ASBMT MDS/MPN UPDATE

Transcription

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

2 Conflict of Interest None relevant to this talk 2

3 MDS Epidemiology 3

4 MDS MDS is predominant in the elderly (above 65 years of age), but it can also affect younger people. Failure of the bone marrow to produce healthy blood cells is a gradual process & different levels of severity (or prognostic risk categories ) of MDS, include: Very low-risk MDS Low-risk MDS Intermediate-risk MDS High-risk MDS Very high-risk MDS Roughly 30 percent of the patients diagnosed with MDS develop acute myeloid leukemia AML. IPSS-R Variable Cytogenetics V. Good - Good - Int Poor V. Poor BM Blast % 2 - >2 - < >10 - HgB <10 < Platelets < ANC 0.8 < IPSS-R Risk Category Risk Score Very Low 1.5 Low > Intermediate > High > Very High >6 4

5 MDS Treatment is Highly Risk Stratified Lower Risk Observation EPO Lenalidomide Immune Suppression Iron Chelation Higher Risk Azacitidine Decitabine Allo-HSCT Clinical Trials Bejar, Hematologica 2014

6 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

7 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 Bejar, Hematologica

8 Higher Risk Lower Risk MDS IPSS-R Lower Risk Patients with Greater than Predicted Risk: IPSS-R Very Low, Low, or Intermediate risk MDS with <5% blasts, no SF3B1 mutation, and one or more adverse mutations IPSS-R Very Low, Low, or Intermediate risk MDS with 5% blasts and one or more adverse mutations (regardless of SF3B1 mutation status) These criteria would include ~20% of MDS patients The median overall survivals of these patients are 2.2 and 2.3 years Does treatment improve OS and prolong transformation free survival Bejar, Hematologica

9 Current Treatments of MDS Azacitidine improves overall survival, but patients with MDS failing HMA treatment have poor prognosis 1,2 Median overall survival following HMA treatment failure was 5.6 months in higher risk MDS 2 The mechanisms of resistance of HMA treatment failure are not understood HMA, Hypomethylating agents. IM, intermediate. 1. Garcia-Manero G. Semin Oncol. 2011;38: Prebet T. J Clin Oncol. 2011;29:

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 Survival Analysis of High Risk MDS Patients Prebet JCO :

13 Transplantation for MDS: Who, When and Which Conditioning Regimen Patients with Intermed 2 or high risk MDS should be considered for up front HCT However some pts with low risk MDS will have poor long term prognosis and need to be considered for HCT earlier. Currently randomized trials in US and Europe of HCT vs supportive care is ongoing In general, the decision-making process requires balancing the risk of TRM, by considering patient and donor features, and the likelihood of disease control, which requires considering disease risk features with HCT vs non-hct therapy. Saber and Horowitz, ASH 2016 Education Book 13

14 Number of Transplants for MDS by Age; Patients Registered for CIBMTR, Wael Saber, and Mary M. Horowitz Hematology 2016;2016:

15 Transplants for MDS by Donor Type; Patients Registered for CIBMTR, Wael Saber, and Mary M. Horowitz Hematology 2016;2016:

16 16

17 17

18 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

19 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 by Adverse Mutation Status Survival in Complex +/- TP53 Mutation Non-Complex Karyotype (n=59) Complex and TP53 Mut Absent (n=12) Complex and TP53 Mut Present (n=16) Bejar et al., JCO

20 Mutations and Transplantations TP53 present in 19% of pts Lindsley et al. NEJM 2017;376(6): N=1524 pts CIBMTR Transplanted

21 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 21

22 Therapeutic Algorithm for Adult Patients with MDS and (very) Low-Risk or Intermediate IPSS- R Risk Scores Recommendations from an Expert International Panel ** indicates poor-risk features (defined as 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 Theo de Witte et al. Blood 2017;129: by American Society of Hematology 22

23 Therapeutic Algorithm for Adult Patients with MDS and Poor IPSSR scores Recommendations from an International Expert Panel. ** indicates poor-risk features (defined as 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 Theo de Witte et al. Blood 2017;129: by American Society of Hematology 23

24 Categorization of Patients According to the Proposed CIBMTR Prognostic System vs. the IPSS-R. Five prognostic factors age, peripheral blood blasts percentage, cytogenetic findings, performance status, and platelet count. Based on the magnitude of risk, these factors were combined into a risk score that divided patients into 4 risk groups (low, intermediate, high, and very high risk) Wael Saber, and Mary M Horowitz. Hematology 2016;2016:

25 CIBMTR Prognostic score for MDS 577 MDS patients receiving HCT from HLA-matched donors and further evaluated in an independent cohort of 405 MDS patients receiving HCT from HLA-mismatched unrelated donors 25

26 OS for patients with no impairments (score = 0), high HCT-CI comorbidity or IADL impairment (score = 1), or both limitations (score = 2). A. All patients B. Age C. Age 60+ Andrew S. Artz Hematology 2016;2016:

27 MDS and HCT In Summary : 1) Allo HCT is curative in HMA failure patients 2) Cytogenetic and Molecular risk defines outcomes after allogeneic HCT 3) Age and Co-morbidity play a great role in Transplant outcome 4) CIBMTR prognostic score will better predict HCT outcome than the IPSS-R 27

28 Myeloproliferative Neoplasms Mutations have redefined diagnostic criteria for MPNs 28

29 Myelofibrosis: To Transplant or Not to Transplant? At present, hematopoietic cell transplantation (HCT) is the only curative therapy for primary (PMF) and secondary myelofibrosis HCT is associated with risk of treatment-related morbidity and mortality. The optimal timing of transplant thus has to be carefully decided CIBMTR data however show that the number of transplants for MF is increasing over the last decade. Ruxolitinib is the only approved medication for MF and 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 Rebecca Devlin and Vikas Gupta ASH Education Book

