Transplantation for Myeloproliferative neoplasms in the JAK inh era PARAMESWARAN HARI MEDICAL COLLEGE OF WISCONSIN MILWAUKEE

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1 Transplantation for Myeloproliferative neoplasms in the JAK inh era PARAMESWARAN HARI MEDICAL COLLEGE OF WISCONSIN MILWAUKEE

2 Abbreviations: HCT, hematopoietic cell transplantation; MF, myelofibrosis; TRM, transplant-related mortality. HCT for Myelofibrosis HCT is the only way of eradication of malignant clone Graft-versus-MF effect and Full resolution of fibrosis Major historic barrier to HCT Perceived risk of non engraftment Myeloablative conditioning and high TRM (30%-45%) Restricted HCT use to younger and fitter patients

3 Case Presentation Patient #1 47 yr old man in March 2000 : Plts -865 x 10 9 / cu.mm Diagnosed with Essential Thrombocytosis after marrow & treated with Aspirin alone found to be JAK2V617F positive Progressive increase in spleen size - 16 cms below LCM CBC in September 2012 Hb 9 g/dl (progressive decline) WBC 17.9 x 10 9 /L with left shift, LE platelets 216 x 10 9 /L, no blasts in PB

4 Case Presentation First transfusion Dec 2012 Marrow biopsy 2012: Grade 2/3 Fibrosis, Cytogenetics 46 XY Post ET-MF according to IMG-MRT criteria Now 59 yrs old at transplant consultation:

5 Audience Question What would you recommend? Wait and Watch Hydroxyurea JAK1/2 inhibitor therapy Reserve transplant (HCT) at failure of JAKI therapy Plan HCT after a response to JAKI therapy Upfront HCT using matched sibling donor

6 Hydroxyurea Splenectomy Low-dose irradiation Only JAK inhibitor currently in advanced development: Therapeutic options available to Treatment for patients with myelofibrosis splenomegaly Ruxolitinib Momelotinib/CYT387 (Gilead) Transfusion support 2 phase III studies completed Erythropoietin Corticosteroids Androgen & prednisone Treatment for anemia Pacritinib (on hold) Novel JAK inhibitors momelotinib IMiDs PRM- 151 Imetelstat Hypomethylating agents Others HiDAC inhibitors SL-401 Combination therapies

7 Transplant Questions Who? WHEN? Balancing Too well to risk it vs. Too ill to do it safely HOW? Integrating JAK inhibitors Before exposure? After response while still responding? After failure of JAK inhibition? Conditioning Dealing with special risks Spleen, Liver / Portal System

8 Guidelines Who to send for HCT consult? Useful to the HCT physician??? Most Use DIPSS or DIPSS plus Most ignore : Leukemic Risk Organ Status The timing question How to transplant & follow

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10 What would you do? 59 yr old man for matched sibling donor allograft for post ET MF Conditioning Regimen: Myeloablative Reduced Intensity If so which regimen? 1. Flu + BU MA 2. Flu + BU RIC 3. Flu + MEL 4. Bu CY 5. Cy TBI

11 Allo HCT Activity for MPN Approx 190 / year now

12 Frequency Regimen Intensity by Year of HCT RIC/NMA MA

13 Probability, % Age at HCT over the past decade < 50 years years years 65 years

14 Probability, % Overall Survival by Year of HCT yr OS 61% 66% 68% 3 yr OS 52% 52% P = NS Years 14

15 Who are the candidates for transplant? DIPSS - Intermediate-2/ high-risk? DIPSS - Intermediate 1 High risk cytogenetics / mutation status Severe cytopenias Transfusion dependent (non-responders to conservative options) Severe thrombocytopenia (<50 x 10 9 /L) blasts in peripheral blood

16 DIPSS Transplant vs non transplant according to DIPSS in patients <65 years p= p= 0.2 Transplant vs medical therapy (JAK#) [poster] Masarova et al., (Mon 6-8pm #4687) p= p= DIPSS = dynamic international prognostic scoring system Kroger et al. Blood ;125(21):

