Case Study: A Patient with PV and Debilitating Symptoms on HU Srdan Verstovsek, MD, PhD Professor of Medicine Director, Hanns A. Pielenz Clinical Research Center for Myeloproliferative Neoplasms Department of Leukemia MD Anderson Cancer Center Houston, Texas, USA

Jeffrey C. Bryan, PharmD, RPh Otitolola Arterbery, MSN, RN, OCN Co-Presenters Jeffrey C. Bryan, PharmD, RPh Clinical Pharmacy Specialist, Leukemia Division of Pharmacy, University of Texas MD Anderson Cancer Center Houston, TX Otitolola Arterbery, MSN, RN, OCN Clinical Nurse MD Anderson Cancer Center Houston, TX

Polycythemia Vera Polycythemia vera (PV) is a myeloproliferative neoplasm associated with overactivation of the JAK/STAT pathway PV is characterized by: Erythrocytosis Debilitating symptoms (eg, pruritus, fatigue) Cardiovascular complications due to thrombosis or hemorrhage Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print].

Risk Classification for Patients with PV Risk Category Risk Variables Low Age < 60 years No thrombosis history High Age ≥ 60 years and/or Thrombosis history Notably, current risk stratification is based on risk for thrombosis and may not adequately address symptom burden. Barbui T, Barosi G, Birgegard G, et al. Philadelphia-Negative Classical Myeloproliferative Neoplasms: Critical Concepts and Management Recommendations From European LeukemiaNet. J Clin Oncol. 2011;29(6):761-770. 1. Barbui T et al. Clin Oncol. 2011;29(6):761-770; 2. Vannucchi AM. Blood. 2014 Oct 2. [Epub ahead of print].

Polycythemia Vera Disease Burden It has become clear that PV has a unique disease burden, regardless of traditional risk classification. Patients with PV experience a broad range of burdens, including (1) a symptomatic burden that is driven by, but not limited to, pruritus, fatigue, and splenomegaly, (2) a reduced quality of life (QoL) that is negatively impacted by the symptomatic burden, (3) a financial burden, driven by increased healthcare utilization and costs, (4) an increased risk of thrombotic and hemorrhagic tendencies, (5) a risk of disease transformation, either to myelofibrosis (MF) or acute myeloid leukemia (AML), (6) the potential development of secondary solid malignancies, and (7) an increase in mortality, driven by thrombotic and hemorrhagic tendencies. Reference: Stein BL, Moliterno AR, Tiu RV. Polycythemia vera burden: contributing factors, impact on quality of life, and emerging treatment options. Ann Hematol. 2014; Oct 2 [Epub ahead of print]. (Fig. 1). Reprinted with permission from: Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print].

PV Burdens Are Associated with Increased Healthcare Costs Component Patients with PV Controls P-value Patients, n 5,752 Mean (SD) cost, $ Inpatient 4,670 (19,092) 2,019 (11,236) P<0.0001 Outpatient 6,806 (14,072) 3,863 (11,211) Medication 2,897 (8,376) 1,724 (4,085) Emergency room 529 (1,602) 306 (1,651) Total 14,903 (29,018) 7,913 (19,017) Several studies have looked at healthcare costs in patients with PV. This recent study showed statistically significant increases in healthcare cost for patients with PV, including inpatient and outpatient costs. References: Mehta J, Wang H, Fryzek JP, Iqbal SU, Mesa R (2014) Health resource utilization and cost associated with myeloproliferative neoplasms in a large United States health plan. Leuk Lymphoma. 2014 Oct;55(10):2368-74. Reference: Stein BL, Moliterno AR, Tiu RV. Polycythemia vera burden: contributing factors, impact on quality of life, and emerging treatment options. Ann Hematol. 2014; Oct 2 [Epub ahead of print]. Mehta J et al. Leuk Lymphoma. 2014;55(10):2368-74.

