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Acute Promyelocytic and Myelogenous Leukemia

Acute Promyelocytic and Myelogenous Leukemia. Martin S. Tallman, M.D. Chief, Leukemia Service Professor of Medicine Weill Cornell Medical College 11 th Annual Indy Hematology Review March 2014. Disclosure Statement.

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Acute Promyelocytic and Myelogenous Leukemia

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  1. Acute Promyelocytic and Myelogenous Leukemia Martin S. Tallman, M.D. Chief, Leukemia Service Professor of Medicine Weill Cornell Medical College 11th Annual Indy Hematology Review March 2014

  2. Disclosure Statement I, Martin S. Tallman, M.D., DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

  3. Acute Myelogeneous LeukemiaState-of-the Art 2014 • Defined by cytogenetic and molecular interactions • Intensified induction important • Less intensive consolidation chemotherapy? • Increased importance of MRD • Resurrection of auto transplantation? • More patients undergoing allo transplantation • Expanded possibilities for older patients • Targeted therapy for specific molecular genetic abn • Cure of most pts with APL

  4. Focus at ASH 2013: AML • Insights into the natural hx of AML • Lengfelder #1406; Gill #2678; Ganzel #63; Burnett #358; Devillier #66 • Targeting high-risk AML • Uy #2653; Cortes #494; Altman #623; Yen #240; Ramadan #829 3. Targeting low-risk AML • Marcucci #357; Burnett #493

  5. APL 0406 Study-Low-Risk Overall Survival 98.7% 100 91.1% 75 ATRA + ATO Overall survival probability 50 25 ATRA+ATO ATRA+Chemo p=0.02 0 0 12 24 36 48 60 Months from diagnosis Lo Coco et al. NEJM, 2013

  6. European ProjectforSalvageTherapy of Relapsed APL- PROMYSE Registry - Poster 1406, ASH 2013 Eva Lengfelder Department of Hematology and Oncology University Hospital Mannheim

  7. APL Relapse Registry (PROMYSE)Inclusion Criteria • Patients with relapsed APL (first or later molecular, hematologic, extramedullary) • Genetic confirmation of relapse • Any treatment (or non-treatment) option for rAPL • Prospective or retrospective registration • from the year 2003 onwards

  8. Rates of Molecular Remission after Induction and Consolidation with ATO (n=149) Ind Cons Ind Cons 51% 71% 54% Cons Ind 62% 100% 100% hematological extramedullary molecular Type of relapse

  9. OS after First Relapse Treated with ATO n = 149 70% 56% Median follow up 2.8 y (6 d to 10 y)

  10. Outcome After Relapsed APL P=0.4 Lengfelder et al. ASH abstr 1406

  11. Conclusions • With ATO-based salvage therapy over 50% of patients in first relapse can probably be cured • Patients in molecular relapse have a lower rate of early complications and death • Long-term survival is possible with transplantation-free approaches, but transplantation seems to improve the outcome

  12. Oral Arsenic Trioxide-Based Maintenance Without Hematopoietic Stem Cell Transplantation at Second Remission in Acute Promyelocytic Leukemia-A Prospective Follow-up Study of 65 Patients Harinder Gill, MBBS, MRCP (UK)1, Wing-Yan Au, MD2 and Yok Lam Kwong, MD1 1Department of Medicine, The University of Hong-Kong, Hong-Kong, China 2Blood Med Clinic, Hong-Kong, China ASH Abstr #2678

  13. Oral Arsenic Trioxide (ATO)-Based Maintenance in Relapsed APL (N=65) • At Rel1: reinduction w/oral ATO, ATRA , ascorbic acid + ida • In CR2: consolidation w/ida followed by oral ATO x 2 yrs • Rel2 in 33% • OS at 5/10 yr: 87%/75% (male gender, prior oral ATO maint in CR1, CNS involv at relapse a/w inferior OS) • LFS at 2/5 yr: 74%/64% (male gender and prior oral ATO maint in CR1 a/w inferior LFS) Conclusion: Durable remissions and long-tern survival were achieved with oral ATO-based maintenance without the need of autologous HSCT at CR2

