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Acute Myelogenous Leukemia and Myelodysplasia- Highlights of ASH 2013

Acute Myelogenous Leukemia and Myelodysplasia- Highlights of ASH 2013. Gary J. Schiller, M.D., F.A.C.P. Professor of Medicine Director Hematological Malignancies / Stem Cell Transplant Program David Geffen School of Medicine at UCLA. A Static Therapeutic Landscape.

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Acute Myelogenous Leukemia and Myelodysplasia- Highlights of ASH 2013

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  1. Acute Myelogenous Leukemia and Myelodysplasia- Highlights of ASH 2013 Gary J. Schiller, M.D., F.A.C.P. Professor of Medicine Director Hematological Malignancies / Stem Cell Transplant Program David Geffen School of Medicine at UCLA

  2. A Static Therapeutic Landscape • Statistical hazards in evaluating new interventions • Limitations on the definition of response viz. survival • Limitations in the regulatory pathway toward approval of novel agents

  3. What Defines Risk in Acute Myelogenous Leukemia? • Clinical Variables • Antecedent hematologic disturbance • Advanced age at presentation • Leukocytosis at presentation • Male gender • Elevated LDH at presentation

  4. What Defines Risk in Acute Myelogenous Leukemia? cont’d… • Biologic Variables • Adverse Cytogenetics • Monosomies • Complex (≥ 3) abnormalities • inv(3), t(3;3), t(6;9), t(6;11), t(9;22), 17p • Less-certain adverse cytogenetic features • 11q23

  5. Refinements in Risk Stratification • Recurrent single-gene mutation • Mutations in kit • flt3 ITD • Routine molecular studies • Investigational molecular studies

  6. Routine Evaluation of AML for the Purpose of Risk-Stratification • STANDARD: Morphology Flow Cytometry / Immunohistochemistry F.I.S.H. for common abnormalities: t(8;21) RUNX1-RUNX1T1 inv(16) or t(16;16) CBFβ-MYH11 t(15:17) PML-RARα t(9;11) MLLT3-MLL inv(3) or t(3;3)RPN1-EVI 1 Karyotype Molecular Studies for mutations in flt3, NPM-1, Kit, CEBPα • POTENTIALLY USEFUL: Molecular studies for mutations in DNMT3a, TET2, MLL, IDH1, IDH2 • INVESTIGATIONAL: Molecular studies for mutations in ASXL1, PHF6, BCOR, CEBPε

  7. Cytogenetic and Molecular Findings Characteristic of Newly-Diagnosed High-Risk AML • Cytogenetic Classification • Intermediate Risk • Normal • +8 • Unfavorable Risk • -5/-7 • 11q23 • 20q- • ≥ 3 abnormalities • Favorable-Risk • t(8;21) • inv(16) or t(16;16) • Mutation • flt3 ITD • Mutant TET2, MLL-PTD, DNMT3a, ASXL1, PHF6 • Kit

  8. Distribution of acute myeloid leukemia patients with intermediate-risk cytogenetics with intermediate mutational risk (Patel JP et al. N Engl J Med.2012;366(12):1079-1089)

  9. Further Clinical Features in Risk-Stratification for AML • Impaired performance status • Co-morbid medical conditions • Disease refractory to conventional induction • Disease relapsed after • allogeneic hematopoietic progenitor cell transplant • recent completion of consolidation chemotherapy

  10. Treatment Strategies for the Management of High-Risk AML • Dose-intensified induction chemotherapy

  11. Dose-Intensified Induction Chemotherapy for AML • No significant survival benefit for AML with flt3 ITD or MLL-PTD. • Survival advantage in favor of higher-dose DNR among those with intermediate- and favorable-risk cytogenetics, not among those with unfavorable-risk karyotype in ECOG study • Greatest benefit in the HOVON/AMLSG/SAKK for high-dose DNR achieved in patients age of 60-65, and for patients with CBF leukemias • No benefit was seen in patients with AML characterized by “very unfavorable” karyotype

  12. Other Dose-Intensification Strategies • Cytarabine • Mitoxantrone and Etoposide • Autologous transplantation

  13. Hazards of Interpreting Trials of Dose-Intensification • Enrollment typically not done on the basis of disease-related or clinical variables • analysis of subgroups, and conclusions, are post-hoc • Randomized trials of novel therapy generally do not restrict or define post-remission management • None of the studies attempt to improve outcome based on distinct AML subtypes

  14. When is Investigational Therapy Warranted for AML? • Refractory and “Early” Relapsed AML • Newly diagnosed AML characterized by adverse cytogenetic + molecular high-risk factors • AML in those over age 70 • Potential Options • Cytotoxic, Molecular, Immunotherapeutic Agents

  15. CLASSIC 1 High-dose Cytarabine +Clofarabine Trial in Refractory and Relapsed AML • Eligible patients • Age ≥ 55 • At least 1, but no more than 2, prior inductions • At least 3 months from last HDAC • Recommended, but not prescribed post-remission treatment plan

  16. CLASSIC 1 Trial Results • Response Rate • EFS at 4 mos • Response Duration • Deaths as a result of AE’s • Survival ara C(1g/m2/d) araC + Clo (40 mg/m2/d) 22.9% 46.9% 16.6% 37.7% 3.8m 7.6m 5.2% 14.3% 6.3m 6.6m

  17. flt3 Tyrosine Kinase Inhibitors

  18. Results of Agents that Target flt3-ITD in AML

  19. Results of Agents that Target flt3-ITD in AML (cont’d)

  20. Results of Agents that Target flt3-ITD in AML (cont’d)

  21. Novel Treatment Strategies for AML

  22. Immunotherapeutic Approaches of High-Risk AML • Tumor Antigens • Immunomodulatory Agents • Induction of autologous anti-leukemia reactivity • Allogeneic hematopoietic stem-cell transplantation

  23. Allogeneic Hematopoietic Stem-Cell Transplantation in High-Risk AML

  24. More Studies of Allogeneic HSCT in High-Risk AML

  25. Potential Flaws in the Methodological Design of Studies in High-Risk AML • Heterogeneous population and disease biology • Heterogeneous post-remission therapy • Heterogeneous end-points that define “success” with an over-reliance on survival as a primary endpoint • Notwithstanding design flaws, several classes of agents are being actively studied

  26. Novel Treatment Strategies in Myelodysplasia

  27. Novel Treatment Strategies for MDS

  28. Novel Treatment Strategies in Myelodysplasia

  29. IPSS-R Cytogenic risk groups

  30. IPSS-R Prognostic Score Values

  31. IPSS-R Prognostic Risk Categories/Scores

  32. IPSS-R: Prognostic Risk Category Clinical Outcomes ***Medians, years ^Median time to 25% AML evolution*Greenberg, Tuechler, Schanz et al, Revised International Prognostic Scoring System (IPSS-R) for Myelodysplastic Syndrome, Blood 120: 2454, 2012.**Schanz J et al, J Clin Oncology 2012; 30:820

  33. Challenges for the Community of Physicians who treat high-risk AML- Summary • Treatment has been developed on the basis of clinical features more often than on biological features • Complete remission has generally been a secondary endpoint of clinical trials • Heterogeneity of post-remission strategies have a significant impact on the use of survival as a primary endpoint • The end-result of clinical-trial strategy has been a static treatment paradigm based on limited drugs

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