17 Benefits Curative Potential Selection of upfront therapy Risk of early mortality QOL - GvHD - Recurrent infections NO Unfavourable karyotypes High risk of leukemic transformation NO NO YES Patient Factors Advanced age Poor performance status i(17q) Prohibitive co-morbidities Disease Factors High molecular -7/7q- risk NO Severe complications HCT of MF such as ASXL1, EZH2, SRSF2, IDH1/2 portal hypertension & 11q23 rearrangement Guglielmelli et al., pulmonary hypertension Leukemia Risks 2014;28,: Mutation number YES High-risk of 12pleukemic transformation +8 MK 5/5q- YES YES YES Complex karyotype inv(3) YES NO Benefits Usually well-tolerated QOL JAK inhibitor Triple negative therapy/ clinical trial Tefferi et al., Leukemia 2014;28(7): Risks Non-curative Unknown duration of response Tefferi et al., Leukemia. 2012; 26(6): % of patients Gangat et al., J Clin Oncol. 2011; 29(4):392-7 discontinue by 3 Transplant Factors Caramazza et al., Leukemia. 2011; 25(1):82-8 years NO Lundberg et al., Well-matched donor Blood 2014;123(14):

18 Selection of upfront therapy High risk of leukemic transformation Severe thrombocytopenia (50 x 10 9 /L) - Consistent data of higher risk of LT - Minimal data on use of JAK# in these patients - Not usually JAK# candidates Gangat et al., J Clin Oncol 2011; 29: Tefferi et al., Leukemia 2014; 28,

19 Probability, % Donors 100 HLA-identical Sibling Unrelated Donor Others

20 Selection of upfront therapy Benefits Curative Potential NO NO NO Patient Factors Advanced age Poor performance status Prohibitive co-morbidities YES YES YES Benefits Usually well-tolerated QOL HCT NO Disease Factors Severe complications of MF such as portal hypertension & pulmonary hypertension YES JAK inhibitor therapy/ clinical trial Risks Risk of early mortality QOL - GvHD - Recurrent infections YES YES High-risk of leukemic transformation Transplant Factors Well-matched donor NO NO Risks Non-curative Unknown duration of response - 50% of patients discontinue by 3 years

21 % of transplants Should there be an upper age limit? Kroger et al. Blood % 80% 40 years 60% years > 60 years 40% 20% 0% Patients in the transplant age group Usually <70 yrs old (varies by health care setting) Reasonable performance status and no prohibitive co-morbidities Age: 70 years

22 What conditioning? Conditioning Regimen Frequency Percent Fludarabine BU (ablative) Fludarabine Melphalan Fludarabine BU RIC BU CY CY TBI ALL others

23 Probability, % Overall Survival by Conditioning Regimen Intensity MA RIC Ablative P 100-d 86% 85% year 66% 65% 0.75 RIC/NMA 0 3-year 51% 55% Years 23

24 Comparison of MAC vs. RIC N Regimen Age NRM (%) OS Comments Abelsson (52 vs. 40) Patriarca (52 / 48) Ballen (60 / 229) Gupta (23 /23) Flu-BU vs. CY- TBI or BU Thiotepa- CY or Flu BU vs. CY- TBI or BU Variety of regimens Flu-Bu or MEL vs. Cy-TBI Median 55 vs. 46 Novel vs. Traditional D yrs 24 vs. 32% 59% vs. 5 yrs * Median 49 yrs with 13% > 60 yrs. 3 yrs 43% overall and 3 yr 42%. No advantage to novel regimens NOT separately reported No benefit shown for conditioning intensity in multivariate analysis. 54 vs. 47 Day vs. 22% 3 yrs- 27 vs. 48% 68% vs. 48% 3 yrs DLI or AHCT2 needed for RIC recipients Early MF associated with better OS. 10 yr OS for RIC <age 60 ( approx 80%). HCT pre1995, URD and long interval from diagnosis -> worse outcome. Progressive decline in NRM over 20 yrs NRM in sibling graft recipients with RIC was lower 1 yr) than for traditional regimens. RIC recipients -> more advanced disease and poor KPS. Low risk of relapse after either conditioning. Abbreviations: DLI, donor lymphocyte infusion; MAC, myeloablative conditioning; NRM, non-relapse mortality; KPS Karnofsky Performance Score Adapted from Gupta V, et al. Blood. 2012;120:

25 Prospective Multicenter Studies EBMT 1 N = 103 MPD-RC 2 N = 66 Conditioning Flu + BU + ATG (F) Flu + MEL +/- ATG (R) Low-risk patients, % 17% 5% URD, % 68% 52% Survival, % NRM vs. relapse, % 5 y NRM: 3 Relapse: 3 y 78% at 2-yrs (RD) 44% at 1-yr (URD) NRM vs. Relapse death 17% vs. 4% (RD) 53% vs. 3% (URD) Relapse-free survival, % 5 y NR Primary graft failure, % 27%; 11% needed stem cell boost 26% (URD) Abbreviations: F, Fresenius ; MPD-RC, myeloproliferative disease research consortium; RD, related donor; URD, unrelated donor. 1. Alchalby et al. Blood (ASH Annual Meeting Abstracts). 2011;118:1019; 2. Rondelli D, et al. Blood (ASH Annual Meeting Abstracts). 2011;118:1750.

