Case Study: An Older Man with PMF and Significant Cytopenias – How to Adjust Ruxolitinib Therapy? 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

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

Patient Overview: Steven B. Patient characteristics – 69-year-old man with multiple CBC abnormalities – Unintentional weight loss over the past 3 months – Otherwise, no major health problems Presentation – Feeling tired and weak; has drenching sweats, abdominal discomfort after eating a small meal – Palpable spleen (15 cm below the costal margin)

Case Study (cont.): Steven B. Hematology – Hemoglobin g/dL [normal range (male), 13.5 – 17.5 g/dL] – Platelet count x 10 9 /L [normal range, 150 – 450 x 10 9 /L] – WBC count – 21 x 10 9 /L [normal range, 3.5 – 10.5 x 10 9 /L] – Left shift without circulating blasts Bone marrow – Megakaryocyte proliferation, atypia – No evidence of reactive marrow fibrosis – Grade 2 reticulin fibers, positive osteosclerosis Genetic testing – BCR-ABL negative – No mutations found in JAK2, MPL, or CALR (triple negative) Diagnosis: primary myelofibrosis (PMF)

Determining Prognosis for Steven B. You have established a diagnosis of primary MF To guide treatment decisions, you assess disease risk using the IPSS (used only at the time of diagnosis) 1 Cervantes F, et al. Blood. 2009;113: IPSS Risk Assessment for PMF 1 Risk Factors No. of Risk Factors Risk LevelMedian OS, mo  Age > 65 yrs0Low135  Constitutional symptoms1Intermediate-195  Hb <10 g/dL2Intermediate-248  WBC count > 25 x 10 9 /L≥ 3High27  Blood blasts ≥1% √ √ Int-2 PMF (2 risk factors; age and MF-related constitutional symptoms)

Rumi E et al. Blood 2014;124: ©2014 by American Society of Hematology Kaplan-Meier Analysis of Survival of PMF Patients Stratified According to Their Driver Mutation

Effect of Driver Mutation on Anemia, Thrombocytopenia Reprinted with permission: Rumi et al. Blood 2014;124: Cumulative incidence of anemia, thrombocytopenia, and marked leukocytosis in PMF patients stratified according to their driver mutation. Rumi E et al. Blood 2014;124:

Q: A clinical sign/symptom of significant thrombocytopenia (i.e., low platelet count) is: A.Fatigue B.Pale skin C.Skin bruising or petechiae D.Tingling of hands/feet

Q: A clinical sign/symptom of significant thrombocytopenia (i.e., low platelet count) is: A.Fatigue B.Pale skin C.Skin bruising or petechiae D.Tingling of hands/feet

Thrombocytopenia: Signs and Symptoms External bleeding – Purpura or petechiae – Prolonged bleeding, even from minor cuts – Nosebleeds or bleeding from tooth brushing – Abnormal vaginal bleeding Internal – Blood in urine or stool – Headaches, neurological problems (rare) Accessed 10/22/2014.

Anemia: Signs and Symptoms Fatigue Shortness of breath Dizziness Headache Coldness in the hands and feet Pale skin Chest pain Accessed 10/22/14.

Myeloproliferative Neoplasm Symptom Assessment (MPN SAF) Form Total Symptom Score: An Assessment Tool for the 10 Most Clinically Important Myeloproliferative Neoplasm Features Sherber R et al. Blood. 2011; 118(2):401-8; Emanuel RM et al, J Clin Oncol 2012;30: Reprinted with permission from: Manea PJ. Clin J Oncol Nursing 2014; 18 (3):

Q: Myelofibrosis is a myeloproliferative disease. Why do cytopenias (i.e., low blood cell counts) occur in these patients? A.Increased destruction of blood cells B.Inefficient hematopoiesis C.Inflammation D.Infection

Q: Myelofibrosis is a myeloproliferative disease. Why do cytopenias (i.e., low blood cell counts) occur in these patients? A.Increased destruction of blood cells B.Inefficient hematopoiesis C.Inflammation D.Infection

