Role of JAK inhibitors and JAK2 V617F mutation monitoring in timing and conduct of transplant in MF Radovan Vrhovac, MD, PhD University Hospital Centre Zagreb, University of Zagreb School of Medicine

Presentation outline Background Timing and choice of candidates for HSCT JAK inhibitors and JAK2 V617F monitoring in the context of HSCT Conclusions

Background Timing and choice of candidates for HSCT JAK inhibitors and JAK2 V617F monitoring in the context of HSCT Conclusions

Background (1/2) Median age of patients with MF is 62-66 yrs Clinical course is very heterogeneous Survival varies (months vs. more than a decade) JAK inhibitors revolutionized treatment of MF, but..

Background (2/2) Allogeneic HSCT remains the only curative treatment. Controversies about: Optimal choice of patients, conditioning and timing of HSCT Place of JAK inhibitors in the pre-HSCT setting Role of JAK2 V617F monitoring in the post-HSCT setting

Background Timing and choice of candidates for HSCT JAK inhibitors and JAK2 V617F monitoring in the context of HSCT Conclusions

Allogeneic HSCT in Myelofibrosis Was traditionally limited to patients aged <60 yrs and those with HLA-identical siblings Historically, high transplant-related mortality due to acute and chronic GVHD Today, increasing use of MUDs and MMRDs1 RIC >>> MAC2 1. Samuelson S et al. Br J Haematol. 2011;153:76-82. 2. Passweg JR et al. Bone Marrow Transplant. 2014;1-7.

Disease indications for an allo-HSCT in Europe in 2012 sdsAD ... number of transplanted patients with MF is expected to increase over time, but HSCT will remain an option only for a minority of MF patients Passweg JR et al. Bone Marrow Transplant. 2014; 1-7

1977-2011 HSCT performed only in a minority of patients (3.4%)

Summary of outcomes of HSCT in MF 1-year NRM ≈ 15-40% 5-year OS ≈ 30-70% Babushok D, Hexner E. Curr Opin Hematol 2014, 21: 114-122

..the risk of allogeneic stem cell-related-complications is justified in transplant-eligible patients whose median survival time is expected to be less than 5 years.

Evolving prognostic scores in MF Lille IPSS DIPSS DIPSS+ Anemia (Hb<10) x Leukocytes ˃25 Blasts ≥1% Constitutional symptoms Age >65 Karyotype (-8, -7, -5, i17q, 12p-, inv 3, 11q23 or complex) Plt <100 RBC transfusion dependent Dupriez 1996 Cervantes 2009 Passamonti 2010 Gangat 2011

DIPSS+ Points DIPSS-low DIPSS-int-1 1 DIPSS-int-2 2 DIPSS-high 3 DIPSS-int-1 1 DIPSS-int-2 2 DIPSS-high 3 Unfavourable karyotype Transfusion dependence Plt<100 Prognostic category Points Median survival (mo) Low 185 Intermediate-1 1 78 Intermediate-2 2-3 35 High 4-6 16 Gangat N. et al. J Clin Oncol 2011; 29: 392

Clonal molecular changes of adverse prognostic significance in MF Gene Overall frequency ASXL1 21.7% EZH2 5.1% SRSF2 8.5% IDH1/2 2.6% Vannucchi AM. et al. Leukemia 2013; 27: 1861

Prognostic effect of calreticulin mutations in MF

Allogeneic HSCT in Myelofibrosis Should be considered in younger, higher risk patients whose survival is expected to be <5 yrs Transplant-related decisions directed by: Prognostic scores Novel prognostic markers Individual perception of benefit/risk of HSCT in a given patient

HSCT outcome according to DIPSS High and intermediate-2 pts have worse outcomes compared to low DIPSS pts Most of the difference attributable to NRM high DIPSS: NRM 3.41 times higher than low DIPSS intermediate-2 DIPSS: NRM 3.19 times higher than low DIPSS Possible reasons: High catabolic rate? Cachexia? Increased cytokine levels? Poor PS? Massive splenomegaly? … Scott BL. et al. Blood 2012; 119:2657

Background Timing and choice of candidates for HSCT JAK inhibitors and JAK2 V617F monitoring in the context of HSCT Conclusions

JAK inhibitor (Company) JAK2 inhibitors Not selective for mutated JAK2 V617F enzyme May benefit patients with and without JAK2 V617F mutation JAK inhibitor (Company) Diseases and studies CEP701 (Cephalon) MF, ET/PV: phase II finished AZD1480 (AstraZeneca) MF: phase I/II finished, development stopped XL019 (Exelixis) SAR302503/TG101348, fedratinib (Sanofi/Targegen) MF: phase I/II/III completed; development stopped BMS-911543 (BMS) MF: phase I/II completed LY2784544 (Lilly) ET/PV/MF: phase I/II completed; MF: phase II ongoing NS-018 (NS Pharma) MF: phase I/II ongoing SB1518, pacritinib (CTI/S*Bio) MF: phase I/IIx2 completed, phase III ongoing CYT387, momelotinib (Gilead/YM/Cytopia) MF: phase I/II QD completed; phase I/II BID completed; phase III ongoing INCB018424/ruxolitinib (Incyte/Novartis) MF: US-approved for intermediate or high-risk MF; EU- approved for disease related splenomegaly or symptoms ET/PV: phase II completed; PV: phase III completed