30 30

31 31

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 Rebecca Devlin and Vikas Gupta ASH Education Book

33 Rebecca Devlin and Vikas Gupta ASH Education Book

34 Rebecca Devlin and Vikas Gupta ASH Education Book

35 Data from CIBMTR Showing Trends in HCT for Primary MF Between Rebecca Devlin and Vikas Gupta Hematology 2016;2016:

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

37 Progression to Acute Myeloid Leukemia 37

38 Impact of Genomic Alterations on Outcomes in Myelofibrosis Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation ASH 2016 Abstract 2301 Raajit K. Rampal, Roni Tamari, Nan Zhang, Caroline Jane McNamara, Franck Rapaport, Rivka Litvin, Molly A. Maloy, Hugo CastroMalaspina, Sergio Giralt, Rona Singer Weinberg, John Mascarenhas, Ruben A. Mesa, Damiano Rondelli, Amylou C. Dueck, Ross L. Levine, Vikas Gupta and Ronald Hoffman The impact of genomic alterations, such as mutations in ASXL1, on the risk of disease progression post transplant in patients with myelofibrosis (MF) were investigated in 84 patients in multicenter study. Impact of mutations like: U2AF1 ASXL1, EZH2, IDH1/2, and SRSF2, on BMT outcomes were studied in addition to other factors 38

39 Results In an multivariate analysis OS were significantly reduced in the presence of U2AF1 and SUZ12 mutations. P<0.001 In patients without the above mutations, having an unrelated donor was associated with worse OS Importantly, mutations previously reported to be associated with reduced OS and RFS in myelofibrosis, such as ASKL1, EZH2, IDH1/2 and SRSF2 were not associated with reduced survival in this analysis. 39

40 Conclusions: This analysis demonstrates that mutations previously associated with poor prognosis in MF, such as ASXL1, do not appear to confer a worsened prognosis in patients undergoing allo-hsct, suggesting transplant may be able to overcome the impact of these mutations. Further studies with larger cohorts of patients are indicated to validate these findings, and to elucidate the impact of these mutations on disease biology. 40

41 Improved Outcome of Alternative Donor Transplantations in Patients with Myelofibrosis: From Unrelated to Haploidentical Family Donors Stefania Bregante, Alida Dominietto, Anna Ghiso, Anna Maria Raiola, Francesca Gualandi, Riccardo Varaldo, Carmen Di Grazia, Teresa Lamparelli, Silvia Luchetti, Simona Geroldi, Lucia Casarino, Sarah Pozzi, Elisabetta Tedone, Maria Teresa Van Lint, Federica Galaverna, Giovanni Barosi, Andrea Bacigalupo Biology of Blood and Marrow Transplantation : Volume 22, Issue 2, Pages (February 2016) DOI: /j.bbmt Retrospective analysis of 95 patients with myelofibrosis who were allografted between 2001 and Patients were studied in 2 time intervals: 2000 to 2010 (n = 58) and 2011 to 2014 (n = 37). The Dynamic International Prognostic Scoring System score was comparable in the 2 time periods, but differences in the most recent group included older age. 41

42 Transplant Related Mortality and Relapse A. Cumulative incidence of transplantation-related mortality (TRM) stratified by transplantation period (2000 to 2010 and 2011 to 2014). B. Cumulative incidence of relapse stratified by transplantation period (2000 to 2010 and 2011 to 2014). 42

43 Overall Survival- By Transplantation Period 43

44 Outcomes Between HLA Identical Sibling and Alternative Donor Grafts Comparison of outcomes between HLA identical sibling and alternative donor grafts: A. In the 2000 to 2010 a significant advantage is seen for siblings (n = 35) over alternative donor grafts (n = 23). B. In the 2011 to 2014 period, the outcomes of siblings (n = 11) and alternative donor grafts (n = 26) are comparable 44

45 MF Patients Stratified for Transplantation Period and DIPSS Actuarial survival of MF patients stratified for transplantation period and DIPSS. A. In the period (A) patients with DIPSS low, intermediate 1, and intermediate 2 risk scores have significantly superior survival compared with patients with DIPSS high-risk scores. B. In the 2011 to 2014 period, improved survival of high-risk patients can be seen, such that the difference with DIPSS low/intermediate 1/intermediate 2 is not statistically significant (B). 45

46 Conclusions MDS and MPN can be cured by allogeneic transplant Molecular analysis can identify high risk patients even in otherwise low risk categorized patients. Molecular and cytogenetic signature of the disease impacts outcomes even after transplantation Haploidentical transplantation especially with post transplant cyclophosphamide has improved outcomes in patients with MDS and MPN disorders Post transplant strategies to prevent relapse will improve transplant outcomes. 46

47 Timing for HCT Consultation Myelodysplastic syndromes (MDS): Any intermediate or high IPSS or IPSS-R score Any MDS with poor prognostic features, including: - Treatment-related MDS - Refractory cytopenias - Adverse cytogenetics - Transfusion dependence - Failure of hypomethylating agents - somatic mutations Myeloproliferative Neoplasms (MPN): Intermediate- or high-risk disease including: High-risk cytogenetics or molecular changes Poor initial response or at progression SOURCE: NMDP/Be The Match & ASBMT Recommended Timing for Transplant Consultation,

48 Thank You! Contact: Thanks to Drs. Yacoub and Skikne from KUMC for sharing some of their slides.

49