  14. Extramedullary Disease Is Common In Newly Diagnosed AML But Has No Independent Prognostic Significance, Including CNS Involvement: Analysis Of 3,522 AML Patients Treated On Consecutive ECOG Trials 1980-2008 CheziGanzel,  Judith Manola, Jacob M. Rowe, Dan Douer, Elisabeth Paietta, Hugo F. Fernandez,  Mark R. Litzow, Ju-Whei Lee, Selina M. Luger, Hillard M. Lazarus, Larry D. Cripe, Martin M. Oken, Peter A. Cassileth,  Martin S. Tallman

  15. % of 3,241 patients Emdsitedistribution

  16. Emdandresponserate • The response rate was equal, with/without EMD (58.8% vs 59.9%) • Spleen involvement tended to compromise response rate compared to the whole cohort (P=0.05) • All other specific EMD sites didn’t impact significantly upon the response rate

  17. Conclusions • EMD is common in newly diagnosed pts (24%) • CNS involvement is rare ~ 1% • EMD rate is similar in pts with favorable and less favorable cytogenetics • EMD doesn’t influence the CR rate, except possibly in splenic involvement • In multivariate analysis, NO independent prognostic impact to EMD, any specific EMD site and number of EMD sites • The impact of EMD among patients with favorable cytogenetics will need to be studied in larger cohorts

  18. Reasons For Survival Improvement In Core Binding Factor AML:  A 25 Year  Analysis Of The UK MRC/NCRI AML Trials Alan K Burnett, Robert K. Hills, Nigel Russell, Donald Milligan, Ann E. Hunter, Richard E. Clark, David Bowen and Mary Frances McMullin On behalf of the UK NCRI AML Working Party

  19. Improvements in outcome for CBF patients (ages 16-59, 1988-2012)

  20. AML15: Use of high dose Ara-C • From 2002-2009, patients were randomised to either receive GO in induction and consolidation and also consolidation with MACE/MidAC or with Ara-C given at either 1.5g/m2 or 3g/m2

  21. OS and RFS: GO + Ara-C FLAG or GO? 5 year survival 89%

  22. Summary • GO is the most significant factor associated both with survival and survival from remission • Effect is independent of type of CBF leukaemia • Ara-C and FLAG-Ida improve relapse free survival but not significant in survival endpoints • In this dataset the combination of GO in induction the HiDAC consolidation gives the best survival (89% at 5 years) • Whether FLAG-Ida is the optimal induction will be tested in our AML19 trial

  23. Induction therapy for AML patients with daunorubicin dose of 60 mg/m² and 90 mg/m² results in similar complete response rate, relapse-free and overall survival RaynierDevillier, MD. ASH 2013 Oral session 613, abstract #66

  24. Introduction • High dose daunorubicin 90 mg/m²/d is a standard • Improved outcome compared with 45 mg/m²/d Fernandez et al. NEJM 2009 Löwenberg et al. NEJM 2009

  25. Response to Induction Therapy

  26. OverallSurvival DNR 60 (n=340) DNR 90 (n=62) 59% Overall Survival 52% p=0.364 24 mo Months after induction therapy

  27. Non Relapse Mortality and Relapse DNR 60 (n=275) DNR 90 (n=55) DNR 60 (n=275) DNR 90 (n=55) Non Relapse Mortality Relapse 11% vs. 12% p=0.944 42% vs. 39% p=0.994 Months after CR/CRi Months after CR/CRi

  28. Conclusions • DNR 60 and 90 mg/m² produce similar outcome • NRM after Allo-HSCT is not increased in DNR 90 • Molecular markers are needed in this situation • DNMT3a mutations • La Rochelle et al. Oncotarget 2011 • Patel et al. NEJM 2013 • CBF leukemia • Prebet et al. ASH 2013, Poster #2681

  29. Targeting High-Risk Disease • FLT3-ITD: novel inhibitors • Sorafenib • AC220 (Quizartinib) • IDH1/2: novel inhibitors • AG221 • MLLleukemias: enzymatic activity of the protein methyltransferase DOT1L has been shown to be a driver of cell proliferation in MLL-rearranged leukemia - aminonucleoside inhibitors of DOT1L

  30. Initial Results Of a Phase II Trial Of Sorafenib Plus Standard Induction In Older Adults With Mutant FLT3 Acute Myeloid Leukemia (AML) (Alliance trial C11001) Geoffrey L. Uy, Ben L. Sanford, Guido Marcucci, Weiqiang Zhao, Susan A. Geyer, Heidi D. Klepin, Bayard L. Powell, Maria R. Baer, Wendy Stock, Richard M. Stone and Richard A. Larson for the Alliance for Clinical Trials in Oncology