Why Do Cytopenias Occur In Patients with Myelofibrosis? Reprinted with permission: Mughal TI et al. Int J Gen Med. 2014;7: Cytopenias vary widely among patients with primary MF

Well characterized signaling pathway in normal hematopoiesis JAK2 specifically mediates cytokine signaling for red blood cells and platelets JAK2 inhibition causes anemia and low platelets – Dose dependent effects Shuai, K. & Liu,B. Nat Rev Immunol. 2003; 3: Reprinted with permission. blood cell JAK Inhibitors and Treatment-Related Cytopenias

Grade 3 or 4 Cytopenias in COMFORT-I Verstovsek S et al. Oncotargets and Ther. 2014;7: ThrombocytopeniaAnemia Worsening of cytopenias can usually be effectively managed with dose modification.

Dose-Related Effect of Ruxolitinib on Platelet Count 1. Verstovsek S et al. Oncotargets and Ther. 2014;7:13-21.

Dose-Related Effect of Ruxolitinib on Hemoglobin Level (Anemia)? Management options include: Ruxolitinib dose modification RBC transfusion Androgens No intervention 1. Verstovsek S et al. Oncotargets and Ther. 2014;7:13-21.

Q: At diagnosis, Steven B. has Int-2 ‘triple-negative’ PMF with significant anemia and thrombocytopenia, and leukocytosis at diagnosis. He has splenomegaly and constitutional symptoms. Is he a candidate for treatment with ruxolitinib? A.Yes B.No C.Consider only if supportive measures first improve his Hb and platelet count

Q: At diagnosis, Steven B. has Int-2 ‘triple-negative’ PMF with significant anemia and thrombocytopenia, and leukocytosis at diagnosis. He has splenomegaly and constitutional symptoms. Is he a candidate for treatment with ruxolitinib? A.Yes – Worsening of cytopenias can usually be effectively managed with frequent monitoring, dose modification/ supportive measures as clinically indicated B.No – alternatives? Not a candidate for HSCT; Dose-limiting cytopenias associated with cytoreductive therapies (eg, hydroxyurea) C.Consider only if supportive measures first improve his Hb and platelet count – manage as clinically indicated; follow ruxolitinib dosing guidelines for thrombocytopenic patients

Case Study (cont.): Steven B. Hematology at diagnosis (Week 0) – Hemoglobin g/dL [normal range (male), 13.5 – 17.5 g/dL] – Platelet count x 109/L [normal range, 150 – 450 x 109/L] – WBC count – 21 x 109/L [normal range, 3.5 – 10.5 x 109/L] Received RBC transfusion (2 Units packed RBC) (Week 2) Follow-up CBC (prior to initiating ruxolitinib) (Week 4) – Hemoglobin – 12.5 g/dL [normal range (male), 13.5 – 17.5 g/dL] – Platelet count x 109/L [normal range, 150 – 450 x 109/L] – WBC count – 20 x 109/L [normal range, 3.5 – 10.5 x 109/L]

Case Study (cont.): Steven B. Q: What starting dose would you choose for this patient? A.25 mg BID B.20 mg BID C.15 mg BID D.5 mg BID

Ruxolitinib Starting Dose Chosen Based on the Patient’s Platelet Count Jakafi Prescribing Information, Steven B.’s platelet count x 10 9 /L Q: What starting dose would you choose for this patient? A.25 mg BID B.20 mg BID C.15 mg BID D.5 mg BID

Filling Prescriptions for Ruxolitinib Available as 5 mg, 10 mg, 15 mg, 20 mg and 25 mg tablets 1 Ruxolitinib is only available through a network of specialty pharmacies 2 – IncyteCARES program coordinates the delivery of ruxolitinib from specialty pharmacies to the patient. It also provides insurance and financial assistance ( Sends prescription and any co-payment assistance information directly to a specialty pharmacy Specialty pharmacy then calls the patient to schedule shipments each month – Prescriptions may also be sent directly to an in-network specialty pharmacy 1. Jakafi prescribing information, Accessed Oct 21, 2014.