Risk-Adapted Management of Patients with PV 1,2 Hematocrit (Hct) control is a key therapeutic goal Maintaining Hct < 45% significantly decreases the risk of cardiovascular death and major thrombotic events3 Risk Category Risk Variables Therapy Low Age < 60 years No thrombosis history Phlebotomy, and Correction of CV risk factors, and Aspirin High Age ≥ 60 years and/or Thrombosis history Cytoreduction, and Aspirin, plus/minus Phlebotomy The goal of therapy in PV is primarily to reduce the risk of thrombosis without increasing the bleeding tendency and enhancing the intrinsic potential of hematologic progression and, secondarily, to ameliorate symptoms, particularly vasomotor manifestations… The cornerstone of treatment is the correction of abnormal blood viscosity associated with the increased red cell volume that can be pursued with phlebotomy only in the low-risk and/or with cytotoxic drugs in the high-risk category [Vannucchi, 2014] Current treatment options are unlikely to significantly improve PV symptoms. Conventional treatments are unlikely to significantly improve symptom burden4 1. Barbui T et al. Clin Oncol. 2011;29(6):761-770; 2. Vannucchi AM. Blood. 2014 Oct 2. [Epub ahead of print]; 3. Marchioli R, et al. N Engl J Med. 2013;368(1):22-33; 4. Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print].

Phlebotomy in PV Management Reduces Hct (hyperviscosity); goal is Hct <45% Does not control systemic symptoms or progressive symptomatic splenomegaly Iron deficiency is common with repeated phlebotomies Associated with fatigue, cognitive impairment, increased pulmonary artery pressure Mascarenhas J et al. Haematologica 2014;99(6):945-49.

Hydroxyurea (HU) in PV Management HU, a cytoreductive therapy, is often used as a first-line treatment for patients with PV who are at high risk for vascular complications1,2 Clinical activities2 Reduces risk of major thrombosis Controls myeloproliferation Reduces splenomegaly Side effects2 Myelosuppression, leg ulcers, hyperpigmentation, fever, alopecia, increased risk of squamous cell carcinoma Possibly leukemogenic 1. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6; 2. Mascarenhas J et al. Haematologica 2014;99(6):945-49.

Hydroxyurea (HU) Resistance in PV Management A subset of patients will develop resistance or intolerance to HU and require treatment with a second-line therapy1,2 Q: What percentage of PV patients on HU therapy will become resistant or intolerant? 2 - 5% 20 – 25% 50 - 60% Almost all However, a subset of patients will develop resistance or intolerance to HU and require treatment with a second-line therapy1,2 1. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6; 2. Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print].

Hydroxyurea (HU) Resistance in PV Management Q: What percentage of PV patients on HU therapy will become resistant or intolerant? 2 - 5% 20 – 25% 1,2 50 - 60% Almost all Consequences of HU Resistance/Intolerance in Patients with PV: HU resistance is associated with: Increased complications and symptom burden Worsening disease transformation Reduced survival Resistance and/or intolerance to HU is associated with 1,2 : Increased symptom burden and complications Worsening disease transformation Reduced survival 1. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6; 2. Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print].

Case Study: Bruce T. 57-year-old man with polycythemia vera (PV) Disease features at presentation: Hemoglobin 18.9 g/dL; Hct 57%; low serum Epo; leukocyte count 10.5 x 109/L; platelet count 419 x 109/L JAK2V617F mutation Non-palpable spleen Symptoms – pruritus, fatigue, night sweats, abdominal discomfort Management Phlebotomies to achieve/maintain Hct < 45% Low-dose aspirin Unremarkable course, except for fatigue that (at times) interfered with his work and other activities Note: Used median hematologic values for presenting male patients with PV from Tefferi Leukemia 2013; 1874-81 (Table 1).

Most Common Symptoms Reported by Patients with PV Incidence Fatigue 79-92% Insomnia 68-70% Decreased mood 65-68% Numbness 65-66% Early satiety 62-66% Concentration problems 60-65% Itching 57-65% Night sweats 52-64% Inactivity 58 – 61% Sexual problems 50-57% Dizziness 51-52% Headache 38-52% Abdominal discomfort 42-51% Bone pains 44-50% PV patients have a high symptom burden, including cytokine-related symptoms, such as fatigue, pruritus (or itching), night sweats; splenomegaly-related symptoms, such as abdominal discomfort or early satiety; and hyperviscosity-related symptoms, such as numbness or tingling in hands or feet, headache, and dizziness. Fatigue is the symptom most frequently reported by patients with PV, although patients may also have a variety of other disease-related symptoms at the same time. Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print].

