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Present and Future Impact of Cytogenetics on Acute Myeloid Leukemia
 

Present and Future Impact of Cytogenetics on Acute Myeloid Leukemia

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Cytogenetics is an advancement in which clinicians can look for specific genetic mutations of chromosomal DNA and use that information to determine patient prognosis and individualize therapy. In ...

Cytogenetics is an advancement in which clinicians can look for specific genetic mutations of chromosomal DNA and use that information to determine patient prognosis and individualize therapy. In this presentation I cover what cytogenetics are, how they impact patient risk, what therapies to use based on risk, and how genetically targeted agents may be used in the future.

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    Present and Future Impact of Cytogenetics on Acute Myeloid Leukemia Present and Future Impact of Cytogenetics on Acute Myeloid Leukemia Presentation Transcript

    • Present and future impact of cytogenetics on AML treatment Marti Larriva PharmD Candidate 2014 September 11, 2013
    • Outline  Background  AML  Cytogenetics  Molecular genetics  Current Practice  Prognosis  Treatment  Future Practice  Novel therapeutics
    • Question  What areas of AML therapy are most fluid and subject to change?
    • Background AML, Cytogenetics, Molecular Genetics
    • Acute Myeloid Leukemia  Excessive production of immature myeloblast cells  Anemia  Thrombocytopenia  Neutropenia  Symptoms  Fatigue  Infection Estey EH. Am J Hematol. 2012;87(1):89-99.
    • Cytogenetics  Examines abnormalities of chromosomes  Inversions, translocations, deletion, monosomy http://cnx.org/content/m45467/latest/ Estey EH. Am J Hematol. 2013;88(4):318-27.
    • Molecular Genetics  Examines abnormalities of genes  Most well studied:  NPM1 (27%)  FLT3 (28%)  CEBPA (6%)  c-KIT(4%)  Less well studied:  DNMT3A(26%)  IDH 1 or 2 (20%) Cancer Genome Atlas Research Network. N Engl J Med. 2013;368(22):2059-74.
    • NPM1  Nucleophosmin  Shuttle between cytoplasm and nucleus  NPMc+ = mutation  Better outcomes NPMc+ Loss of function Oncogene Paolo S. Pediatric Reports. 2011;3(s2):11-13.
    • FLT3  FMS-like tyrosine kinase 3  FLT3 – ITD = mutation  Associated with poor outcomes FLT3-ITD Constitutive Activation Proliferation Impaired Apoptosis Leung AY, Man CH, Kwong YL. Leukemia. 2013;27(2):260-8.
    • CEBPA  CCAAT enhancer binding protein alpha  Transcription factor essential for myeloid differentiation  Double mutation (both chromosomes) = better outcomes CEBPA Mutation Lack of transcription factor binding Missing elements for myeloid differentiation Pabst T, Mueller BU. Clin Cancer Res. 2009;15(17):5303-7.
    • c-KIT  Receptor tyrosine kinase  Expressed on surface of hematopoietic progenitor cells  More common in core binding factor (CBF) AML  inv (16) and t (8; 21)  Poor outcomes c-KIT overexpression c-KIT mutation Proliferation and survival Paschka P, Marcucci G, Ruppert AS et al.. J Clin Oncol. 2006;24(24):3904-11.
    • DNMT3A and IDH 1/2 Enzymes involved in epigenetic regulation  DNA (cytosine-5) methyltransferase 3 alpha DNMT3Amut Altered DNA methylation Abnormal silencing and activation of DNA transcription  IDH 1/2 – Isocitrate Dehydrogenase 1 and 2 IDH1/2 mut Neomorphic Activity Depletion of cofactors for epigenetic machinery Gaidzik VI, Schlenk RF, Paschka P et al. Blood. 2013;121(23):4769-77. Rakheja D, Konoplev S, Medeiros LJ et al Hum Pathol. 2012;43(10):1541-51.
    • Complex Heterogeneity Patel JP, Gonen M, Figueroa ME et al. N Engl J Med. 2012;366(12):1079-89.
    • Making sense of it all
    • Current Impact of Cytogenetics Prognosis, Treatment
    • Risk stratification and Prognosis Risk Cytogenetics Molecular Abnormalities 5-year Survival Better Risk Inv (16) t(16;16) t(8;21) t(15,17) Normal cytogenetics: NPM1 w/o FLT3ITD or isolated double mutation CEBPA 55-65% Intermediate Risk Normal cytogenetics +8 only t(9;11) CBF [t(8;21), inv(16), t(16;16)] with c-KIT mutation 24-40% Poor Risk Complex (≥3 abnormalities) -5, -7, 5q-, 7qAbnormalities of 11q23 excluding t(9;11) Inversion 3 t(3;3), t(6;9), t(9;22) Normal cytogenetics: with FLT3-ITD mutation 5-14% National Comprehensive Cancer Network. Acute Myeloid Leukemia (version 2.2013)
    • Treatment  Stratified based upon cytogenetics  Two stages  Induction  Consolidation  HSCT – CR1 vs. CR2
