Ruxolitinib + Azacitidine in Newly Diagnosed or R/R, Intermediate- or High-Risk Myelofibrosis New Findings in Hematology: Independent Conference Coverage of ASH 2016*; December 3-6, 2016; San Diego, California *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. R/R, relapsed/refractory. This activity is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, and Seattle Genetics.

RUX + AZA in Myelofibrosis: Background RUX, a potent oral JAK1/2 inhibitor, decreases symptoms and splenomegaly in pts with MF[1,2] AZA, a hypomethylating agent, demonstrates activity in approximately 25% of MF pts[3] Combination or sequencing of these agents may improve response, decrease toxicity compared with either drug given as monotherapy[4] Current study evaluates RUX + AZA combination in pts with newly diagnosed or R/R, intermediate- or high-risk MF[5] AZA, azacitidine; MF, myelofibrosis; R/R, relapsed/refractory; RUX, ruxolitinib. 1. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 2. Harrison C, et al. N Engl J Med. 2012;366:787-798. 3. Quintás-Cardama A, et al. Leukemia. 2008;22:965-970. 4. Daver N, et al. Haematologica. 2015;100:1058-1063. 5. Daver N, et al. ASH 2016. Abstract 1127. Slide credit: clinicaloptions.com

RUX + AZA in Myelofibrosis: Study Design Open-label, nonrandomized phase II study[1] Primary endpoint: objective response, defined as CR + PR + CI Response assessed by IWG-MRT 2013 criteria[2] Cycles 1-3* Cycle 4-on* Pts with newly diagnosed or R/R, intermediate-1–risk, intermediate-2–risk, or high-risk MF, no prior RUX or AZA , platelets ≥ 50 x 109/L, ANC ≥ 1.0 x 109/L (N = 44) Ruxolitinib 15-20 mg PO BID Ruxolitinib 15-20 mg PO BID + Azacitidine† 25 mg/m² IV QD Days 1-5 *1 cycle lasted 4-6 wks. †Dosage could be increased to 50 or 75 mg/m². ANC, absolute neutrophil count; AZA, azacitidine; CI, clinical improvement; IWG-MRT, International Working Group-Myeloproliferative Neoplasms Research and Treatment; MF, myelofibrosis; R/R, relapsed/refractory; RUX, ruxolitinib. 1. Daver N, et al. ASH 2016. Abstract 1127. 2. Tefferi A, et al. Blood. 2013;122:1395-1398. Slide credit: clinicaloptions.com

RUX + AZA in Myelofibrosis: Baseline Characteristics RUX + AZA (N = 44) Median age, yrs (range) 66 (48-87) Myelofibrosis diagnosis, n Primary/post ET/post PV 25/11/8 IPSS score, n Int-1/int-2/high 8/9/27 DIPSS score, n 15/19/10 EUMNET fibrosis grade, n MF-1/MF-2/MF-3 4/22/18 Prior therapy, % 57 Splenomegaly, % 86 Peripheral blasts ≥ 1%, % 64 Characteristic RUX + AZA (N = 44) Median WBC x 109/L (range) 12.1 (2.2-70.8) Median Hb, g/dL (range) 10.3 (6.8-16.2) Median platelets x 109/L (range) 271 (125-1070) Cytogenetics, % Diploid/abnormal 59/39 JAK2 positive, % 55 Molecular panel, n TET2 ASXL1 IDH1/2 EZH2 DNMT3/NRAS (n = 28) 6 4 2 1/2 AZA, azacitidine; DIPSS, Dynamic International Prognostic Scoring System; ET, essential thrombocythemia; EUMNET, European Myelofibrosis Network; Hb, hemoglobin; Int, intermediate; IPSS, International Prognostic Scoring System; MF, myelofibrosis; PV, polycythemia vera; RUX, ruxolitinib; WBC, white blood cell count. Slide credit: clinicaloptions.com Daver N, et al. ASH 2016. Abstract 1127.

