Allogreffe dans les syndromes myélo-prolifératifs. DU ALLOGREFFE DE CSH 17 avril 2015 Marie Robin, MD, PhD Hôpital Saint-Louis, Paris, France

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1 Allogreffe dans les syndromes myélo-prolifératifs DU ALLOGREFFE DE CSH 17 avril 2015 Marie Robin, MD, PhD Hôpital Saint-Louis, Paris, France

2 Plan Indication de l allogreffe dans les SMP Risques spécifiques Prise de greffe Stratégies d immuno-thérapie et de traitement post greffe Résultats à long terme

3 Gale R P et al. Blood 1998;91: Probabilities of survival in patients with CML who received a transplantation or who dit not No BMT Transplantation: TRM Transplantation: Long-term survivors Same question in all chronic diseases including MPN: when should we take the risk of TRM in patients with a chronic disease not curable without transplantation?

4 When to transplant? if the best available treatment gives survival > 90%! In CML, no more indication to transplant in CP1 Indication are reserved to patient with «poor outcome»: resistant to TKI, in AP or BP Moreover, not all patients with AP benefit from ALLO, depending on risk factor published by Jiang et al (Blood 2011; 117:3032): CML duration > 12 months peripheral blasts > 5% hemoglobin < 10 gr/dl

5 Blood 2011; 117:3032. Jian

6 When to transplant if patient median survival ranges from a few months to > 10 years? In MF, different prognostic scoring systems help to the decision to transplant (LILLE, CERVANTES, DIPSS-plus ) Patients with survival > 4 years (in median) can be postponed to transplantation because median survival after HSCT ranges from 4 to 6 years No study prospectively compares outcome of patients with or without transplantation

7 Score Lille Cervantes IPSS DIPSS Age- DIPSS DIPSSplus Age>65 y Constitutional symptoms Hemoglobin tfs WBC Blasts>1% Platelet < Cytogenetics 1 MEDIAN OVERALL SURVIVAL (months) Low risk Not A. Not A. 185 Intermediate Intermediate (-2) High

8 Impact des mutations somatiques? Blood 2014 Tefferi

9 Leukemia 2014 Vanucchi Blood 2014 Tefferi

10 Mutations et greffes Leukemia 2014 Panagiota

11 Results after allogeneic HSCT - MF N= Median age/ High-int risk Splenectomy TRM Survival 30 % 30% / 76% 49% 27% (1 y) 47% (5 y) 60% / 53% 36% 32% (3 y) 58% (3 y) / 58% 38% ND 61% (5 y) / 90% 38% 43% (3 y) 42% (3 y) / 83% 14% 16% (1y) 67% (5 y) / 64% 24% 35-50%(5 y) 37% (5 y) / 83% 40% 29% (4 y) 39% (4 y) / 75% 21% 28% (1y) 53% (5y) / 88% 25% 24% (5 y) 47% (5y) /84 % 15% 22 (S) vs 59 (UR) 72 vs 32% 1-Blood 1999*2001. Guardiola. 2-Blood Deeg. 3-BBMT Kerbauy. 4-Haemtologica. Patriarca; 5-Blood Kroger; 6-BBMT Ballen; 7-BJH Robin; Haematol 2012 Ditschkowski; BBMT 2014 Gupta; Blood 2014 Rondelli

12 HR: 5,6 HR: 1,6 HR: 0,55 HR: 0,37 DIPSS - Age > 65 y - Constitutional symptoms - Hb < 10 - WBC>25 - Circulating blasts Blood 2015 Kroger

13 Thrombotic / bleeding risk MPN are the main cause of Budd-Chiari syndrome and increased the risk of thromboses MPN is not an independant risk factor for thrombosis but the history of pregraft thrombosis is a risk factor Thrombocytopenia does not protect against thrombosis (most patients have plat < ) The anticoagulation increases the risk of bleeding Venous thrombo-embolism incidence on day 180 is 4,6% Bleeding incidence on day 180 is 15% Blood Gerber 2008;112:504

14 Risk factor for Venous thromboembolism 586 allo 928 auto Blood Gerber 2008;112:504

15 Liver and myelofibrosis Biopsy findings often show minimal changes Hepatic myeloid metaplasia Increased reticulin network: sinusoid or perisinusoid fibrosis Among 97 pts with polycythemia Vera or MF (Hepatology 1990;12:1166) 7 patients had cirrhosis 10 pts had esophageal varices without cirrhosis (lesions «thrombi type» in small and/or medium sized portal veins, 30 had ascitis) Portal hypertension is very frequent in these patients Nodular regenerative hyperplasia also frequent After allo: hepatic fibrosis increased risk of VOD