Myeloproliferative Neoplasm Symptom Assessment (MPN SAF) Form Total Symptom Score: An Assessment Tool for the 10 Most Clinically Important Myeloproliferative Neoplasm Features Excerpt from Manea: Research indicates that the use of patient-reported symptom checklists improves documentation and management with corresponding improvements in health-related QOL (Williams et al., 2012). The Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) is a tool that includes the 10 most clinically important characteristics of myeloproliferative disorders, with the goal to assess symptom burden in clinical practice (Emanuel et al., 2012; Scherber et al., 2011) Currently, no standard symptom assessment form is in use across oncology centers; therefore, the oncology team may choose to develop specific questionnaires or evaluate the use of the MPN-SAF TSS. Regardless of the tool used, questions should be simple and phrased consistently from visit to visit to obtain an accurate picture of symptom burden. The information captured with these tools can be augmented with questions about the timing of symptom onset to determine if symptoms are related to treatment or disease to further guide treatment decisions. Manea - Note. From “The Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF): International Prospective Validation and Reliability Trial in 402 Patients,” by R. Scherber, A.C. Dueck, P. Johansson, T. Barbui, G. Barosi, A.M. Vannucchi, . . . R.A. Mesa, 2011, Blood, 118, p. 404. Copyright 2011 by the Mayo Clinic. Reprinted with permission. Sherber R et al. Blood. 2011; 118(2):401-8; Emanuel RM et al, J Clin Oncol 2012;30:4098-103. Reprinted with permission from: Manea PJ. Clin J Oncol Nursing 2014; 18 (3): 330-7.

Systemic Symptoms - Mean MPN-SAF Scores Incidence Mean SAF Score, range Fatigue 79-92% 3.0 – 4.4 Insomnia 68-70% 2.5 – 3.1 Decreased mood 65-68% 2.0 - 2.3 Numbness 65-66% 2.1 – 2.6 Early satiety 62-66% 2.0 - 2.5 Concentration problems 60-65% 1.9 – 2.7 Itching 57-65% 1.9 – 2.8 Night sweats 52-64% 2.0 – 2.7 Inactivity 58 – 61% 1.8 – 2.4 Sexual problems 50-57% 2.5 – 2.9 Dizziness 51-52% 1.8 – 1.9 Headache 38-52% 1.2 – 1.9 Abdominal discomfort 42-51% 1.3 – 1.6 Bone pains 44-50% 1.5 – 2.1 Fatigue is the most frequently reported symptom, but is the most challenging to treat Many patients turn to lifestyle changes to improve their energy level (eg, exercise, dietary changes, social interactions) Fatigue can be severe. Although it is the most frequently reported and troublesome symptom, fatigue is also the most challenging to treat. Patients may need help with lifestyle changes that may improve their energy level (eg, exercise routines, dietary changes, social interactions) Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print].

Case Study (cont.): Bruce T. 3 years from diagnosis he had a thromboembolic event (thrombophlebitis) – he was started on HU, 1 g/day 7 months later, he had abdominal pain and a palpable spleen (5 cm below the costal margin) – HU was increased to 2 g/day Spleen response Symptoms worsened At today’s visit (1 year later), he has uncontrolled itching, persistent worsening of fatigue, and abdominal discomfort affecting his ability to eat

Case Study (cont.): Bruce T. Q: Does this patient have resistance/intolerance to HU? Yes No Not sure

Case Study (cont.): Bruce T. 3 years from diagnosis he had a thromboembolic event (thrombophlebitis) – he was started on HU, 1 g/day 7 months later, he had abdominal pain and a palpable spleen (5 cm below the costal margin) – HU was increased to 2 g/day Spleen response Symptoms worsened At today’s visit (1 year later), he has uncontrolled itching, persistent worsening of fatigue, and abdominal discomfort affecting his ability to eat Q: Does this patient have resistance/intolerance to HU? Yes No Not sure

European Leukemia Net Criteria for Resistance to, or Intolerance of Hydroxyurea Table from Stein, 2014; Vannuchi 2014 – adapted from: Barbui 2011 JCO. European LeukemiaNet (ELN) criteria define a patient as HU intolerant or resistant based on the need for phlebotomy to maintain hematocrit level <45 %, uncontrolled myeloproliferation, splenomegaly, and the presence of HU-related nonhematologic toxicities. However, this definition is based on expert opinion consensus rather than clinical trial evidence. Barbui T, Barosi G, Birgegard G, Cervantes F, Finazzi G, Griesshammer M, Harrison C, Hasselbalch HC, Hehlmann R, Hoffman R, Kiladjian JJ, Kroger N, Mesa R, McMullin MF, Pardanani A, Passamonti F, Vannucchi AM, Reiter A, Silver RT, Verstovsek S, Tefferi A, European L (2011) Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 29(6):761–770 Barbui T et al, J Clin Oncol 2011;29(6):761–770.

