Myelodysplastic Syndrome MDS and Myelofibrosis Syndromes Whats Next

Myelodysplastic Syndrome (MDS) and Myelofibrosis Syndromes: What’s 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 TET 2 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) – TET 2 mutated mice with MDS treated with hypomethylating agent respond better to azacytidine than TET 2 wild type mice. (Bejar et al. Blood 2014)

Following transplant, certain mutations retain prognostic value • mutations in TP 53, TET 2, and DNMT 3 A 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(5 q) 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-ß 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-SWOG 1117 • SWOG 1117 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 Prébet

High-risk MDS: Rigosertib (ONTIME trial-phase 3 multicenter) • Rigosertib: a novel small molecule inhibitor of PI 3 -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

CALR-mutant MPN patients are characterized by a gene signature associated with activated JAK 2

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 1. 5 Constitutional symptoms 0. 5 Hb <10 g/dl 0. 5 Platelets <200, 000/dl 1. 0 Triple negative (JAK 2, MPL, CALR) 1. 5 JAK 2 or MPL 0. 5 SRSF 2 0. 5 ASXL 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 (c. GVHD) occurred in 49% and relapse (29%) (Kroger et al. Blood 2009)

Prospective Trial MPD-RC 101 with Flu. Mel conditioning (RIC) © 2014 by American Society

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.

And improves survival…. . Overall 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 JAK 2+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=30 K. Bone marrow biopsy showed myelofibrosis, no increase in blasts. Normal cytogenetics • Now what?

Limitations of JAK 2 inhibitor therapy • ineffective in reversing abnormalities in peripheral blood or histopathologic abnormalities in the marrow • eliminating marker cytogenetic abnormalities • Reducing the JAK 2 V 617 F 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 CD 4+ T cell activation and differentiation both in vitro and in vivo (Yajnanarayana. Br J Hem 2015)

JAK 2 inhibitors in development Geyer H L , and Mesa R A Blood

Geyer H L , and Mesa R A Blood 2014; 124: 3529 -3537 ©

Future Directions Alternative pathways to target • • PI 3/Akt pathway m. To. R inhibitors Telomerase inhibitors-Imelstat HDAC inhibitors AB 0024, a monoclonal antibody inhibiting LOXL 2 TGF-βsignaling inhibitor MDM 2 -p 53 inhibitor Aurora kinase inhibitors

Thank you!