16 Hyperbilirubinemia after SCT Wong et al. Biol Blood Marrow Transplant. 2012;18(10):

17 How to estimate TRM: EBMT score Donor type Stage of disease Age of recipient at transplantation Sex of donor and recipient Time from diagnosis to transplantation Risk factor HLA identical sibling Unrelated First chronic phase Accelerated phase Other < 20 years years >40 years Other Male recipient for female donor < 12 months > 12 months Score Lancet 1998; 352:1087. Gratwohl et al

18 TRM > 50% when the score > 4 The score has been recently confirmed (BMT 2012 Khoury) The score has been confirmed in patients in chronic phase (BJH 2004 Passweg) The score has been successfully extended to other diseases (BMT 2011 Gratwohl) Lancet 1998; 352:1087. Gratwohl et al

19 Impact of pre-transplant treatment? Controversy with INF IM before SCT is not reported to increase TRM Pregraft IM response influence post-transplant outcome (despite longer time from diagnosis to SCT) Better OS in patients treated by IM before SCT Few data for ruxolitinib before SCT (ongoing prospective phase II study) Blood 2007 Oether, Blood 2008 Lee, Leukemia 2014 Stubig

20 Better outcome in patients with CML receiving IM before transplantation Blood 2008; 112:3500. Lee et al Similar results from Giralt et al. BJH 2007;137:461 and Deiniger et al. Haematological 2006; 91:452

21 What about the spleen in patients with MPN receiving a transplantation? Splenomegaly is associated with delayed engraftment in MF reverted by splenectomy Robin BJH 2010;150:700

22 Controversy on pregraft splenectomy in patients with MPN (MF) Con Comorbidity (hemorrhage, thrombosis, death) Bacterial infection included long-term after HSCT Relapse Liver dysfunction Pro Engraftment (less transfusions, shorter aplasia duration) Survival Relapse Mesa Cancer 2006; Kroger Blood 2009, Robin Leukemia 2005; Lopez- Guillermo Acta Haematol 1991 Rondelli Haematologica 2008, Robin BJH 2011; Bacigalupo BMT 2010

23 Engraftment Many obstacles to engraftment: Proliferative disease «Untreated» patients Splenomegaly Myelofibrosis

24 Engraftment and myelofibrosis Basic data First report in patients with MF (n=55) transplanted after MAC from 1979 to 1997 Engraftment in 80% of patients (KM), influenced by splenectomy, myelofibrosis stage, and number of nucleated cells infused Median time to complete histo-hematological remission: 6 months (1 to 24 months) Engraftment is possible but survival is limited in patients older than 45 years (14%) MF infrequent before 45 years Blood Guardiola

25 Engraftment and RIC Excess of mortality with MAC Age in median 60 years Development of RIC but risk of non engraftment? FLUDA + MELPHALAN in patients > 45 years: 4 pts: all engrafted, no TRM (Blood 2002 Devine) FLUDA + OTHER in patients in median 54 years (Blood 2005 Rondelli, Blood 2009 Kroger)

26 Convinced results for RIC in patients with myelofibrosis 100% of patients «chimerism donor» 100% engraftment DFS: 84% Blood Rondelli BJH Kroger

27 Convinced results for RIC use in patients with CML? Excellent rate of engraftment but less donor chimerism (# 70%) and more relapse Blood 2005;106:2669. Crawley Possible effect of conditioning regimen intensity: RIC do better than NMA (Blood 2012; 119:4086, Warlick)

28 Strategy of RIC + IM +/- DLI 22 pts refered to RIC fluda + bu + alemtuzumab, CSA IM D+35 => 12 months (95% 3 log reduction during IM) 2 graft failures Patients in molecular or CG relapse received escalating dose of DLI after IM discontinuation (n=15) GVHD after a first dose at 10 7 cells/kg; other patients received 10 6 cells/kg without severe GVHD 15 DLI, 10 molecular response 3-y OS = 87% Olavarria Blood 2007;110:4614

29 Is there a graft-versus-mpn effect? CML has been a model for GVL Increased risk of relapse: in patients without GVHD(Enright Blood 1996, Gratwohl Blood 2002) in recipients of T-cell-depleted marrow ( Hessner 1996) in syngenic transplants Efficiency of DLI (Kolb 1990, Cullis 1992a, Kolb 1995) with BCR- ABL as putative leukemia-specific antigen