Clinical Perspective Why is our patient (Bruce T.) considered HU - resistant/intolerant? ELN criteria are useful for clinical studies, but not always practical for everyday decision-making1 In practice, some patients do not meet ELN criteria but remain symptomatic and, thus, are poorly served by HU therapy2 Dr V comment: This is useful for clinical studies (as suggested in the paper itself), not practical for everyday decision making (abstract to be presented at upcoming ASH). Some patients do not meet ELN criteria for HU resistance/intolerance but remain symptomatic and are poorly managed by HU. Indeed, some patients do not meet ELN criteria for HU resistance/intolerance but nonetheless remain symptomatic and are poorly served by HU [62, 12, 61]. Included among patients poorly managed by HU are those with side effects that are not part of the ELN criteria, such as aphthous ulcers and acne [79]. In addition, concerns about potential leukemic transformation may lead some patients and even their physicians to avoid HU therapy altogether 1. Barbui T et al, J Clin Oncol 2011;29(6):761–770; 2. Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print].

Case Study (cont.): Bruce T. Q: For this PV patient with debilitating fatigue on HU, what would you recommend? Stay on 2 g/day HU, with supportive management of fatigue Increase dose to 2.5 g/day HU, with supportive management of fatigue Hold all therapy except aspirin, phlebotomy until fatigue improves A change in PV therapy and supportive management of fatigue

Case Study (cont.): Bruce T. Q: For this PV patient with debilitating fatigue on HU, what would you recommend? Stay on 2 g/day HU, with supportive management of fatigue Increase dose to 2.5 g/day HU, with supportive management of fatigue Hold all therapy except aspirin, phlebotomy until fatigue improves A change in PV therapy, with supportive management of fatigue

Case Study (cont.): Bruce T. Q: What would you recommend for second-line therapy? Busulfan Pipobroman Pegylated interferon alfa JAK inhibitor (ruxolitinib) Histone deacetylase (HDAC) inhibitor (givinostat, vorinostat)

Case Study (cont.): Bruce T. Q: What would you recommend for second-line therapy? Busulfan Pipobroman Pegylated interferon alfa Jak inhibitor (ruxolitinib) HDAC inhibitor (givinostat, vorinostat) Reserved for exceptional cases1-3 Most data on the use of alternative therapies in this patient group come from retrospective analyses or clinical studies originating from a single or few academic centers, with a relatively small number of patients and short follow-up time. In addition, these studies have used different treatment response criteria that have not been prospectively validated (as they are consensus opinion of the experts in the field). Pipobroman, busulfan and radioactive phosphorus are recommended by the ELN as second-line agents for patients after failure of primary therapy with either HU or IFN- α [7]. However, the use of these agents is reserved for exceptional cases, due to the proven potential of these agents to increase the risk of transformation to acute leukemia. [ie, elderly patients (> 80 years) or those with advanced disease, where the risk of thrombosis outweighs the risk of AML/MDS.] 1. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6; 2. Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print]; 3. Alvarez-Larran A et al. Ann Hematol. 2014 Jul 2 [Epub ahead of print].

Case Study (cont.): Bruce T. Q: What would you recommend for second-line therapy? Busulfan Pipobroman Pegylated interferon alfa Jak inhibitor (ruxolitinib) HDAC inhibitor (givinostat, vorinostat) Reserved for exceptional cases1-3 High hematologic response rates in phase 2 4,5; may be alternative for HU-refractory PV 6 Based on phase 2 studies, PEG-IFN- α -2a, given subcutaneously, resulted in high hematologic response rates, particularly in patients with PV, and was better tolerated than short acting IFN- α. Although no phase III data are available to support its use for patients who are refractory to HU, PEG-IFN- α -2a is a reasonable second-line alternative 1. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6; 2. Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print]; 3. Alvarez-Larran A et al. Ann Hematol. 2014 Jul 2 [Epub ahead of print]; 4. Quintas-Cardama A et al. J Clin Oncol. 2009;27:5418-24; 5. Quintas-Cardama A et al. Blood 2013;122:893-901; 6. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6.