26 Benefits of ruxolitinib Spleen size reduction in myelofibrosis patient treated with ruxolitinib pre-therapy Harrison et al., Leukemia 2016; 30(8): after 2 months of therapy Photos Courtesy of Serge Verstovsek, M. D. Anderson Cancer Center.

27 % discontinuation Limitations of ruxolitinib Disease persistence (non curative) COMFORT-II 5 year study results Limited anti-clonal activity Lack of improvement or worsening of cytopenias Atypical infections Does not risk of LT Rate of discontinuation No convincing effect on bone marrow fibrosis Harrison et al., Leukemia 2016; 30(8): Spiegel et al [poster] #4263 Monday 6-8pm 1 year 2 years 3 years

28 Graft failure prospective studies in MF EBMT N=103 (Kroger et al, Blood, 2009) Low-risk pts 17% 5% MPD-RC N=66 % URD tx 70/103 (68%) 34/66 (52%) (Rondelli et al, Blood, 2014) Survival 78% at 2-yrs (MRD) 44% at 1-yr (MUD) LFS NR Primary graft failure 2%*, 11% needed stem cell boost 24% URD Tx Kroger et al. Blood 2009;114: Rondelli et al. Blood 2014;124: URD = unrelated donor MRD = matched related donor MUD = matched unrelated donor LFS = leukemia-free survival EBMT = European group for blood and marrow transplantation MPD-RC = myeloproliferative disorders research consortium

29 High-risk of graft failure in MF: bad soil or more than that? Potential causes Marrow fibrosis Significant splenomegaly No consistent data Biology of graft failure is poorly understood Transfusion dependency?? Cytokines - TNF-alpha is a negative regulator of expansion and renewal of normal HSC, and facilitates expansion of JAK2+ cells* HSC = hematopoietic stem cell *Bryder D et al J Exp Med 2001;194:941-52

30 First attempt to correlate the neuro-niche model in human BM Arranz et al., Nature Aug 7;512(7512):78-81

31 Transplant when? Overall survival in MF patients transformed to leukemia Upfront: Clinical improvement or stable disease on JAK inhibitor therapy Delayed: Delay the transplant as long as benefiting from JAK inhibitor therapy, and consider transplant if: Intolerant to JAK inhibitors due to toxicities Worsening anemia transfusion dependence / blast count (10-19%) Sub-optimal/loss of response requiring change in therapy Too late: Progressed to leukemic transformation Quite poor Adapted from Shavanas & Gupta, Kennedy Best Pract et Res al,. Clin Blood Haematol. 2013;121: ; 27:165-74

32 Transplant after Leukemic Transformation Mesa et al. (2005) Retrospective review of 91 patients with transformed MF Median survival mo Tam et al. (2008) Retrospective review of 74 patients Median survival of 5 months TRANSPLANT After Leukemic Transformation generally too late Abbreviations: CR, complete remission; MPN, myeloproliferative neoplasm; Ph, Philadelphia chromosome. Mesa RA, et al. Blood. 2005;105: ; Tam CS, et al. Blood. 2008;112:

33 Early vs delayed transplant Outcomes of transplantation in MF according to response to JAK inhibitor therapy Group A: clinical improvement Group BCD: group of others Group E: leukemic transformation Shanavas et al. (2016) BBMT 22(2):432-40

34 Older patient Advanced disease Worse prognostic score Constitutional symptoms Other options have failed Higher risk of HCT failure Timing of Hematopoietic Cell Transplantation in Myelofibrosis Worsening prognostic score Splenomegaly Portal hypertension Iron overload Leukemic transformation Ideal Decision Analysis : Survival time Loss of potential life years with each strategy Quality adjusted life years & costs Risks of delay Modeling different strategies early, late, and risk adapted Younger patient Early disease Better prognostic score Likely to be OK with nonhct Higher chance of HCT success NRM shortening of life span Quality of life impact

