The Past, Present, and Future of Acute Myeloid Leukemia Carter T. Davis, MD Hematology-Oncology Fellow Duke University Health System September 10, 2016
Overview Overview of Acute Myeloid Leukemia Review of therapeutic advances in AML Acute myeloid leukemia in the modern era Emerging research in the biology and therapy of AML Translational Research in AML
Acute Myeloid Leukemia http://seer.cancer.gov/statfacts/html/amyl.html
Acute Myeloid Leukemia http://seer.cancer.gov/statfacts/html/amyl.html
Acute Myeloid Leukemia Klepin et al. JCO 2014.
Acute Myeloid Leukemia Proliferation of myeloblasts in the bone marrow May have systemic manifestations (constitutional symptoms, skin findings, infections) OR simply be detected as blood abnormality (leukocytosis OR cytopenias) Acute complications may include tumor lysis syndrome and leukostasis
Classification of AML AML with recurrent genetic abnormalities AML with myelodysplasiarelated features Therapy-related AML and MDS AML, not otherwise specified
Historical Perspectives on Therapy - Mainstay of induction therapy has not changed in over 30 years In fit patients, standard induction consists of an anthracycline + infusional cytarabine ( 7+3 ) Over 70% of patients will achieve a complete response with standard induction therapy Induction
Historical Perspectives on Therapy - Consolidation 40% CALGB 9222 Moore et al, Blood. 2005.
AML in the Modern Era Classificaiton and Prognosis
AML in the Modern Era Classification and Prognosis FAVORABLE INTERMEDIATE-1 INTERMEDIATE-2 ADVERSE Döhner H et al. N Engl J Med 2015;373:1136-1152 t(8;21); RUNX1-RUNX1T1 Inv(16) While Mutated useful prognostically, NPM-1 without FLT-3 ITD information Biallelic mutated is often CEBPA not available at the time (without of diagnosis FLT-3) FLT-3 ITD mutation Main influence of prognostic category is in selection of postremission T(9;11)(p22:q23) MLLT3- therapy KMT2A Cytogenetics not classified as favorable or adverse Inv(3)(q21q26.2); GATA2- MECOM (EV11) t(6;9)(p23;q34) Del(5q); -7 Complex karyotype
AML in the Modern Era Classification and Prognosis NPM1 most frequently mutated, favorable outcome, benefit for ASCT in young patients CEBPA Favorable outcome, familial AML FLT-3 Unfavorable outcomes KIT associated with core-binding factor AML; confers unfavorable prognosis in t(8;21) RUNX1 older patients, unfavorable outcomes TET2 unclear significance ASXL1 frequently associated with AML secondary to MDS, adverse prognosis TP53 very poor outcomes, often detected with many other cytogenetic abnormalities Döhner H et al. N Engl J Med 2015;373:1136-1152
AML in the Modern Era Classificaiton and Prognosis
AML in the Modern Era Therapy Advances Daunorubicin 90 mg/m2 vs 45 mg/m2 in patients <60 Fernandez et al. NEJM 2009;361:1249-59
AML in the Modern Era Role of allogeneic SCT Cornellisen and Blaise, Blood 2016;127:62-70
AML in the Modern Era Approach to the Older Patient Patients >65 yo have longer median overall survival with azacitiding compared with conventional care 10.4 months vs 6.5 months Dombret et al. Blood 2015;126(3):291-9
Emerging Prospects in AML- Role of MRD Hills et al. NEJM 2016;374:422-33
Emerging Prospects in AML- Role of MRD Hills et al. NEJM 2016;374:422-33
Emerging Prospects in AML molecular characterization Döhner H et al. N Engl J Med 2015;373:1136-1152
Emerging Prospects in AML Targeted Therapies Döhner H et al. N Engl J Med 2015;373:1136-1152
Midostaurin Median OS: 74.7 vs 26.0 months (p <0.007) Placebo Blood 2015 126:6;
Fingolimod (FTY720) FDA approved drug in the treatment of relapsing/remitting multiple sclerosis Binds to Sphingosine-1- phosphate receptors (S1PRs), which impacts T-cell lymphocyte motility S1PRs internalize with binding of FTY720, resulting in T cells remaining in lymph nodes
SET and PP2A PP2A is a tumor suppressor, implicated in a variety of tumor types SET is a proto-oncogene, which forms complexes with PP2A and inhibits its action FTY720 CIP2A (CML) SET (AML, CLL) PP2A SETBP (AML) FTY720 is capable of disrupting these SET/PP2A complexes and indirectly activating PP2A, resulting in tumor suppression in both in vitro and in vivo models Inhibition of growth Promotion of apoptosis
Research Question Can FTY720 be repurposed as an antileukemic agent that would benefit patients with AML? What is the cytotoxic effect of FTY720 in various patients with AML? Does FTY720 offer synergy to conventional chemotherapeutic agents? Is the cytotoxicity of FTY720 dependent on SET expression in AML?
Cytotoxicity of AML We have evaluated the cytotoxicity of AML using both cell lines and patient samples HL60 cells THP-1 cells IRB Pro00065916 and IRB Pro00006268 Cytotoxicity tested with mitochondrial colorimetric assay (MTS) and by flow cytometry using Annexin V and propidium iodide
MTS Assay Sample HL-60 cell line. N=3
Estimated IC50 of AML Patient Samples PATIENT ID IC50 (μm) DP0341 3.7 DP0313 2.3 DP0331 4.8 DP0332 3.9 DP0355 1.5 MEAN 3.24
Flow cytometric analysis 120% 100% 80% 60% 40% 20% Untreated Cells 0% Annexin V positive PI positive FTY720_2.5uM
Drug synergy experiments IC50: 0 µm FTY720 5 µm FTY720 No drug xxx μm xxx μm Idarubicin 0.02 μm 0.01 μm Cytarabine 0.6 μm 0.4 μm Azacitidine 7.9 μm 6.7 μm Cell line: HL-60 cells
Conclusions of FTY720 Experiments FTY720 is effective in inducing cell death as evidenced by MTS assays and flow cytometry studies Inhibitory concentration of 50% of cells appears to be in the micromolar (1 10) range FTY720 is neither synergistic nor additive to the effects of standard chemotherapy agents used in the treatment of AML
Summary AML remains a burdensome disease with low overall survival and difficult treatment The modern landscape in the diagnosis and management of AML is now incorporating molecular profiles, which may soon aid prognostication Future therapeutic directions in AML will be aimed at molecular targets to improve outcomes and tolerability of medical regimens.