Pegylated Interferon Alfa-2a: Efficacy Results from a Phase II Study in Patients with PV (and ET) In this phase 2 study, PEG-IFN--2a resulted in high rates of hematologic and molecular responses in patients with advanced, previously treated PV. The JAK2V617F mutation becomes undetectable in a subset of patients receiving PEG-IFN--2a, suggesting a preferential effect on the malignant clone. Patients failing to achieve complete molecular remission tended to have higher frequencies of mutations in genes other than JAK2. Quintas-Cardama A et al. Pegylated interferon alfa-2a yield high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. JCO 2009;27:5418-24. Quintas-Cardama et al. Molecular analysis of patients with polycythemia vera or essential thrombocythemia receiving pegylated interferon a-2a. Blood 2013;122:893=901. 1. Quintas-Cardama A et al. J Clin Oncol. 2009;27:5418-24; 2. Quintas-Cardama A et al. Blood 2013;122:893-901.

Pegylated Interferon Alfa-2a: Phase II Study Safety Results Overall Grade 3 or 4 Toxicities in Patients with PV (n=40) Toxicity Grade 3, n (%) Grade 4, n (%) Neutropenia 3 (8) Elevated LFTs 2 (5) Fatigue 1 (3) Pain Infection Depression Diarrhea Mucositis Blurred vision Dizziness Anemia A starting dose of PEG-IFN-alfa-2a 45 or 90 μ g/week given subcutaneously was better tolerated than is short acting IFN- α, with minimal grade 3 or 4 toxicities. Neutropenia was the most frequent grade 3- 4 toxicity. Many patients are currently receiving PEG-IFN--2a at 90 g weekly or even less intense dose schedules with excellent efficacy. [Sever] However, some caution is necessary as, similar to its native formulation, it is contraindicated in patients with thyroid and psychiatric disorders. Also, relative to HU, data on its prevention of thromboembolic events is limited. [Sever] Quintas-Cardama A et al. Pegylated interferon alfa-2a yield high rates of hematologic and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. JCO 2009;27:5418-24. 1. Quintas-Cardama A et al. J Clin Oncol. 2009;27:5418-24.

Case Study (cont.): Bruce T. Q: What would you recommend for second-line therapy? Busulfan Pipobroman Pegylated interferon alfa Jak inhibitor (ruxolitinib) HDAC inhibitor (givinostat, vorinostat) Reserved for exceptional cases1-3 High hematologic response rates in phase 2 4,5; may be alternative for HU-refractory PV 6 Much emphasis is on the development of new agents for these patients. The JAK inhibitor, ruxolitinib, was first approved for treatment of patients with intermediate or high-risk myelofibrosis including post-PV and post-ET myelofibrosis. Recently, ruxolitinib was recently approved for patients who have had an inadequate response to or are intolerant to hydroxyurea. 1. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6; 2. Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print]; 3. Alvarez-Larran A et al. Ann Hematol. 2014 Jul 2 [Epub ahead of print]; 4. Quintas-Cardama A et al. J Clin Oncol. 2009;27:5418-24; 5. Quintas-Cardama A et al. Blood 2013;122:893-901; 6. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6; 7. Jakafi (ruxolitinib) prescribing information; Dec 2014. Approved for treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea7

Phase II Study of Ruxolitinib (JAK1/JAK2 Inhibitor) in Patients with PV Refractory or Intolerant to HU Hematologic response rate: 97% 85% maintained Hct >45% for 48 weeks without phlebotomy Benefits for PV-related symptoms and splenomegaly Most AEs grade 1 or2; ≥grade 3 AEs included: Anemia, thrombocytopenia (9% each) Neutropenia, pyrexia, vomiting, asthenia (3% each) Ruxolitinib, a potent JAK1/JAK2 inhibitor, was evaluated for PV in a phase 2 trial2 -- Ruxolitinib was well tolerated and effectively controlled hematocrit and reduced splenomegaly and symptoms in patients with PV refractory or intolerant to hydroxyurea. Verstovsek S, et al. A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea. Cancer 2014;120(4):513-20. Verstovsek S, et al. Cancer. 2014;120(4):513-520.