    • Better Risk (Best) Treatment Better Risk CBF AML [inv (16), t(16;16) or t(8;21)] NK with NPM1 mutation and no FLT3-ITD Consolidation Induction CBF with 7+3 (Cytarabine + Daunorubicin) c-KIT +? NK with double mutated CEBPA Yes Dasatinib in clinical trial Estey EH. Am J Hematol. 2013;88(4):318-27. No High Dose Cytarabine
    • Intermediate 1 Treatment Intermediate 1 Risk NK w/o NPM1 mutation or FLT3-ITD Cytogenetic abnormalities other than best or unfavorable Induction 7+3 (Cytarabine + Daunorubicin) Clinical Trial Consolidation Estey EH. Am J Hematol. 2013;88(4):318-27. Matched sibling donor (MSD) HCT High dose Cytarabine
    • Intermediate 2 Treatment Intermediate 2 Risk FLT3-ITD+ Induction Clinical Trial involving FLT3 inhibitor Consolidation Matched sibling donor (MSD) or matched unrelated donor (MUD) HCT Estey EH. Am J Hematol. 2013;88(4):318-27. High dose Cytarabine Clinical trial involving FLT3 inhibitor
    • Intermediate 3 Treatment Intermediate 3 Risk Unfavorable cytogenetics without monosomal karyotype Induction Clinical Trial Consolidation Matched sibling donor (MSD) or matched unrelated donor (MUD) HCT Estey EH. Am J Hematol. 2013;88(4):318-27. Clinical trial for nontransplant candidates HCT clinical trial involving new preparative regimen or means to prevent relapse
    • Poor Risk (Worst) Treatment Poor Risk Monosomal karyotype Induction Clinical Trial Consolidation Matched sibling donor (MSD) or matched unrelated donor (MUD) HCT Estey EH. Am J Hematol. 2013;88(4):318-27. Clinical trial for nontransplant candidates HCT clinical trial involving new preparative regimen or means to prevent relapse
    • Treatment Summary Prognostic Group Subsets Induction Post-Remission Best inv (16), t(16;16) or t(8;21) NK with NPM1 mutation and no FLT3-ITD 7+3 Cytarabine at 1g/m2 BID daily x 6 Dasatinib in clinical trial if CBF with c-KIT mutation NK with double mutated CEBPA Intermediate 1 Intermediate 3 7+3 HCT from matched sibling donor (MSD) Cytogenetic abnormalities other than best of unfavorable Intermediate 2 NK w/o NPM mutation or FLT3-ITD Clinical trial Cytarabine as above or clinical trial if not HCT candidate FLT3-ITD+ Clinical trial involving FLT3 inhibitor HCT from MSD or matched unrelated donor (MUD); consider trial with FLT3 inhibitor Clinical trial HCT from MSD, MUD; consider trial involving new prep regimen or means to prevent relapse after HCT Unfavorable cytogenetics without monosomal karyotype Cytarabine as above or clinical trial if not HCT candidate Clinical trial if not HCT candidate Worst Monosomal karyotype Estey EH. Am J Hematol. 2013;88(4):318-27. Clinical trial As in intermediate 3
    • Future Impact of Cytogenetics FLT3 inhibitors, c-KIT inhibitors, Hypomethylating agents
    • Predicting the future… “While theoretically and technically television may be feasible, commercially and financially I consider it an impossibility, a development of which we need waste little time dreaming.” – Lee DeForest, American radio pioneer, 1926. “Well informed people know it is impossible to transmit the voice over wires, and that were it possible to do so, the thing would be of no practical value.” – Editorial in the Boston Post, 1865
    • FLT3 inhibition  No FDA approval yet  Efficacy and resistance issues  Ongoing trials  Several multi-TKI inhibitors exist – tandutinib, sorafenib, sunitinib, midostaurin, lestaurtinib  Oral FLT3 specific inhibitor – quizartinib  Monotherapy for relapsed/refractory disease after 2nd line chemotherapy or HSCT Patient group FLT3-ITD + FLT3-ITD - All patients CRc 44% OS 23.1 weeks CRc 34% OS 25.6 weeks ≥ 70 years old CRc 53% OS 21.0 weeks CRc 43% OS 19 weeks  DLT – QT prolongation, myelosuppression Grunwald MR, Levis MJ. Int J Hematol. 2013;97(6):683-94. Levis MJ, Perl AE, Dombret H, Dohner H et al. Blood (ASH Annual Meeting Abstracts). 2012; 120:Abstract 673.
    • c-KIT inhibition  No clear clinical benefit, still in clinical trials  c-KIT overexpression in CBF AML  Case reports of success and failure  c-KIT inhibitors – midostaurin, dasatinib, imatinib, nilotinib  Clinical trials evaluating:  monotherapy in relapsed/refractory disease  combination with induction and salvage chemotherapy  combination with low dose chemo for older patients Smith CC, Shah NP. Am Soc Clin Oncol Educ Book. 2013;2013:313-8.
