ASBMT MDS/MPN Update Sunil Abhyankar, MD

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1 ASBMT MDS/MPN Update Sunil Abhyankar, MD Professor of Medicine Medical Director, Pheresis and Cell Processing Division of Hematologic Malignancies and Cellular Therapeutics Department of Internal Medicine The University of Kansas Cancer Center 1

2 Conflict of Interest None relevant to this talk 2

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4 NCCN Guidelines Version Myelodysplastic Syndromes 4

5 NCCN Guidelines Version Myelodysplastic Syndromes 5

6 Beyond the IPSS-R IPSS- R does not consider somatic mutations Somatic mutations are common in MDS Several mutated genes have prognostic significance independent of the IPSS-R How to weigh prognostic mutations in clinical practice remains unclear 6

7 Overall Survival by Mutation Number ASXL1 CBL DNMT3A ETV6 EZH2 IDH1 IDH2 JAK2 KRAS NPM1 NRAS RUNX1 SRSF2 TET2 TP53 U2AF1 SF3B1 Overall Survival (%) 17 genes sequenced in 1996 patients with OS data IPSS- R does not consider somatic mutations Somatic mutations are common in MDS Several mutated genes have prognostic significance independent of the IPPS-R How to weigh prognostic mutations in clinical practice remains unclear Bejar, Hematologica

8 Genetic Prognosis Summary Somatic mutations in many genes have prognostic significance independent of the IPSS-R Typical mutations of SF3B1 are associated with favorable risk and longer overall survival Mutations of TP53, EZH2, RUNX1, and PRPF8 are adverse across IPSS-R risk groups Mutations of SRSF2, U2AF1, NRAS, and IDH2, are adverse primarily in lower IPSS-R risk groups Mutations of TP53 are the strongest adverse risk factors even in patients with complex karyotypes 8

9 Survival Analysis of High Risk MDS Patients Prebet JCO :3322 9

10 Definition of HMT Failure Progression of MDS at anytime after HMT therapy Increasing blasts in peripheral blood (or bone marrow) Failure to achieve HI, PR, CR after 4-6 cycles of HMT at standard dosing Progression of disease after initial response (HI/PR/CR) Unable to tolerate HMT due to unmanageable toxicities Severe repeated infections, bleeding, nausea, diarrhea and others Cheson BD, et al. Blood 2006; 108:419 10

11 Overall Survival After 5AC Failure (HR-MDS) Prebet et al, JCO :3322, Jabbour 116:

12 Therapeutic algorithm for adult patients with MDS and (very) low-risk or intermediate IPSS-R risk indicates nonfit (patients with multiple comorbidities and/or poor performance) or fit (patients with no comorbidities and good performance status). * indicates nontransplant strategies according to most recent versions published by international MDS expert groups, including ELN and NCCN. & indicates failure of nontransplant strategies Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel Theo de Witte et al. Blood 2017;129:

13 Therapeutic algorithm for adult patients with MDS and poor IPSS-R indicates nonfit (patients with multiple comorbidities and/or poor performance) or fit (patients with no comorbidities and good performance status). * indicates nontransplant strategies according to most recent versions published by international MDS expert groups, including ELN and NCCN. & indicates failure of nontransplant strategies Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel Theo de Witte et al. Blood 2017;129:

14 MDS Patients Stem Cell Transplant 87 MDS patients transplanted at DFCI from Unknown (9%) Normal (33%) Complex (32%) -7/del(7q) (14%) Ablative Reduced Intensity Bejar et al., JCO

15 Mutations and Transplantation Gene TP53 (n=18) TET2 (n=11) DNMT3A (n=16) Adjusted HR (95% CI) 2.30 (1.10, 4.81) 2.40 (1.07, 5.38) 2.08 (1.00, 3.26) p-value Survival in Complex +/- TP53 Mutation Survival by Adverse Mutation Status Non-Complex Karyotype(n=59) Complex and TP53 Mut Absent (n=12) Complex and TP53 Mut Present (n=16) Bejar et al., JCO

16 Mutations and Transplantation Lindsley et al. NEJM 2017;376(6):

17 Genetic Alterations Predict Outcomes in Patients with MDS Receiving Allogeneic Hematopoietic Stem Cell Transplantation ASH 2016 Abstract 69; R. Coleman Lindsley, MD, PhD et al 17

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20 Transplantation for MDS : who, when and which conditioning regimen Patients with Intermed 2 or high risk MDS should be considered for up front HCT Low/Intermed 1 with high risk features (poor-risk cytogenetic characteristics, persistent blast increase [>50% or with >15% BM blasts], life-threatening cytopenias [neutrophil counts, < /L; platelet counts, <30 109/L], high transfusion intensity 2 units per months for 6 months; molecular testing should be seriously considered, in case of absence of poor-risk cytogenetic characteristics or persistent blast increase) balancing the risk of TRM, patient and donor features, MAC vs RIC Allogeneic HCT Autologous HCT Low/intermeditate-1 risk C N Intermediate-2/high risk S N Myelodysplastic syndromes Therapy related AML/MDS CR1 S 20

