Whom should you refer for allogeneic stem cell transplantation? Myelofibrosis: Whom should you refer for allogeneic stem cell transplantation? Those with the greatest disease risk will gain the greatest benefit Ronald Hoffman, MD Albert A. and Vera G. List Professor of Medicine Mount Sinai School of Medicine New York, NY

Disclosures Research Funding Roche/Genentech Novartis Geron Incyte

I.W.G. Prognostic Scoring System Risk factors at presentation of PMF selected at the stepwise Cox regression model for their significant association with shorter survival * ______________________________________________________________________________________ Risk factor Frequency in the series Hazard ratio (95% CI) z-test p value Age > 65 years 44.6% 1.95 (1.61 – 2.36) 6.84 < 0.0001 Constitutional symptoms 26.4% 1.97 (1.62 – 2.40) 6.77 < 0.0001 Hb < 10 g/dL 35.2% 2.89 (2.46 – 3.61) 11.24 < 0.0001 WBC count > 25 x 109/L 9.6% 2.40 (1.83 – 3.14) 6.37 < 0.0001 Blood blasts ≥ 1% 36.2% 1.80 (1.50 – 2.17) 6.29 < 0.0001 * In 1,001 patients with the five variables available Cervantes et al. Blood 2009: 113, 2895-2901

Cervantes et al. Blood 2009: 113, 2895-2901 I.W.G. Prognostic Scoring System Definition, frequency and survival of the risk groups of the prognostic scoring system of PMF Risk group No. of factors Proportion of patients Median survival Proportion of deaths (95% CI) * Low 0 22% 135 (117 – 181) 32% Intermediate-1 1 29% 95 (79 – 114) 50% Intermediate-2 2 28% 48 (43 – 59) 71% High ≥ 3 21% 27 (23 – 31) 73% * In month Cervantes et al. Blood 2009: 113, 2895-2901

COMFORT-1 Percent Change From Baseline in Spleen Volume in Individual Patients at Week 24 Ruxolitinib (n = 139) Placebo (n = 106) 35% decrease At week 24, ruxolitinib-treated patients had a median 33.0% decrease in spleen volume and placebo-treated patients had a median 8.5% increase (P < 0.0001) Verstovsek S et al. NEJM 2012: 366, 799-807

Proportion of Patients with ≥50% Reduction in Total Symptom Score Over Time Ruxolitinib Placebo % of Patients Weeks From Day 1 24 60 50 40 30 20 10 2 4 6 8 12 14 16 18 22 Patients who discontinued or had missing data were considered non-responders Verstovsek S et al. NEJM 2012: 366, 799-807

Overall Survival Update: ITT HR=0.50 (0.25–0.98) P=0.04 Number of Patients at Risk—Ruxolitinib 155 155 155 154 153 152 148 144 143 143 140 134 102 68 52 37 18 8 3 Number of Patients at Risk—Placebo 154 152 151 148 147 147 142 139 132 131 123 115 83 58 45 35 20 9 3 No effect on marrow histopathololgy, JAK2V617F allele burden and marker cytogenetic abnormalities Verstovsek S et al. NEJM 2012: 366, 799-807 7

AZD1480 (JAK 1/2 Inhibitor) Treatment Resulted in Reductions in Both Splenic and PB MF Hematopoietic Progenitor Cells (HPCs) A B (% of Cytokines Alone) Splenic MF Colonies (% of Cytokines Alone) PB MF Colonies ** *** *** *** **P<0.01;***P<0.001. n=10 Wang X, et al. ASH 2013

Effects of Treatment with AZD1480 on MF SCID Repopulating Cells (SRC) Wang X, et al. ASH 2013

Ruxolitinib is an Effective Agent for Symptomatic Improvement But Does Not Prevent Clonal Evolution of MF Kremyanskaya M, et al. unpublished

Development of Acute Leukemia in Myelofibrosis Patients on Ruxolitinib at Mt. Sinai Patient 1 2 3 4 5 Age 56 70 62 58 83 Sex F M Type of MPN Post-PV MF PMF Post-ET MF Molecular Marker JAK2V617F 36.6% negative MPL W515L 70.16% 22.6% Extramedullary Disease Yes No Site of Extramedullary Disease Skin N/A Bone (granulocytic sarcoma) Karyotype at Transformation Complex Del 13q Normal Bone Marrow Involvement Peripheral Blood Blasts 6% 2% 1% 20% Type of Leukemia AML CMML Length of Ruxolitinib tx 3 months 12 months 18 months 14 months

Allogeneic Hematopoietic At Present, Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Is The Only Treatment Modality That Has The Potential To Cure Myelofibrosis

Background Number of Patients Age Poor Risk Regimen TRM (at 1 year) CR OS Guardiola, et al. (Blood 1999/NEJM 2000) 55 42 50% Myeloabl 27% 40% 14% (>45 yrs.) at 5 yrs. 62% (<45 yrs.) Daly, et al. (BMT 2003) 25 48 28% 48% 33% 41% 2 yrs. Deeg, et al. (Blood 2003) 56 43 23% 32% 53% 58% 3 yrs. Devine, et al. (Blood 2002) (Updated FU) 4 100% Flu-Mel 0% 4/4 100% 3.5 yrs.

Overall Survival Following Allogeneic Transplantation for Intermediate/High Risk MF Patients with Reduced Intensity Conditioning Median follow-up (months) 22.6% (1.5-122) Overall Survival 85% (18/21) Event-free Survival 80% (17-21) Relapse 10% (2/19) TRM d100 & 1 yr. Rondelli D, Blood 2005 105: 1115-9

Reduction of Spleen Size and Marrow Fibrosis After Allogeneic RIC HSCT Ciurea et al. Br J Haemat. 2008

Patient Characteristics of EBMT MF Transplant Trial Donor Unrelated n = 69 Related n = 33 JAK2 Positive n = 51 Negative n = 29 HLA-typing matched (8/8 allele) n = 86 Mismatched n = 12 DRB1 n = 2 DQB1 n = 5 A n = 4 B n = 1 Kroger, et al. Blood 2009; 114: 5264-5270

Disease-free survival after Allogeneic Stem Cell Transplantation for PMF DFS 500 1000 1500 2000 1,0 0,8 0,6 0,4 0,2 58% Kroger, et al. Blood 2009; 114: 5264-5270 17

Survival of MF Patients in Seattle With Transplantation by DIPSS MF Patients: 170 Age: 12.1 - 78.9 (51.5) 86 Related Donors, 84 Unrelated Donors DIPPS Risk Survival (median; years) No Transplant (at reporting) Transplant (med F/U 5.9 years) Low Not Reached Intermediate 1 14.2 Intermediate 2 4 7 High 1.5 2.5 Provided by J. Deeg, Seattle Scott et al. Blood 2012; 119: 2657-2664

Who Should go for Transplant? Benefit Risk

Candidates for Allogeneic Stem Cell Transplantation Intermediate and High Risk MF Patients with Available Stem Cell Donor Patients w/ Primary Myelofibrosis and MDS following ET or PV All young patients ≤ 55 Ages between 55 and 70 with good performance status MPN patients who have evolved to AML following successful induction therapy Individuals for Whom Allogeneic Stem Cell Transplantation Should Not be Considered: Pre-fibrotic form of myelofibrosis Low risk MF ET PV Age≥70 years No stem cell donor available- results with CB donors and haplo-indentical donors are unknown Poor performance status