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Myelodysplastic Syndrome (MDS) and Myelofibrosis Syndromes: Whats Next? Irum Khan MD Asst. Professor University of Illinois

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Landscape of genetic lesions in 944 patients with myelodysplastic syndromes Haferlach et al. Leukemia 2014

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Cancer cell signaling pathways and the cellular processes they regulate Bert Vogelstein et al. Science 2013;339:1546-1558 Published by AAAS

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Mutations may segregate with clinical subsets Elli Papaemmanuil et al. Blood 2013;122:3616-3627

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IPSS

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Overall Survival, According to Clinical (IPSS) Risk Category and Mutational Status Bejar R et al. N Engl J Med 2011;364:2496-2506.

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MDS treatment algorithm. 2014 by American Society of Hematology

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Mutations to guide therapy Some data to suggest TET2 mutations may predict response to hypomethylating agents Response rate to azacytidine was 82% in MUT versus 45% in WT patients (P=0.007) (Itzykson et al. Leukemia 2011) TET2 mutated mice with MDS treated with hypomethylating agent respond better to azacytidine than TET2 wild type mice. (Bejar et al. Blood 2014)

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Following transplant, certain mutations retain prognostic value Rafael Bejar et al. JCO 2014;32:2691-2698 2014 by American Society of Clinical Oncology mutations in TP53, TET2, and DNMT3A are predictors of survival 60% of patients with MDS without these mutations were alive and disease free 3 years after HSCT.

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MDS-002: Lenalidomide Versus Placebo in RBC-Transfusion Dependent Patients with IPSS Low/Intermediate (Int-1)-Risk MDS without Del(5q) and Unresponsive or Refractory to Erythropoiesis-Stimulating Agents (ESAs) * Discontinuation rate=31.9% in Len arm versus 11% with placebo

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Targeting Smad signaling to alleviate anemia in low risk MDS ACE-536 binds to ligands in the TGF- superfamily, inhibits Smad 2/3 signaling, and promotes late-stage erythroid differentiation 6/7 low transfusion burden patients achieved RBC transfusion independence (RBC-TI) for 8 weeks during the study. 6/19 high transfusion burden patients had a 4 unit or 50% reduction in RBC units transfused over an 8-week Platzbecker et al. ASH 2014. Abstract # 411.

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Combination studies with hypomethylating agents-SWOG1117 SWOG1117 failed to show benefit of combination strategy with vorinostat or lenalidomide Sekeres et al. ASH 2014. Late Breaking Abstract #5

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Thomas Prbet et al. JCO 2011;29:3322-3327 2011 by American Society of Clinical Oncology Patients with failure of hypomethylating agents are challenging due to poor outcomes

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High-risk MDS: Rigosertib (ONTIME trial-phase 3 multicenter) Rigosertib: a novel small molecule inhibitor of PI3-kinase and PLK pathways Improved survival in patients refractory to hypomethylating agents Garcia-Manero et al. ASH 2014. Abstract # 163

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Low dose decitabine- a new look at dosing Complete remission (CR) (normalization of blood counts) : in 4 of 25 HI in 7 of 25 (overall response rate, 44%) subjects these were highly durable, the median duration of treatment-induced freedom from transfusion was 999 days for platelets; and 695 days for RBCs Suanthararajah et al. JCI 2015

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A new conundrum-CHIP (clonal hematopoiesis of indeterminate potential) somatic mutations in hematopoietic cells leading to clonal expansion are commonly acquired during human aging this is associated with an increased risk of subsequent diagnosis of myeloid or lymphoid neoplasia and increased all- cause mortality MDS is defined by cytopenias, dysplastic morphology of blood and marrow cells, and clonal hematopoiesis most individuals who acquire clonal hematopoiesis during aging will never develop MDS Steensma et al. Blood 2015

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MYELOPROLIFERATIVE NEOPLASMS

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Genomic landscape of MPNs Jyoti Nangalia, and Tony R. Green Hematology 2014;2014:287-296 2014 by American Society of Hematology