21 Myeloproliferative Neoplasms Mutations have redefined diagnostic criteria for MPNs 21

22 NCCN Guidelines Version Myelodysplastic Syndromes 22

23 Myelofibrosis: to transplant or not to transplant? At present, HCT is the only curative therapy for primary (PMF) and secondary (post-essential thrombocythemia or post-polycythemia vera) myelofibrosis (collectively termed MF ). HCT is associated with significant risk of treatment-related morbidity and mortality. The optimal timing of transplant thus has to be carefully decided and HCT CI should be reviewed for transplant risks. Ruxolitinib (Jakafi) has resulted in significant improvement on the QOL of patients with MF and reduction in splenomegaly - However it can cause anemia and low plts about 50% of patients who start the drug will stop in 3 years due to side effects. Use of Ruxolitinib pre HCT one study should detriment in GvHD another showed benefit larger studies needed Rebecca Devlin and Vikas Gupta ASH Education Book

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26 Myelofibrosis: Risk Stratification IPSS DIPSS Cervantes et al., Blood 2009 Passamonti et al., Blood 2010 n=1054 Initial Diagnosis 5 variables Age, Hgn, WBC, PB blast %, Symptoms n=525 Anytime in patient course Same five variables DIPSS - Plus Gangat et al.,jco 2011 n=793 Anytime in patient course DIPSS variables + karyotype, platelet count and transfusion status 26

27 Prognostic Significance of Mutations in MPN 27

28 ASH 2017: Abstract 200 MIPSS70: Mutation Enhanced Prognostic Score System for Transplant-Age Patients with Primary Myelofibrosis Alessandro M. Vannucchi, Paola Guglielmelli, Terra L Lasho, Giada Rotunno, Carmela Mannarelli, Annalisa Pacilli, Animesh Pardanani*, Elisa Rumi, Vittorio Rosti, Curtis A Hanson*, Francesco Mannelli, Rhett P Ketterling*, Naseema Gangat*, Alessandro Rambaldi, Francesco Passamonti, Giovanni Barosi, Mario Cazzola, Tiziano Barbui & Ayalew Tefferi The study included 986 PMF patients divided into learning (n=588) and validation (n=398) cohorts. Screening done for mutations involving JAK2,MPL, CALR, EZH2, ASXL1, IDH1/2 and SRSF2. The clinical variables assessed were those previously identified as being prognostically-relevant by IPSS or DIPSS-plus. The prognostic model (MIPSS) was developed through a stepwise selection process 28

29 MIPSS70-plus Risk Score Variables Associated with Reduced OS Variables HR (95% CI) P Weighted value Hb <100g/L 1.5 ( ) PB blasts 2% 1.6 ( ) Constitutional Symptoms 1.9 ( ) < Absence CALR Type1 2.4 ( ) < HMR* 1.8 ( ) < HMR mutations 2.4 ( ) < Unfavorable Karyotype** 3.1 ( ) < *Any mutation in: ASXL1, EZH2, SRSF2, IDH1/2 ** any abnormal karyotype other than normal karyotype or sole abnormalities of 20q-, 13q-, +9, chr. 1 translocation/duplication, -Y, or sex chromosome abnormality other than -Y. 29

30 MIPSS70-plus Risk Score Risk category Low Intermediate High Very High Score >7 OS (y) HR ( ) 6.4 (4.1-10) 17.0 ( ) In the Italian validation cohort, the 5y survival was: low-risk: 100% intermediate-risk: 90% high-risk: 76%, very high risk: 46.5% Learning cohort: Mayo cohort 30

31 Guglielmelli et al., J. Clin Onc 35 Published online Dec 98,

32 Allo HCT for MF: How should candidates be selected for HCT vs nontransplant therapies? Role of allo HCT well established fro Intermd 2 and high risk features. What is the role of allo HCT in intermed-1 disease? Age, Performance status and co morbidities Donor type What is the optimal timing of HCT Should JAK1/2 inhibitors be part of the HCT? What intensity for conditioning What is the role of splenectomy Alternative donor transplants? Myelofibrosis & myeloproliferative diseases Allogeneic HSCT Autologous HSCT Primary, low risk C N Primary, intermediate/ high risk C N Secondary C N Hypereosinophilic syndromes, refractory R N 32

33 Long-Term Survival in Myelofibrosis after Allogeneic Hematopoietic Cell Transplantation Using Fludarabine/Melphalan Conditioning Regimen Haris Ali, et al ( City of Hope) Blood :199; A total of 110 consecutive patients with MF without prior acute leukemic transformation, underwent allo-hct between 2004 and 2017 at COH. Median age was 58.5 years (range: years) with median interval from diagnosis MF to HCT of 15.2 months (range: months). A majority of patients (n=107) received PB SC. AlloHCT donors were MRD: n=49, MUD: n=32, MMUD: n=27. DIPSS score at the time of allohct was Intermediate-2 or high risk in 83 patients (76%). All patients received FluMel conditioning. Graft-versus-host disease (GVHD) prophylaxis was predominantly sirolimus/tacrolimus-based regimen, n=100 (91%) 33

34 Haris Ali et al. Blood 2017;130: by American Society of Hematology 34

35 Choosing Between Nontransplant Therapies VS HCT for GVHD Rebecca Devlin and Vikas Gupta Hematology 2016;2016:

36 Timing Matters Early referral is perhaps the single most important step that can affect survival. Patients transplanted earlier in their disease have better outcomes than patients with advanced disease, regardless of the degree of match. Pindala J. Blood. 2014; 124(16): Lee SJ et al. Blood. 2007;Vol 110:

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