Phase III Study of Ruxolitinib vs BAT (RESPONSE) Extended treatment phase Ruxolitinib 10 mg BID Week 208 Resistance to or intolerance of HU (modified ELN criteria) Phlebotomy requirement Splenomegaly n = 110 Crossover to ruxolitinib Pre-randomization (day −28 to day −1) Hct 40%-45% Randomized (1:1) Week 208 BAT n = 112 Week 32 (primary endpoint) Week 48 Week 80 RESPONSE was a phase 3 study that evaluated ruxolitinib vs best available therapy (BAT) in patients with PV who were resistant to or intolerant of hydroxyurea (HU). Patients were stratified by HU intolerance/resistance and randomized to: Ruxolitinib 10 mg BID starting dose (individually titrated up to a maximum of 25 mg BID) – At week 32, two-thirds of patients in the ruxolitinib arm were receiving doses of 10 mg BID or 15 mg BIDa - Most dose adjustments occurred within the first 8 weeks of treatment Investigator-selected BAT as monotherapy (HU, IFN/peg-IFN, anagrelide, pipobroman, IMIDs, or observation); BAT could be changed in case of lack of response or BAT-related toxicity requiring drug discontinuation Patients receiving BAT could cross over to ruxolitinib at week 32 if they failed to meet the primary endpoint or later in case of progression (phlebotomy requirement and/or splenomegaly progression) Patients were to receive low-dose aspirin unless medically contraindicated Primary end point (composite) Reference: Verstovsek et al. Results of a prospective, randomized, open-label phase 3 study of ruxolitinib (RUX) in polycythemia vera (PV) patients resistant to or intolerant of hydroxyurea (HU): the RESPONSE trial. ASCO 2014 oral presentation. Primary endpoint (composite): % of patients who achieved both Hct control and spleen response at week 32 Hct control: No phlebotomy eligibility from week 8 to 32, with no more than 1 post- randomization phlebotomy eligibility up to week 8 Phlebotomy eligibility was defined as Hct > 45% and ≥ 3% higher than baseline or > 48% Spleen response : ≥ 35% reduction from baseline in spleen volume by MRI Verstovsek S et al. J Clin Oncol 2014;32 (5s): Abstract 7026.

RESPONSE: Baseline Characteristics Parameter Ruxolitinib (n = 110) BAT (n = 112) Age, median (range), years 62 (34-90) 60 (33-84) Male, % 60 71 HU resistance/intolerance, % Resistance 46.4 45.5 Intolerance 53.6 54.5 JAK2 V617F mutation positive, % 94.5 95.5 History of prior thromboembolic event, % 35.5 29.5 Hct, mean (SD), %a 43.6 (2.2) 43.9 (2.2) WBC × 109/L, mean (SD) 17.6 (9.6) 19.0 (12.2) Platelet count × 109/L, mean (SD) 485 (323) 499 (319) ≥ 3 Phlebotomies in prior 24 weeks, % 30.9 42.0 Palpable spleen length, median (range), cm 7 (0-24) 7 (0-25) Spleen volume, median (range), cm3 1195 (396-4631) 1322 (254-5147) a Following Hct control period prior to randomization. BAT included HU (n = 66; 59%), IFN/pegylated IFN (n = 13; 12%), anagrelide (n = 8; 7%), pipobroman (n = 2; 2%), IMIDs (n = 5; 4%), and observation (n = 17; 15%) Verstovsek S et al. J Clin Oncol 2014;32 (5s): Abstract 7026.

RESPONSE: Rate of Phlebotomy Procedure Between Week 8 and 32 The phlebotomy rate between week 8 and 32 was > 3 times higher in the BAT arm compared with the ruxolitinib arm Only 2.8% of patients in the ruxolitinib group vs 20.2% in the BAT group required 3 or more phlebotomies during this time Verstovsek S et al. J Clin Oncol 2014;32 (5s): Abstract 7026.

RESPONSE: Percentage Change in Spleen Volume (Week 32) 120 120 Ruxolitinib BAT 100 100 80 80 60 60 40 40 Change From Baseline in Spleen Volume at Week 32, % 20 Change From Baseline in Spleen Volume at Week 32, % 20 −20 −20 −40 35% reduction −40 35% reduction −60 −60 −80 −80 Verstovsek S et al. J Clin Oncol 2014;32 (5s): Abstract 7026.

