Myelodysplastic Syndrome (MDS) and Myelofibrosis Syndromes: Whats Next?

Myelodysplastic Syndrome (MDS) and Myelofibrosis Syndromes: Whats Next?

Myelodysplastic Syndrome (MDS) and Myelofibrosis Syndromes: Whats Next? Irum Khan MD Asst. Professor University of Illinois Landscape of genetic lesions in 944 patients with myelodysplastic syndromes

Haferlach et al. Leukemia 2014 Cancer cell signaling pathways and the cellular processes they regulate Bert Vogelstein et al. Science 2013;339:1546-1558 Published by AAAS

Mutations may segregate with clinical subsets Elli Papaemmanuil et al. Blood 2013;122:3616-3627 IPSS Overall Survival, According to Clinical (IPSS) Risk Category and Mutational Status

Bejar R et al. N Engl J Med 2011;364:2496-2506. MDS treatment algorithm. 2014 by American Society of Hematology 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) Following transplant, certain mutations retain prognostic value 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. Rafael Bejar et al. JCO 2014;32:2691-2698 2014 by American Society of Clinical Oncology 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 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. 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

Patients with failure of hypomethylating agents are challenging due to poor outcomes Thomas Prbet et al. JCO 2011;29:3322-3327 2011 by American Society of Clinical Oncology High-risk MDS: Rigosertib (ONTIME trialphase 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 Low dose decitabine- a new look at dosing

Suanthararajah et al. JCI 2015 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 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 allcause 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 MYELOPROLIFERATIVE NEOPLASMS Genomic landscape of MPNs 2014 by American Society of Hematology

Jyoti Nangalia, and Tony R. Green Hematology 2014;2014:287-296 CALR-mutant MPN patients are characterized by a gene signature associated with activated JAK2 signaling. 2014 by American Society of Hematology

Raajit Rampal et al. Blood 2014;123:e123-e133 Survival data of 793 patients with primary myelofibrosis evaluated at presentation and risk stratified Gangat N et al. JCO 2011;29:392-397 Prognostic impact of molecular features

Rumi et al Blood. 2014 Mutation-Enhanced International Prognostic Scoring System : MIPPS Risk factors Risk Score

Age>60 years Constitutional symptoms Hb <10g/dl Platelets <200,000/dl Triple negative (JAK2, MPL, CALR) JAK2 or MPL SRSF2 ASXL

1.5 0.5 0.5 1.0 1.5 0.5 0.5 0.5 low (score 0-0.5)

Intermediate-1 (score 1-1.5) Intermediate-2 (score 2-3.5) high (score 4 or greater) Vannucchi et al. ASH 2014. Abstract #405 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)

Prospective Trial MPD-RC 101 with FluMel conditioning (RIC) 2014 by American Society of Hematology Rondelli D et al. Blood 2014;124:1183-1191 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 MPD-RC 114 (open) Ruxolitinib x 56 days (+ 4 of tapering) RIC stem cell transplant with Fludarbine/low dose Busulfan/ ATG Will JAK inhibition be helpful in HSCT?

Verstovsek S et al., NEJM 2010; 363:1117 Improve engraftment? Reduce GVHD/rejection? Phase 3 trial of Ruxolitinib in myelofibrosis Verstovsek S et al. N Engl J Med 2012;366:799-807

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

Verstovsek S et al. N Engl J Med 2012;366:799-807 Which begets the question.. = ??? 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?

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

Geyer H L , and Mesa R A Blood 2014;124:3529-3537 2014 by American Society of Hematology 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 signaling inhibitor MDM2-p53 inhibitor Aurora kinase inhibitors

Thank you!

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