30 Enright Blood 1996;88:714

31 Increase OS in patients with myelofibrosis transplanted with T-repleted graft Guardiola et al Blood 1999;93:2831

32 Effect of DLI in patients relapsing from myelofibrosis after SCT Kroger Blood 2007; 109:1316

33 BCR ABL monitoring Correlation between bcr abl+ RT PCR and relapse Low positivity can be persistent without relapse Kinetic of increasing BCR ABL levels must be taken into account Relapse 10/70% for pts with PCR+ Relapse < 2% for pts with PCR- Some pts have very late relapse (> 10 years) Blood 1995 Radich; 85:2632; Blood 1996 Lin; :4473; Blood 2006 Kaeda; 107:4171

34 Monitoring of BCR ABL PCR > 0,02% x 4 or > 0,05% x 2 PCR+ PCR- PCR + without criteria for MR Blood 1995 Radich; 85:2632; Blood 2006 Kaeda; 107:4171

35 Molecular Monitoring of BCR-ABL transcripts after HSCT for CML 87 pts with RT Q-PCR analysis, 63 pts with > 2analyses No patients with persistent undetectable transcripts relapsed Patients with low BCR ABL < 0,1% relapsed in 15,8% but relapse did not correlate with the number of occurrence of MRD+ or with the time to the first MRD+ BBMT 2013; 19:735. Arpinati et al

36 TKI or/and DLI? TKI is capable of inducing durable molecular response for CML in relapse after HSCT (BBMT 2010 Wright; 16:639) Excellent response rate with 100% OS for patients in CP, #80% for AP, #20% for BP (Olavarria Leukemia 2003; 17:1707. Kantarjian et al Blood 2002;100:1590) Favorable tolerance of IM after SCT Interruption of IM after SCT is followed by high rate of MR Second-generation TKI seem to have similar efficacy (but more side effect?) Atallah Blood 2006; 108:4520; Kyuchnikeb Acta Haematol 2009;1122:6 Beneficial effect of DLI + IM (Savani et al, BMT 2005;36:1009) DLI in cases of ITK failure (Hess JCO 2005;23:7583)

37 (Savani et al, BMT 2005;36:1009)

38 OS after DLI for CML relapse post SCT Basak (EBMT) BMT 2013, 48:837

39 Molecular monitoring of JAK2 V617F status Development of highly sensitive quantitative real time PCR, the detection of a + PCR predicts the relapse (Kroger, Blood 2007;109:1316) Patients who cleared JAK2-V617F mutation level before the 6th month have less probability of relapse (Alchalby Blood 2010;116:3572) Salvage or pre-emptive DLI based on JAK2- V617F level in blood is efficacious (Blood 2009;113:1866)

40 Place of targeted therapy after HSCT. JAK2 inhibitors JAK2 inhibitors can control constitutionnal symptoms and reduce spleen size JAK2 inhibitors does not induce hematological or molecular remission There is no data for JAK2 inhibitors after SCT in prevention or treatment

41 Monitoring of BCR ABL or JAK2 status Correlation between (quantitative) MRD and relapse Low positivity can be persistent without relapse Kinetic of increasing MRD levels must be taken into account Salvage or pre-emptive therapy (DLI or TKI) is feasable and efficient Some pts have very late relapse (> 10 years) Blood 1995 Radich; 85:2632; Blood 1996 Lin; :4473; Blood 2006 Kaeda; 107:4171, Blood 2007 Kroger; 109:1316, Blood 2010 Alchalby; 116:3572

42 A specificity for long-term FU in patients transplanted for MPD? The main cause of death in long-term survival is reported to be the relapse (NEJM Socie 1999;341:14) Late relapse can occur (> 10 years) Late severe bacterial infections are frequent (37% in a French cohort) (Leukemia Robin 2005;19:1613) A large US study (Blood 2004 Baker; 140:1898) shows that: comorbidities in long-term survivors are > to their sibling (ocular, oral health, endocrine, gastrointestinal, musculoskeletal, neurosensory, and neuromotor impairments) The major risk factor for these comorbidities is the chronic GVHD Overall health was reported as excellent, very good, or good in 78% of subjects

43 Transplant specific issues in MPN: conclusions Item Chronic disease / date of transplant Thrombotic disease Liver disease No chemo before transplantation Targeted inhibitors before transplantation Splenomegaly CONSEQUENCES Choice the best time to transplant balancing TRM risk and disease risk Thrombotic risk / bleeding risk possibly increased Liver toxicity possibly increased No impact Improved outcome (Ruxo?; TKI = yes)) Delay engraftment Splenectomy Accelerate engraftment, relapse? Survival? Myelofibrosis Graft-versus-MPN Molecular marker May delay engraftment YES! Minimal residual disease after SCT Long-term Good quality of life for > 75%