Transcript of Myelodysplastic Syndrome (MDS) and Myelofibrosis Syndromes: What’s Next? Irum Khan MD Asst....
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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!