RESPONSE: Primary Analysis (Week 32) Primary Endpoint Individual Components of Primary Endpoint P < .0001 OR, 28.64 (95% CI, 4.50-1206) SV, spleen volume. Primary endpoint (composite): % of patients who achieved both Hct control and spleen response at week 32 77% in the ruxolitinib group met at least 1 component of the primary endpoint 91% of patients who met the primary endpoint had a confirmed response at week 48 Verstovsek S et al. J Clin Oncol 2014;32 (5s): Abstract 7026.

RESPONSE: Complete Hematologic Remission (Week 32) P = .0034a OR, 3.19 (95% CI, 1.37-7.79) n = 26 n = 10 88.5% of patients (23/26) who achieved CHR maintained it at week 48 a P value, odds ratio, and 95% CI were calculated using stratified exact Cochran-Mantel-Haenszel test. CHR is defined as Hct control, PLT count ≤ 400 × 109/L, and WBC count ≤ 10 × 109/L. Verstovsek S et al. J Clin Oncol 2014;32 (5s): Abstract 7026.

RESPONSE: Improvement in Symptoms Percentage of Patients With a ≥ 50% Improvement in MPN-SAF Symptom Score at Week 32a n = 74 81 74 80 71 80 63 71 MPN-SAF Total Symptom Score Cytokine Symptom Cluster Hyperviscosity Symptom Cluster Splenomegaly Symptom Cluster Tiredness Itching Muscle ache Night sweats Sweating while awake Headache Concentration problems Dizziness Skin redness Vision problems Ringing in ears Numbness/tingling in hands/feet Fullness/early satiety Abdominal discomfort a In patients with scores at both baseline and week 32. MPN-SAF, Myeloproliferative Neoplasm Symptom Assessment Form. Verstovsek S et al. J Clin Oncol 2014;32 (5s): Abstract 7026.

RESPONSE: Improvement in Individual Symptoms Median Percentage Changes From Baseline at Week 32 in Individual Symptom Scores (MPN-SAF) Improvement Median Change From Baseline at Week 32, % Patients with assessments at baseline and week 32, with baseline value >0. Verstovsek S et al. J Clin Oncol 2014;32 (5s): Abstract 7026.

RESPONSE: Thromboembolic Events to Week 32 Patients, n (%) Ruxolitinib (n = 110) BAT (n = 111) All grade Grade 3/4 All thromboembolic events 1 (0.9) 6 (5.4)a 2 (1.8)a Portal vein thrombosis Myocardial infarction Deep vein thrombosis 2 (1.8) Pulmonary embolism Splenic infarction Thrombophlebitis Thrombosis a 1 patient in the BAT group had both myocardial infarction and pulmonary embolism. A higher proportion of patients in the ruxolitinib arm had a history of prior thromboembolic events at baseline than in the BAT arm (35.5% vs 29.5%) There was 1 additional event in the ruxolitinib group over the course of randomized treatment (median exposure 81 weeks) Verstovsek S et al. J Clin Oncol 2014;32 (5s): Abstract 7026.

RESPONSE: Nonhematologic Adverse Events to Week 32 (Regardless of Causality) Patients, % Ruxolitinib (n = 110) BAT (n = 111) All Grades Grade 3/4 Headache 16.4 0.9 18.9 Diarrhea 14.5 7.2 Fatigue 15.3 2.7 Pruritus 13.6 22.5 3.6 Dizziness 11.8 9.9 Muscle spasms 4.5 Dyspnea 10.0 1.8 Abdominal pain 9.1 11.7 Asthenia 7.3 10.8 Events occurring in at least 10% of patients in either treatment group. When adjusted for exposure (per 100 patient-years), the rates of adverse events and grade 3/4 adverse events over the entire course of treatment were lower in patients randomized to ruxolitinib compared with those randomized to BAT (64.7 vs 145.6 and 28.8 vs 44.0) Rate of herpes zoster infection was higher in the ruxolitinib group (6.4% vs 0; all grade 1-2) Verstovsek S et al. J Clin Oncol 2014;32 (5s): Abstract 7026.

RESPONSE: New or Worsening Hematology Laboratory Values to Week 32 Patients, % Ruxolitinib (n = 110) BAT (n = 111) All Grades Grade 3/4 Hemoglobin (low) 43.6 1.8 30.6 0.0 Platelets (low) 24.5 5.5 18.9 3.6 Neutrophils (low) 0.9 8.1 No patients discontinued treatment because of anemia or thrombocytopenia Verstovsek S et al. J Clin Oncol 2014;32 (5s): Abstract 7026.