  31. Schema Induction 7+3 + Sorafenib Ara-C 100 mg/d CIVI D1-7 DNR 60 mg / m2 / d D1-3 Sorafenib 400 mg PO BID d1-7 Eligibility Criteria -Age ≥ 60 -FLT3 mutation (ITD or point mut) -No t(15;17), t(8;21) or inv(16) -2nd AML allowed if no prior tx for MDS/AML Primary Endpoint -1 yr OS of FLT-3 ITD pts only (Δ from 30% to 50%) No CR CR 5+2 + Sorafenib CR Consolidation 2 cycles q4-6wks IntDAC #1 Ara-C 2 g/m2/ d d1-5 Sorafenib 400 mg PO BID d1-28 IntDAC #2 Ara-C 2 g/m2/ d d1-5 Sorafenib 400 mg PO BID d1-28 Maintenance Up to 12 cycles Sorafenib 400 mg PO BID d1-28

  32. Response to Induction • 41/54 achieved CR (36) /CRi (5) (76%) • 4/54 (7%) of patients died within 30 days of starting their most recent induction. • No additional patients died within 60 days.

  33. Conclusions • Rapid screening for FLT3mutations feasible • Sorafenib for older adults with AML • associated with a high rate of CR • relatively low risk of mortality during induction • acceptable toxicity profile. • Follow-up for Primary endpt 1 yr OS ongoing • Correlative studies ongoing

  34. Results Of a Phase 2 Randomized, Open-Label, Study of Lower Doses of Quizartinib (AC220; ASP2689) In Subjects With FLT3-ITD Positive Relapsed or Refractory Acute Myeloid Leukemia (AML) J. E. Cortes1, M. S. Tallman2, G. Schiller3, D. Trone4, G. Gammon4, S. Goldberg5, A. E. Perl6, J-P. Marie7, G. Martinelli8, M. J. Levis9 1The University of Texas M. D. Anderson Cancer Center, Houston, TX 2Memorial Sloan-Kettering Cancer Center, New York, NY 3UCLA School of Medicine, Los Angeles, CA 4Ambit Biosciences Corporation, San Diego, CA 5Hackensack University Medical Center, Hackensack, NJ 6University of Pennsylvania, Philadelphia, PA 7Saint-Antoine Hospital, Paris, France 8University of Bologna, Bologna, Italy 9Johns Hopkins University School of Medicine, Baltimore, MD

  35. Lower Dose QuizartinibInitial Results: Overall Response

  36. Lower Dose QuizartinibInitial Results: Overall Survival by Dose • Thirty-seven subjects (49%) remain censored for overall survival (2 randomized but not treated; and 35 subjects remain alive). • Of the 35 subjects who remain alive (range: 7.4 – 40.4+), there are 24 subjects alive >24 weeks and 2 alive >36 weeks (37.9+ weeks, and 40.4+ weeks).

  37. Lower Dose QuizartinibInitial Results: Conclusions • Sustained efficacy and decreased QT signal with lower doses of quizartinib • Efficacy • Substantial activity at both doses • Safety • Similar safety profile at 30 and 60 mg doses • QTcF prolongation dose dependant: decreased QTcF at 30 and 60 mg doses compared to prior Phase 2 Study at 90mg and 135 mg/day • Next Step: • Global phase 3 randomized study of quizartinib in FLT3-ITD(+) patients in 1st relapse planned to start in early 2014

  38. What’s New in FLT3 Inhibition? • Combination with chemotherapy (Altman #623 ASH 2013); maintenance strategies • Resistance occurs - Constitutively Activating Mutations at the FLT3 Activation Loop Residue D835 Are Associated with Clinical Resistance to AC220 • Development of agents active against D835 - Crenolanib

  39. IDH1 Mutant Inhibitor Induces Cellular Differentiation and Offers a Combination Benefit with Ara-C in a Primary Human IDH1 Mutant AML XenograftKatharine Yen, PhD, Rene Lemieux, PhD, JanetaPopovci-Muller, Yue Chen, PhD, Hua Yang, Kim Straley, Sung Choe, Marion Dorsch, Samuel Agresta, MD, Davod P Schenkein, MD, Scott Biller, Michael Su, Fang Wang.