JAK inhibition before allogeneic HSCT Author N Conditioning Graft failure GVHD II-IV TRM Med. Duration of ruxo. (mos) Spleen response Stop of ruxo. Withdrawal syndrome Stübig et al. Leukemia 2014 22 RIC None 36% 14% 3 45% (>50%) 24% (<50%) At conditioning Jaekel et al. BMT 2014 14 MAC/RIC/ NMA 7% 6.5 64% Tapering off at conditioning Lebon et al. ASH 2013 11 45% N.R. 72% Different Robin et al. 23 (16 eval. for response, 8 HSCT) RIC (Flu/Mel) 2 deaths due to GVHD 50% Severe AE after discontinuation in 10 pts

N=22; Median age 59 years (range: 42-76) 21 patients (96%) had constitutional symptoms and all patients had splenomegaly Median time from start of ruxolitinib to allogeneic HSCT was 133 days and the median treatment duration was 97 days It was planned to give ruxolitinib until first day of conditioning treatment Stübig T et al., Leukemia 2014; Feb 26

Patients characteristics (n=22) JAK2 V617F positive Negative n = 15 n =  7 IPSS at transplant Low Intermediate-1 Intermediate-2 High n = 0 n = 3 n = 14 n = 5 RIC conditioning Busulfan 10 mg/kg / fludarabine Treosulfan 36 g/m2 / fludarabine Melphalan 140 mg/m2 / fludarabine n = 16 n =  3 Donor HLA-identical sibling matched unrelated mismatched unrelated n =  2 n = 14 n =  6 Stem cell source PBSC BM n = 21 n =  1 Stübig T et al., Leukemia 2014; Feb 26

Results Med. duration of ruxolitinib prior to HSCT 97 days (range: 30 – 316) Response to ruxolitinib: Spleen size reduction > 50% Spleen size reduction < 50% No response/loss of response at SCT Constitutional symptoms 45% 23% 31% 86% Graft failure n = 0 Leukocytes > 1.0 x 109/l med. 15 days (10 – 66) Platelets > 20 x 109/l med. 17 days (8 – 122) Acute GvHD II-IV III-IV 38% 27% Stübig T et al., Leukemia 2014; Feb 26

Survival according to spleen response Overall survival Survival according to spleen response at time of HSCT n=12 n=10 p=0.02 Stübig T et al., Leukemia 2014; Feb 26

Immune reconstitution on day 100 (mean) Ruxo (n = 10) RIC without Ruxo (n = 11) CD3+ 1174 / µl 978 / µl CD4+ 159 / µl 139 / µl CD8+ 566 / µl 620 / µl CD4/CD45RA 12 / µl 23 / µl Stübig T et al., Leukemia 2014; Feb 26

JAK inhibition before allogeneic HSCT Author N Conditioning Graft failure GVHD II-IV TRM Med. Duration of ruxo. (mos) Spleen response Stop of ruxo. Withdrawal syndrome Stübig et al. Leukemia 2014 22 RIC None 36% 14% 3 45% (>50%) 24% (<50%) At conditioning Jaekel et al. BMT 2014 14 MAC/RIC/ NMA 7% 6.5 64% Tapering off at conditioning Lebon et al. ASH 2013 11 45% N.R. 72% Different Robin et al. 23 (16 eval. for response, 8 HSCT) RIC (Flu/Mel) 2 deaths due to GVHD 50% Severe AE after discontinuation in 10 pts

JAK2 V617F monitoring post HSCT Rapid clearance of JAK2 V617F mutation is associated with a reduced risk of relapse Lange T et al., Haematologica 2013; 98:772

JAK2 V617F monitoring post HSCT In cases of residual disease persistence, pre-emptive donor lymphocyte infusion can induce molecular remissions All 8 patients with MRD achieved mCR following DLI Kroger N et al. Blood 2009; 113: 1866

Background Timing and choice of candidates for HSCT JAK inhibitors and JAK2 V617F monitoring in the context of HSCT Conclusions

Role of JAK inhibitors and JAK2 V617F mutation monitoring in timing and conduct of transplant in MF Conclusions (1/3) Treatment of MF patients with JAK inhibitors and HSCT not mutually exclusive Ruxolitinib improves performance status and spleen size in the majority of MF patients prior to HSCT Ruxolitinib does not appear to adversely affect early outcome after RIC allo HSCT Preliminary data suggest that patients responding to ruxolitinib prior to HSCT have a more favorable outcome

Role of JAK inhibitors and JAK2 V617F mutation monitoring in timing and conduct of transplant in MF Conclusions (2/3) Only a few studies, limited number of patients, various conditioning regimens Studies have somewhat different results Use of ruxolitinib before transplantation needs further investigation: Timing of drug stoppage? Interaction with other drugs / conditioning regimen? Prospective clinical trials!

Role of JAK inhibitors and JAK2 V617F mutation monitoring in timing and conduct of transplant in MF Conclusions (3/3) Rapid clearance of JAK2 V617F mutation post-transplant is associated with a reduced risk of relapse Monitoring JAK2 mutant allele burden post-transplant can guide prophylactic immunotherapy to prevent or treat relapse

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