RESPONSE: Conclusions In patients with PV who had an inadequate response to or were intolerant of HU, ruxolitinib was superior to BAT in: Controlling Hct without phlebotomy Normalizing blood cell count Most adverse events grade 1/2; a few patients developed grade 3/4 cytopenias Ruxolitinib is a valuable new treatment option in this population of patients with PV Reducing spleen volume Improving symptoms Rate of Herpes zoster infection was higher in the ruxolitinib group 85% of patients in the ruxolitinib arm were still receiving treatment at a median follow-up of 81 weeks Verstovsek S et al. J Clin Oncol 2014;32 (5s): Abstract 7026.

Case Study (cont.): Bruce T. Q: What would you recommend for second-line therapy? Busulfan Pipobroman Pegylated interferon alfa Jak inhibitor (ruxolitinib) HDAC inhibitor (givinostat, vorinostat) Reserved for exceptional cases1-3 High hematologic response rates in phase 2 4,5; may be alternative for HU-refractory PV 6 Approved for treatment of patients with PV who have had an inadequate response to or are intolerant of hydroxyurea7 Another novel targeted strategy being tested in patients with PV is inhibition of histone deacetylase (HDAC). Two HDAC inhibitors (givinostat and vorinostat) are currently in phase II studies, alone or in combination with other therapies, including hydroxyurea and JAK inhibitor therapy. [See Stein; see also Sever] Primary HDAC inhibitor references cited in reviews by Stein and Sever: Finazzi G , Vannucchi AM , Martinelli V , et al . A phase II study of givinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapy. Br J Haematol 2013 ; 161 : 688 – 694. Andersen CL, McMullin MF, Ejerblad E, Zweegman S, Harrison C, Fernandes S, Bareford D, Knapper S, Samuelsson J, Lofvenberg E, Linder O, Andreasson B, Ahlstrand E, Jensen MK, Bjerrum OW, Vestergaard H, Larsen H, Klausen TW, Mourits-Andersen T, Hasselbalch HC (2013) A phase II study of vorinostat (MK-0683) in patients with polycythaemia vera and essential thrombocythaemia. Br J Haematol 162(4):498–508. 1. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6; 2. Stein BL, et al. Ann Hematol. 2014; Oct 2 [Epub ahead of print]; 3. Alvarez-Larran A et al. Ann Hematol. 2014 Jul 2 [Epub ahead of print]; 4. Quintas-Cardama A et al. J Clin Oncol. 2009;27:5418-24; 5. Quintas-Cardama A et al. Blood 2013;122:893-901; 6. Sever M et al. Leuk Lymphoma. 2014; Early Online: 1-6; 7. Jakafi (ruxolitinib) prescribing information; Dec 2014; 8. Finazzi G et al. Br J Haematol 2013;161: 688 – 694; 9. Andersen CL et al. Br J Haematol 2013;162:498–508. Investigational, phase II 8,9

Case Study (cont.): Bruce T. This case highlights recent advances in second- line treatment for patients with PV Bruce T was taking HU for thrombotic and splenic control, but he had persistent symptoms that continued to worsen After discussing options, he was enrolled in a clinical trial of ruxolitinib (prior to its PV approval) For patients with PV, the approved ruxolitinib starting dose is 10 mg given orally twice daily

Summary PV is associated with a unique set of burdens attributed to systemic symptoms, healthcare costs, thrombosis, and disease transformation. First-line treatment may not be effective for all patients with PV; a proportion of patients still have symptoms that continue to worsen and require second-line treatment With its recent approval, ruxolitinib is a valuable new treatment option for patients with PV who have had an inadequate response to or are intolerant of hydroxyurea1 it has become clear that PV has a unique burden, regardless of traditional risk classification, attributed to systemic symptoms, healthcare costs, thrombosis, and disease transformation. Unfortunately, current therapies may not always address this PV burden, and effective treatment options are needed. The recent approval of ruxolitinib for HU/refractory/intolerant PV provides a valuable new treatment option for these patients. Reference: Stein BL, Moliterno AR, Tiu RV. Polycythemia vera burden: contributing factors, impact on quality of life, and emerging treatment options. Ann Hematol. 2014; Oct 2 [Epub ahead of print]. 1. Jakafi (ruxolitinib) prescribing information; Dec 2014.