    • Hypomethylation  Use of azacitadine and decitabine increasing  Older adults ≥ 65 + intermediate/poor risk disease  Phase III trial decitabine vs. Treatment of choice (supportive care or low dose cytarabine): Treatment group Decitabine TC P-value OS 7.7 months 5.0 months 0.108 CR 17.8% 7.8% 0.001  Stratification by IDH, TET2, or DNMT3A status? Kantarjian HM, Thomas XG, Dmoszynska A et al. J Clin Oncol. 2012;30(21):2670-7.
    • Combination Regimens  AML Heterogeneity  Multiple mechanisms of therapy
    • AML Clinical trials at Mayo  c-KIT overexpression:  Nilotinib and 7+3 (DATA) – Phase II  Hypomethylation  Clofarabine OR 7+3 followed by decitabine OR Observation (Older patients with newly diagnosed AML)  SGI-110 in intermediate or poor risk MDS or AML- Phase I/II  FLT3-ITD  Midostaurin + SOC vs. SOC post HSCT to prevent relapse- Phase II  Bortezomib + Sorafenib for De Novo AML with high allelic ratio FLT3-ITD – Phase III http://www.mayo.edu/research/clinical-trials/search-results?keyword=acute%20myeloid%20leukemia
    • Summary & Conclusions Tried and true vs. room for something new
    • Summary  FLT3-ITD and c-KIT  Bad prognostic markers  Alternative therapies, HSCT in CR1  Maybe future drug targets  NPM1, double CEBPA  Better prognostic markers  Standard therapy is an option, HSCT in CR2
    • Summary & Conclusions Tried & true  7+3 induction for better risk disease and HiDAC consolidation  HSCT for worst risk disease after first CR Something new?  Molecular targeted therapies (FLT3, c-KIT)  Combination regimens  Bridge to HSCT  Hypomethylating agents  Particularly in elderly population  Characterization of epigenetics for prognosis?
    • References 1. Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059-74. 2. Dohner H, Estey EH, Amadori S et al. Diagnosis and management of acute myeloid leukemia in adults: Recommendations from an international expert panel, on behalf of the european LeukemiaNet. Blood. 2010;115(3):453-74. 3. Estey EH. Acute myeloid leukemia: 2013 update on risk-stratification and management. Am J Hematol. 2013;88(4):318-27. 4. Estey EH. Acute myeloid leukemia: 2012 update on diagnosis, risk stratification, and management. Am J Hematol. 2012;87(1):89-99. 5. Ferrara F, Schiffer CA. Acute myeloid leukaemia in adults. Lancet. 2013;381(9865):484-95. 6. Gaidzik VI, Schlenk RF, Paschka P et al. Clinical impact of DNMT3A mutations in younger adult patients with acute myeloid leukemia: Results of the AML study group (AMLSG). Blood. 2013;121(23):4769-77. 7. Grunwald MR, Levis MJ. FLT3 inhibitors for acute myeloid leukemia: A review of their efficacy and mechanisms of resistance. Int J Hematol. 2013;97(6):683-94. 8. Kantarjian HM, Thomas XG, Dmoszynska A et al. Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. J Clin Oncol. 2012;30(21):2670-7. 9. Leung AY, Man CH, Kwong YL. FLT3 inhibition: A moving and evolving target in acute myeloid leukaemia. Leukemia. 2013;27(2):260-8. 10. Levis MJ, Perl AE, Dombret H, Dohner H et al. Blood (ASH Annual Meeting Abstracts). 2012; 120:Abstract 673.
    • References 11. Magenau J, Couriel DR. Hematopoietic stem cell transplantation for acute myeloid leukemia: To whom, when, and how. Curr Oncol Rep. 2013. 12. Mrozek K, Marcucci G, Nicolet D et al. Prognostic significance of the european LeukemiaNet standardized system for reporting cytogenetic and molecular alterations in adults with acute myeloid leukemia. J Clin Oncol. 2012;30(36):4515-23. 13. National Comprehensive Cancer Network. Acute Myeloid Leukemia (version 2.2013). Accessed 9/8/13. http://www.nccn.org/professionals/physician_gls/pdf/aml.pdf 14. Pabst T, Mueller BU. Complexity of CEBPA dysregulation in human acute myeloid leukemia. Clin Cancer Res. 2009;15(17):5303-7. 15. Paolo S. How does the NPM1 mutant induce leukemia? Pediatric Reports. 2011;3(s2):11-13. 16. Paschka P, Marcucci G, Ruppert AS et al. Adverse prognostic significance of KIT mutations in adult acute myeloid leukemia with inv(16) and t(8;21): A cancer and leukemia group B study. J Clin Oncol. 2006;24(24):3904-11. 17. Patel JP, Gonen M, Figueroa ME et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079-89. 18. Rakheja D, Konoplev S, Medeiros LJ et al. IDH mutations in acute myeloid leukemia. Hum Pathol. 2012;43(10):154151. 19. Smith CC, Shah NP. The role of kinase inhibitors in the treatment of patients with acute myeloid leukemia. Am Soc Clin Oncol Educ Book. 2013;2013:313-8.
    • Questions?