Srdan (Serge) Verstovsek M.D., Ph.D. Professor of Medicine Department of Leukemia University of Texas MD Anderson Cancer Center Houston, Texas, USA Therapy of early-stage MF: Are JAK inhibitors for everyone?

Passamonti F et al. Blood 2010;115:1703-8; Barbui T et al. Blood 2010; 115;778-82; Passamonti F et al. Blood 2010; 116: Main Clinical Problems in MF Clinical need Anemia (Hb <10 g/dL) Leukocytosis (>25x10 9 /L) Thrombocytopenia (<100x10 9 /L) Splenomegaly Hepatomegaly Extramedullary hematopoiesis Thrombosis Constitutional symptoms Leukemia transformation 65% 1-3% 7.2 % 27% 13% 36% 83% 16% 10%

Scherber R et al. Blood 201;118:401-8  «Constitutional Symptoms»  Splenomegaly  Myeloproliferation  Role / Functioning Symptomatic Burden in MF Symptoms related to:

Efficacy of ruxolitinib in patients with MF without clinically significant splenomegaly All pts were symptomatic Ruxolitinib was administered at the dose of 25mg BID Patients with MF n=6 Previously treated 5 Post splenectomy 3 Transfusion dependent 3 JAK2 V617F4 Patient dispositionEffects of ruxolitinib Patients with MF n=6 Fatigue improved 6 Resolution of night sweats 2 Itching2 Weight gain (up to 17%) 5 Improved performance status Reduction of liver size 50-68% No improvement in marrow fibrosis Benjamini et. al., Blood 2012; 120:

The approved indication is: “Ruxolitinib is indicated for the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis (also known as chronic idiopathic myelofibrosis), post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis.”

U.S. Food and Drug Administration On November 16, 2011, the Food and Drug Administration (FDA) approved ruxolitinib phosphate for the treatment of intermediate and high risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. No contraindications

Cervantes et al., Blood 2009;113: Prognostic factors Age > 65 years Constitutional symptoms Hb < 10 g/dL Leukocytes > 25 x 10 9 /L Blood blasts > 1% Age > 65 years Constitutional symptoms Hb < 10 g/dL Leukocytes > 25 x 10 9 /L Blood blasts > 1% International Prognostic Scoring System (IPSS): Risk classification of PMF at presentation Risk groups Low 0 Intermediate-11 Intermediate-22 High > 3 Low 0 Intermediate-11 Intermediate-22 High > 3

135 months 95 months 48 months 27 months International Prognostic Scoring System to predict survival (IPSS) 22% 29% 28% 21% Cervantes et al, Blood 2008

Overall Survival: ruxolitinib vs. placebo (int-2/high risk MF) Placebo Ruxolitinib Survival Probability Weeks Placebo Ruxolitinib No. at risk No. of deaths: Ruxolitinib = 27; Placebo = 41; HR = 0.58 (95% CI: 0.36, 0.95); P =.028 Median follow-up: 102 weeks. Most patient on placebo (n=111) were given ruxolitinib ( after average of 41 weeks )

Overall Survival: MDACC Phase 1-2 Study Cohort vs. Historical Control by IPSS Risk Category High Risk Intermediate-2 Hazard ratio= % CI: 0.31–0.81 p-value=0.006 Months Survival Probability Number of Patients at Risk—Historical Control Number of Patients at Risk—MDACC Study Hazard ratio= % CI: 0.43–1.71 p-value=0.71 Months Number of Patients at Risk—Historical Control Number of Patients at Risk—MDACC Study

Overall Survival in MDACC Phase 1-2 Study Cohort: Intermediate-2 vs. High Risk *Hazard ratio >1 favors intermediate-2 risk group. Number of Patients at Risk—Intermediate-2 Risk Number of Patients at Risk—High Risk Hazard ratio=1.36* 95% CI: 0.64–2.89 p-value=0.43

Ruxolitinib: Compassionate Use Program n = 1556* PMF, Post-ET/PV MF Irrespective of JAK2 mutation status High risk OR INT-1/INT-2 with an enlarged spleen PBC < 10% Adequate organ function ECOG 0, 1, or 2 Baseline platelet count of 100,000/µL to 200,000/µL will begin dosing at 15 mg BID FPFV = Feb 2011 * Approved Patients by 19 November 2012 Participating Countries: Australia, HK, India, Israel, Korea, Kuwait, Lebanon, Philippines, KSA, Singapore, Taiwan, Thailand, Turkey, UAE Baseline platelet count >200,000/µL will begin dosing at 20 mg BID Korea: 43 patients Taiwan: 35 patients

Expanded Access Program Endpoints: Collect additional safety of INC424 in patients with PMF/PPVMF/PET-MF; QoL; MRU Participating Countries: Algeria, Egypt, Israel, Kuwait, Russia, Saudi Arabia, South Africa, Thailand, Tunisia, UAE, Morocco Baseline platelet count of 100,000/µL to 200,000/µL will begin dosing at 15 mg BID Baseline platelet count > 200,000/µL will begin dosing at 20 mg BID FPFV = 16/08/2011 Baseline platelet count of 75,000/µL to 99,000/µL will begin dosing at 5 mg BID N = 1600 PMF, Post-ET/PV MF Irrespective of JAK2 mutation. High risk OR INT-1/INT-2 with an enlarged spleen PBC < 10% Adequate organ function ECOG 0, 1, or 2

Therapy of early-stage MF: Are JAK inhibitors for everyone? If defined as patients without splenomegaly or without disease related symptoms If defined as low-risk patients MY ANSWER: It deserves to be studied whether intervention in these patients, to prevent the development of clinically relevant disease related signs and symptoms, results in meaningful outcome (to be defined)

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