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CALR-mutant MPN patients are characterized by a gene signature associated with activated JAK2 signaling. Raajit Rampal et al. Blood 2014;123:e123-e133 2014 by American Society of Hematology

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Gangat N et al. JCO 2011;29:392-397 Survival data of 793 patients with primary myelofibrosis evaluated at presentation and risk stratified

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Prognostic impact of molecular features Rumi et al Blood. 2014

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Mutation-Enhanced International Prognostic Scoring System : MIPPS Risk factorsRisk Score Age>60 years1.5 Constitutional symptoms0.5 Hb

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Treatment Options Allogeneic Stem cell transplant is the only curative option for myelofibrosis largest retrospective series (n=289), allogeneic transplantation resulted in long-term relapse-free survival (RFS) in 1/3 of patients. (Ballen et al. Biol Blood Marrow Transplant 2010) RIC transplant study, 5-year DFS was estimated at 51%; chronic graft-versus-host disease (cGVHD) occurred in 49% and relapse (29%) (Kroger et al. Blood 2009)

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Prospective Trial MPD-RC 101 with FluMel conditioning (RIC) Rondelli D et al. Blood 2014;124:1183-1191 2014 by American Society of Hematology

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Challenges and future direction of transplant in MF Hepatotoxicity (Wong. BBMT 2012) moderate/severe hyperbilirubinemia (44% vs 21%, P.02) veno-occlusive disease (36% vs 19%, P.05) Graft Failure prospective study MPD-RC 101: higher rate of primary GF in URD transplantation compared with MSD (25% vs 3%). GVHD Alarmingly high incidence of severe GVHD in URD transplants despite the use of thymoglobulin inflammatory cytokines act as mediators of GVHD

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MPD-RC 114 (open) Ruxolitinib x 56 days (+ 4 of tapering) RIC stem cell transplant with Fludarbine/low dose Busulfan/ ATG

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Will JAK inhibition be helpful in HSCT? Verstovsek S et al., NEJM 2010; 363:1117 Improve engraftment? Reduce GVHD/rejection?

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Phase 3 trial of Ruxolitinib in myelofibrosis Verstovsek S et al. N Engl J Med 2012;366:799-807

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Verstovsek S et al. NEJM 2010 Sep 16;363(12):1117-27. Ruxolitinib suppresses inflammatory mileu in myelofibrosis

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Overall Survival. Verstovsek S et al. N Engl J Med 2012;366:799-807 And improves survival..

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= Which begets the question.. ???

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Case 79 year old Hispanic male was diagnosed with JAK2+ive MF in 2009. He was started on Ruxolitinib for symptomatic splenomegaly in 2011. Did very well on this drug for 2 years. March 2014: presents with anemia, thrombocytopenia and fatigue. Found to have Hb=6, plts=30K. Bone marrow biopsy showed myelofibrosis, no increase in blasts. Normal cytogenetics Now what?

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Limitations of JAK2 inhibitor therapy ineffective in reversing abnormalities in peripheral blood or histopathologic abnormalities in the marrow eliminating marker cytogenetic abnormalities Reducing the JAK2V617F allele burden to a significant degree rapid return of splenomegaly and MF-related symptoms after discontinuation of the drug Effects on immune function ruxolitinib inhibits CD4+ T cell activation and differentiation both in vitro and in vivo (Yajnanarayana. Br J Hem 2015)

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Geyer H L, and Mesa R A Blood 2014;124:3529-3537 2014 by American Society of Hematology JAK2 inhibitors in development

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Geyer H L, and Mesa R A Blood 2014;124:3529-3537 2014 by American Society of Hematology

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Future Directions Alternative pathways to target PI3/Akt pathway mToR inhibitors Telomerase inhibitors-Imelstat HDAC inhibitors AB0024, a monoclonal antibody inhibiting LOXL2 TGF-signaling inhibitor MDM2-p53 inhibitor Aurora kinase inhibitors

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Thank you!