RUX + AZA in Myelofibrosis: Response IWG-MRT 2013 Response, n (%) RUX + AZA (n = 39) Objective response 27 (69) PR 2 (7) Cl spleen + TSS 8 (30) CI TSS + hemoglobin Cl spleen + CR cytogenetic CI TSS + CR cytogenetic 1 (4) CI TSS only CI spleen only 4 (15) None 12 (31) Spleen Response RUX + AZA Baseline spleen ≥ 5 cm, n CI in spleen by IWG-MRT criteria, n (%) Median time to CI in spleen, mos (range) > 50% reduction in palpable spleen length at Wk 24, n (%) > 50% reduction in palpable spleen length at any time, n (%) 29 16 (55) 1.8 (0.9-16.8) 14 (48) 23 (79) 5 of 16 pts (31%) demonstrated clinical improvement of splenomegaly after AZA addition to regimen Median time to spleen improvement: 1.8 mos after AZA (range: 1.0-13.8) AZA, azacitidine; CI, clinical improvement; IWG-MRT, International Working Group-Myeloproliferative Neoplasms Research and Treatment; RUX, ruxolitinib; TSS, total symptom score. 6 of 27 pts (22%) had clinical response by IWG-MRT criteria after AZA addition to regimen Median time to improvement: 4.2 mos after AZA (range: 0.1-16.5) Slide credit: clinicaloptions.com Daver N, et al. ASH 2016. Abstract 1127.

RUX + AZA in Myelofibrosis: Fibrosis Change Improvement: 11 pts Stable: 10 pts Worsening: 6 pts 17 of 27 responders were JAK2 positive 15 pts underwent serial JAK2 analysis Clinical response by IWG-MRT criteria similar In pts with JAK2 mutations vs those without (18/24 vs 9/20, respectively; P = .31) In pts with 0-1 mutations vs those with > 1 (19/33 vs 8/19, respectively; P = .67) n = 4 3 3 n = 4 n = 5 n = 5 2 2 n = 2 Fibrosis Grade n = 4 Fibrosis Grade n = 1 JAK2 Response, n RUX + AZA (n = 15) 0% to 20% reduction 6 20% to 50% reduction 4 > 50% reduction 3 Stable/increase 2 AZA, azacitidine; IWG-MRT, International Working Group-Myeloproliferative Neoplasms Research and Treatment; RUX, ruxolitinib. n = 1 1 1 n = 1 Baseline Wk 24 Slide credit: clinicaloptions.com Daver N, et al. ASH 2016. Abstract 1127. Reproduced with permission.

RUX + AZA in Myelofibrosis: Adverse Events AE Occurring in ≥ 5% of Pts, n (%) RUX + AZA (N = 44) Grade 1/2 Grade 3/4 Thrombocytopenia 20 (45) 10 (23) Anemia 14 (3) 16 (36) Constipation Nausea 4 (9) 1 (2) Neutropenia 3 (7) 8 (18) Diarrhea Pruritis 2 (5) Insomnia Fatigue Time Point RUX + AZA (N = 44) Median Hb, g/dL New Grade 3/4 Anemia, n Baseline 10.3 NA Wk 1-12 9.5 13 Wk 13-24 9.4 3 Wk 24-on 9.9 In pts with cytopenias: New onset cytopenia, n = 16 ≥ 2-grade change, n = 4 D/c due to cytopenia, n = 1 AE, adverse event; AML, acute myeloid leukemia; AZA, azacitidine; D/c, discontinued; Hb, hemoglobin; MUD-SCT, matched unrelated donor stem cell transplantation; NA, not applicable; RUX, ruxolitinib. 14 deaths occurred: progression to AML, n = 5; pneumonia, n = 3; other infections, n = 2; meningitis with seizure, cardiac arrest, metastatic melanoma, post MUD-SCT, n = 1 each Slide credit: clinicaloptions.com Daver N, et al. ASH 2016. Abstract 1127.

RUX + AZA in Myelofibrosis: Conclusions Study investigators suggest that combination ruxolitinib + azacitidine is feasible and promising in pts with newly diagnosed or R/R MF ORR by IWG-MRT criteria: 69% CI spleen by IWG-MRT: 55% Wk 24 splenomegaly reduction by > 50%: 48% Overall splenomegaly reduction by > 50%: 79% Acceptable tolerability; rate of cytopenias similar to that of single-agent ruxolitinib Improvement in bone marrow fibrosis observed but requires confirmation Analysis of Hb improvement, OS, JAK2 alleles, and fibrosis ongoing AZA, azacitidine; CI, clinical improvement; Hb, hemoglobin; IWG-MRT, International Working Group-Myeloproliferative Neoplasms Research and Treatment; MF, myelofibrosis; R/R relapsed/refractory; RUX, ruxolitinib. Slide credit: clinicaloptions.com Daver N, et al. ASH 2016. Abstract 1127.

Go Online for More CCO Coverage of ASH 2016! Short slideset summaries of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in: Leukemias Lymphomas/CLL Myeloma/plasma cell disorders MDS and myeloproliferative neoplasms clinicaloptions.com/oncology