  40. Breakdown of IDH Mutations in AML IDH1m (7.5%) in AML IDH2m (15%) in AML

  41. AG-221 Offers Survival Advantage In a Primary Human IDH2 Mutant AML Xenograft Model • Potentselective inhibitor • of IDH2 mutant enzyme • Phase I trial is underway • Reduces –HG levels by >90% • Reduces histone and DNA • hypermethylation in vitro • Induces differentiation in • leukemia cell models

  42. Survival Improvement of Secondary Acute Myeloid Leukemia Over Time: Experience From 962 Patients Included In 13 EORTC-GIMEMA-HOVON Leukemia Group Trials Safaa M. Ramadan, MD, PhD; Stefan Sucia, PhD, Marian J-P-L Stevens-Kroef, PhD, RoelofWillemze, MD, PhD, Sergio Amadori, Theo De Witte MD, Bob Lowenberg, MD, PhD, Petra Muus, MD, PhD, Boris Labar, MD, PhD, LivMeert, Gaetan de Schaetzen, Giovanna Meloni, MD, Giouseppe Leone, MD, MafrcoVignetti, Franco Mandelli, MD, Frederic Baron, MD, PhD, Jean-Pierre Marie, MD ASH Abstr #829

  43. Secondary AML (sAML) • 13 EORTC collaborative trials 1986-2008 • N=8,858 • Med age 63 yrs (range 16-85) • Cohort A-after MDS N=509 • Cohort B-after other malignant diseases N=362 • Cohort C-after nonmalignant conditions and/or toxic exposure N=91

  44. Secondary AML • CR in pts </=60 • 59%; 55% in SD-Ara-C and 89% in HD-Ara-C • Allo in 21%; 5%<1990 and 25% >2000 • CR in pts 61 and > • 45% • Med OS • 14.5 mo in young and 9 mo in elderly • 5-yr OS • 28% in younger and 11% in elderly Conclusion: Outcome of sAML in younger pts has improved in parallel with HD-Ara-C in induction of remission. HD-Ara-C should be considered for younger pts with AML

  45. Targeting Low-Risk AML

  46. Adding the KIT inhibitor Dasatinib (DAS) to standard induction and consolidation therapy for Newly Diagnosed Patients with Core Binding Factor (CBF) Acute Myeloid Leukemia: Initial Results of the CALGB 10801 (Alliance) study Guido Marcucci, Susan Geyer, Weiqiang Zhao, Andrew J. Carroll, Donna Bucci, Bayard L. Powell, William Blum, Geoffrey L. Uy, Meir Wetzler, Wendy Stock, Clara D. Bloomfield, Richard A. Larson, and Richard M. Stone on behalf of the Alliance for Clinical Trials in Oncology

  47. Rationale • The overall survival for patients with CBF AML, a favorable cytogenetic subset with t(8;21) and inv(16), is only 55-60%. • KIT mutations, which result in a constitutively active tyrosine kinase, are present in ~ 25-30% of CBF AML, and are associated with worse outcomes. • Wild-type KIT is also over-expressed in CBF AML. • In this study, we tested a combination of the tyrosine kinase inhibitor dasatinib plus chemotherapy to improve the current results in CBF AML.

  48. Why Dasatinib? KIT mutations are associated with a higher frequency of relapse in CBF AML.

  49. CALGB 10801A Phase II Study of Induction (Daunorubicin/Cytarabine) and Consolidation (High-Dose Cytarabine) Chemotherapy Plus Dasatinib in Newly Diagnosed CBF AML PRE-REGISTRATION REGISTRATION CR SCREENING Ara-C Daunorubicin + Dasatinib X 1-2 courses High-dose Ara-C + Dasatinib X 4 cycles Dasatinib X 12 months Remission induction Remission consolidation Maintenance

  50. Clinical Outcomes(median follow up of 14 months) • 30-day survival rate = 97% (95% CI: 89 -100%) • CR rate = 89% (95% CI: 78 - 95%) • 91% for patients < 60 years old • 80% for patients > 60 years old • 12-month EFS rate = 85% • 12-month OS rate = 89% • 20 patients still continue on treatment • 2 patients (3%) have had progression or relapse

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