35 The price of early transplant Benefits Curative Potential NO NO NO Patient Factors Advanced age Poor performance status Prohibitive co-morbidities YES YES YES Benefits Usually well-tolerated QOL Acute GVHD HCT Risks Risk of early mortality QOL - GvHD - Recurrent infections NO YES YES Chronic GVHD joint contracture Disease Factors Severe complications of MF such as portal hypertension & pulmonary hypertension High-risk of leukemic transformation Transplant Factors Well-matched donor YES NO Chronic GVHD scleroderma NO JAK inhibitor therapy/ clinical trial Risks Non-curative Unknown duration of response - 50% of patients discontinue by 3 years Images courtesy of Dennis (Dong Hwan) Kim, Princess Margaret Cancer Centre

36 Risk Model From EBMT study 3 major prognostic factors: JAK2 wild type Age 57 years Constitutional symptoms Abbreviations: JAK, Janus kinase; SCT, stem cell transplantation. Alchalby H, et al. Br J Haematol. 2012;157:75-85.

37 Do JAK inhibitors have a role in transplant? Graft failure? Bone marrow fibrosis = poor environment for the stem cell Significant Splenomegaly Cytokines? GVHD? Decreased cytokine levels may reduce the risk of severe GVHD Spoerl et al,. Blood. 2014;123(24): Carniti et al., Clin Cancer Res. 2015;21(16): TRM? Better performance status prior to transplant may yield improved outcomes JAK 1/2# 1. Spleen size 2. QoL scores 3. Cytokine levels (anti-jak1 mediated) Improve constitutional symptoms GVHD = graft versus host disease; TRM = transplant-related mortality

38 Robin M, et al. ASH Annual Meeting. New Orleans, Louisiana; December 7-10, Abstract 306. JAK ALLO Recruitment temporarily stopped due to unexpected SAEs Study in progress under modified protocol No. 1 RUXO: spleen 25% FLU,MEL, ATG G APLASIA ENGRAFTMENT TLS Gr 3-4 GVHD D+7 Death 5 months No. 2 RUXO: spleen stable One day FLU + ATG G Stable disease Splenectomy Cardio. shock Alive 11 months No. 3 RUXO: spleen 25% FLU,MEL, ATG G Progressive disease Splenectomy Cardio. shock Multiple thromboses Death 7 months

39 Lessons learnt from retrospective studies on using JAK inhibitor in pre-hct setting Shanavas et al. (2016) BBMT 22(2): All symptoms: 10 Return of MF related baseline symptoms: 6 TLS:1, HA-1, resp failure-2 (transplant delayed) Patient JAK# Interval Events Outcome F 64 PPV-MF F 52 PPV-MF Rux 5m CI Rux 16m SD 10 Pulm-infiltrates, splenomegaly Transplant rescheduled Alive 16 m 7 Fever, hypoxic resp failure Transplant rescheduled. Recurrence 2 nd time. Died d+37 resp failure Incidence: all patients (n=66): 15% JAK-HCT interval 6 days (n=20): 30% JAK-HCT interval <6 days (n=46): 9% p= 0.06

40 Conclusions 1. Selection of patients Individualized decision making at all stages All transplant age appropriate patients should be seen at specialist centre for consideration 2. Transplant vs non-transplant - Complex: transplant, disease, patient factors, other available therapies - Revisit suitability during a patient s disease course (if not used upfront) Continual enrollment into clinical trials is crucial to improve transplant outcomes for MF patients

41 Portal decompression followed by Transplant JAN 2015 JAN 2014

42 Does Fibrosis Resolve? Intra sinusoidal hematopoiesis Patient #1 Common and oft repeated myth that it does not resolve

43 Speed of Resolution of Fibrosis predicts OS Pre transplant 3 months after HCT 12 months after HCT

44 Osteosclerosis resolves too August 2012 August 2013 August 2014

45 Donor Lymphocyte Infusions and Second HCT can Salvage Relapsed Myelofibrosis After HCT N=30 Dose escalated DLI +/- reduced intensity second HCT Klyuchnikov E, et al. Br J Haematol. 2012;159:

46 Summary Increase in hematopoietic cell transplantation (HCT) activity in recent years driven by Ruxolitinib Ruxolitinib taper protocols - safe Reduced intensity conditioning widely practiced now Flu/BU and Flu-MEL Special risk situations related to advanced myelofibrosis Ideal myelofibrosis prognostic classification for HCT undefined Since high level evidence is scant: Patient selection for HCT is an ART in this disease