Whom should you refer for allogeneic transplantation? - Those with the best performance status will gain the greatest benefit - Srdan (Serge) Verstovsek M.D., Ph.D. Professor of Medicine Department of Leukemia University of Texas MD Anderson Cancer Center Houston, Texas, USA 1

Allogeneic HCT in Myelofibrosis Consider in younger, higher risk patients whose survival is expected to be <5 years Traditionally limited to patients aged <60 years and those with HLA-identical sibling match, although increasing use of MUDs and MMRDs1 High transplant related mortality due to acute and chronic GVHD Estimated 1-year treatment-related mortality: approximately 30%2-5 OS with alloSCT: approximately 50%2-4 BOTTOM LINE: less than 10% of patients undergo SCT IPSS high risk Median survival: ~27 mo IPSS intermediate-2 risk Median survival: ~48 mo alloSCT: allogeneic stem cell transplant; GVHD: graft-versus-host disease; HLA: human leucocyte antigen; IPSS: International Prognostic Scoring System; MMRD: mismatched related donors; MUD: matched unrelated donor. 1. Samuelson S et al. Br J Haematol. 2011;153:76-82. 2. Ballen KK et al. Biol Blood Marrow Transplant. 2010;16:358-367. 3. Kroger N et al. Blood. 2009;114:5264-5270. 4. Patriarca F et al. Haematologica. 2008;93:1514-1522. 5. Bacigalupo A et al. Bone Marrow Transplant. 2010;45:458-463.

Performance Status is a negative risk factor for survival after HCT

Splenomegaly is a negative risk factor for survival after HCT Risk variables Spleen >22 cm Transfusions >20 Donor other than HLA-id sibling Low risk= 0-1 variables High risk= >2 variables 1 Bacigalupo A, BMT 2010; 45:458-63

Potential Impact of JAK2 Inhibitors on HCT Therapeutic Decisions   McLornan DP, BJH 2012; 157:413-25

Spleen Volume Response: Ruxolitinib vs. BAT 132 (97%) 35 (56%) ↑ Spleen volume 4 (3%) 28 (44%)

Improvement in Symptoms Worsening Improvement * Fatigue * Dyspnea * Appetite loss * Insomnia * Pain * Diarrhea Nausea/vomiting Constipation Financial impact Overall Adjusted Mean Change From Baseline Score Ruxolitinib BAT

Improved Exercise Capacity and Body Weight 6-minute walk test (6MWT) is well established measure of exercise capacity MF patients walk 60-90 meters less than age-matched healthy volunteers 28 56 84 112 140 168 -9.5 -7.5 -5.5 -3.5 -1.5 0.5 2.5 4.5 6.5 8.5 10.5 12.5 Mean Lowest Quartile Days on Study Change in Body Weight, kg Ruxolitinib phase I/II

Efficacy of ruxolitinib in patients with MF without clinically significant splenomegaly Fatigue improved 6 Resolution of night sweats 2 Itching Weight gain (up to 17%) 5 Improved performance status Reduction of liver size 50-68% 3 of 3 All pts were symptomatic Ruxolitinib was administered at the dose of 25mg BID Benjamini et. al., Blood 2012; 120:2768-2769

Overall Survival: ruxolitinib vs. BAT (int-2/high risk MF) 52% reduction in risk of death in the ruxolitinib arm compared to BAT arm (HR = 0.48; 95% CI, 0.28-0.85; log-rank P = .009)

What happens if therapy with ruxolitinib is interrupted? Number of patients: 34 33 33 34 34 33 33 33 36 37 39 40 40 40 34 29 26 23 24 24 22 22 22 20 21 20 18 17 15 Days Around Dose Change Return of the symptoms within 7 days

Ruxolitinib as Pretreatment Before Allogeneic Stem Cell Transplantation For Myelofibrosis N=22; Median age 59 years (r: 42 – 76) 21 patients (96%) had constitutional symptoms and all patients had splenomegaly Median time from start of ruxolitinib to allogeneic SCT was 133 days and the median treatment duration was 97 days It was planned to give ruxolitinib until first day of conditioning treatment Busulfan 10 mg/kg / fludarabine most commonly used (n=16) conditioning Nicolaus Kröger at al. Abstract 392

Results overall at transplant Med. duration of ruxolitinib prior to SCT 97 days (r: 30 – 316) Response to ruxolitinib: Spleen size reduction > 50% Spleen size reduction < 50% No response/loss of response at SCT Constitutional symptoms 45% 41 % 23% 14 % 31% 45% 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% overall at transplant Immunoreconstitution on day 100 not affected

Survival according to response at time of SCT response yes n=12 no / lost response n=10 p=0.02

Conclusions Ruxolitinib improves performance status and spleen size in the majority of myelofibrosis patients prior to allogeneic stem cell transplantation Ruxolitinib does not appear to adversely affect early outcome after reduced allo HCT Preliminary data suggest that patients responding to Ruxolitinib have a more favorable outcome to those who received the transplant after loosing response or being refractory to Ruxolitinib

Ruxolitinib Before HCT: The JAK-ALLO Study Design Lille Or IPSS Primary or secondary MF High- or intermediate-risk patients HLA-matched sibling: 9/10 or 10/10 UR Donor search 15 mg BID Progressive ↕ day -1 Ruxolitinib 4 months No donor Fludarabine 90 mg/m2 Melphalan 140 mg/m2 Donor Ruxolitinib Splenectomy? Allo SCT Robin M. ASH 2013. Abstract 306.

17 patients with a donor on ruxolitinib 16 patients eligible for HSCT JAK-ALLO: Results 17 patients with a donor on ruxolitinib 16 patients eligible for HSCT 2 TLS after conditioning regimen 5 deaths after transplantation (incl. acute GVHD) 1 graft rejection 1 cardiogenic shock 11 days after HSCT 3 splenectomies 14 HSCT Robin M. ASH 2013. Abstract 306.

“Allogeneic hematopoietic cell transplantation for myelofibrosis in patients pretreated with ruxolitinib” 14 patients (median age 58 years) Before ruxolitinib, allogeneic HCT was not considered to be the appropriate median exposure of 6.5 months to ruxolitinib MF-related symptoms were ameliorated in 10 (71.4%) patients and palpable spleen reduced by a median of 41% in 7 (64%) of 11 patients with splenomegaly. ruxolitinib was continued up to the day preceding the start of the conditioning regimen related (3) and unrelated (11) donors Median follow-up was 9 months Jaekel N, Behre G, Behning A, Wickenhauser C, Lange T, Niederwieser D, Al-Ali HK. Bone Marrow Transplant. 2014 Feb;49(2):179-84.

Conditioning: fludarabine-based RIC in 11 (78.6%) (with busulphan p.o. in 7 and TBI in 4), and myeloablative conditioning in 3 (21.4%) patients. engraftment in 13 (93%) patients, acute GvHD grade-III occurred in 2 (14%) patients Survival, EFS and treatment-related mortality were 78.6, 64 and 7%, respectively overall probability of survival at 1 year was 50%

Why the Difference in Results? Small trials with limited numbers of patients Different conditioning regimens Contradictory results suggest that combination of ruxolitinib in transplant protocols should be used with caution Appropriate drug regimen and timing of stoppage of therapy must still be determined The use of ruxolitinib prior to transplant should be preferentially used as part of prospective clinical trials or at experienced centers

Potential Impact of JAK2 Inhibitors on HCT Therapeutic Decisions   McLornan DP, BJH 2012; 157:413-25

THANK YOU sverstov@mdanderson.org