjian HM et al. Abstract No. 414

32 Conclusions Advances in biology for both AML and MDS, most that are not (yet) clinically relevant for day-to-day clinical practice, will be the cornerstone for novel therapies in the next decade. What about your practice today? For non-high risk APL, ATO-based induction viable option – Albeit an expensive one Maintenance decitabine does not appear to improve outcomes in younger AML patients in CR1 Many promising early phase clinical studies in AML and/or MDS, next year?

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