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AML and MDS: Highlights from 2012

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

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AML and MDS: Highlights from 2012

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  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* * International expert panel recommendations on behalf of ELN (Blood 115:453-74, 2010)

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

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

  6. Intensified Induction in AML Patients < 60ECOG E1900 Untreated AML, N=657, median age 47 Induction Post -Remission DNR 45 mg/m2 x 3 days Observation 1-2 course to CR High-dose Cytarabine x 2 + Cytarabine 100 mg/m2 x 7 days Auto- HCT DNR 90 mg/m2 x 3 days Gemtuzumab Ozogamicin 6 mg/m2 IV day 1 (DISCONTINUED) Sibling Allogeneic HCT Fernandez HF, et al. N Engl J Med. 2009;361(13):1249-1259.

  7. Induction Treatment DNR 45 mg/m2/day DNR 90 mg/m2/day ECOG E1900: Overall Survival Favorable andIntermediate Cytogenetics All Patients (N = 647) 1.0 0.9 0.8 0.7 1.0 0.6 N = 178 Probability 0.5 0.9 0.4 0.3 0.8 N = 180 Log Rank P=0.004 0.2 0.7 0.1 0.0 0.6 0 10 20 30 40 50 60 70 0.5 Probability Month N = 327 0.4 Unfavorable Cytogenetics 0.3 1.0 0.9 0.2 N = 330 0.8 Log Rank P = 0.003 0.1 0.7 0.6 0.0 Probability 0.5 0 10 20 30 40 50 60 70 80 0.4 N = 63 0.3 Month Log Rank P = 0.45 0.2 N = 59 0.1 0.0 0 10 20 30 40 50 60 Month Fernandez HF, et al. N Engl J Med. 2009;361(13):1249-1259.

  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 Plenary abstract Lo-Coco et al. Abstract No. 6

  9. 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 (0.07-50.4) • 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 Decitabinein 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 DFSbut not OS in older patients; Lowenberg, JCO 1998 • Gemtuzumabozogamicin, 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 efficaciousbut did not meet survival endpoint; Kolitz, CALGB 19808

  13. CALGB 10503newly diagnosed, untreated *AML<60 years*including t-AML CALGB 19808newly diagnosed, untreated AML<60 years IL-2 maintenance randomization Decitabine maintenance therapy Core binding factor (CBF) + AML High dose Ara-c (HIDAC) x 3 ADE Bu/VP autologous PBSCT (or HIDAC x2) Non-CBF AML HIDAC/VP chemomob Kolitz, et al, manuscript in review

  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 60-90 days of last consolidation/autoPBSCT • Decitabine 20mg/m2/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

  17. Decitabine administration data, N=132 Total number of cycles given, N 770 Median number of cycles given/patient, N 7 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. Myelosuppressionand infection, per cycle N, Number of patients with adverse event in each cycle U, Unknown cycle number

  19. DFS for 10503 (and historical control, 19808), based on CBF status DFS, 10503 vs. 19808, CBF AML DFS, 10503 vs. 19808, non-CBF AML

  20. DFS for 10503 (and historical control, 19808), based on CBF status DFS, 10503 vs. 19808, CBF AML DFS, 10503 vs. 19808, non-CBF AML

  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. 19.0 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. 25.6 ITD- • Primary Grade 3-4 toxicities myelosuppression and QTc prolongation * FLT3 D835 mutations resistant to AC220; new inhibitor, crenolanib, appears to have activity in vitro (Smith CC et al. Abstract No. 141) Levis MJ et al. Abstract No. 673

  25. CALGB 100103/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 100103/BMT CTN 0502 • AML CR1, age 60-74 • 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 100103/BMT CTN 0502Demographics • 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 100103/BMT CTN 0502Disease free/Overall Survival DFS at 2 yrs: 39% (95% CI: 30-50%) OS at 2 yrs: 46% (95% CI: 36-57%) Median follow up: 3.3 yrs (related: 3.9 yrs; unrelated: 2.9 yrs)

  29. MDS • Kantarjian, et al--Update on randomized trial placebo vsromiplostim 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 oralazacitidine 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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