Most Patients will Require Ruxolitinib Dose Adjustments Initially or Over the Course of Treatment 1. Verstovsek S et al. Oncotargets and Ther. 2014;7:13-21; 2. Jakafi Prescribing Information, 2014; 3. Mesa RA, Cortes J. J Hematol Oncol. 2013;6:79. In addition, dose adjustments and RBC transfusions may be considered for the management of anemia

Appropriate Monitoring/Dose Adjustments are Needed to Optimize Outcomes Dose adjustments, including timing, need to be tailored to each patient and be accompanied by monitoring of both clinical manifestations (symptoms and splenomegaly) and hematologic parameters. Monitor CBC every 2 to 4 weeks, or as clinically indicated, during the first 8 to 12 weeks of therapy or until a stable dose is reached Aggressive dose increases during the first 3 months of therapy should only be considered if a patient consistently maintains adequate platelet counts Dose titration in patients with platelet counts should follow the guidelines in accordance with US prescribing information Jakafi Prescribing Information, 2014.

Case Study (cont.): Steven B. Ruxolitinib Dose Adjustments Starting platelet count 105 x 10 9 /L Starting dose 15 mg BID Monitor CBC every 2-4 weeks Stabilized dose 10 mg BID; considering increase to 15 mg Weeks 96 – reduced dose to 10 mg BID 83 – reduced dose to 5 mg BID, given precipitous drop in platelets, worsening anemia 90 – stabilized; increased dose to 10 mg BID Effects of therapy: Spleen reduction Substantial improvement in constitutional and abdominal symptoms RBC transfusion (Hb 9.5 g/dL)

Efficacy by Final Titrated Dose (COMFORT-I) 1. Verstovsek S et al. Oncotargets and Ther. 2014;7:13-21.

Ruxolitinib Starting Dose for Patients With Platelet Count 50 x 10 9 /L Alternate Case Scenario: Steven B.’s platelet count - 95 x 10 9 /L Q: What starting dose would you choose for this patient? A.25 mg BID B.20 mg BID C.15 mg BID D.5 mg BID

Ruxolitinib Starting Dose for Patients With Platelet Count 50 x 10 9 /L Alternate Case Scenario: Steven B.’s platelet count - 95 x 10 9 /L Q: What starting dose would you choose for this patient? A.25 mg BID B.20 mg BID C.15 mg BID D.5 mg BID

Dose Modifications in Patients With Platelet Count 50 x 10 9 /L Jakofi PI, 2014

Ruxolitinib in MF Patients with Low Platelet Counts Interim results from a phase II study Talpaz M, et al. J Hematol. 2013;6:81-91.

Ruxolitinib in MF Patients with Low Platelet Counts: Safety (N=50) Adverse Event (AE)All Grades, n (%)Grade 3 or 4, n (%) New-onset Hematologic AEs Hemorrhage8 (16)1 (2) Bruising6 (12)0 Anemia29 (64)19 (42) Thrombocytopenia32 (64)28 (56) Nonhematologic AEs (>20%) Diarrhea14 (28)2 (4) Peripheral edema13 (26)0 Nausea12 (24)2 (4) Abdominal pain12 (24)2 (4) Fatigue11 (22)2 (4)

Expand: Phase 1b, Open-label, Dose Finding Study of ruxolitinib in Patients with MF and Baseline Platelet Counts Between 50 x 109/L and 99 x 109/L Dosing strategy starting at 5 mg BID (with gradual titration based on hematologic parameters and response) can provide clinical benefit in patients with platelet counts 50– 100 × 109/L Reductions in palpable spleen length and improvements in symptoms observed as early as week 4 (when most patients were receiving 5 mg BID dosing) By week 24: – 62% achieved stable ruxolitinib dose ≥10 mg BID – Majority of patients had ≥10% reduction in spleen volume (associated with clinically meaningful improvements in symptoms and QoL). Harrison CN, et al. ASH Annual Meeting Abstracts 2012; 120:177.

Conclusions Cytopenias may develop in some patients with PMF due to inefficient hematopoiesis; incidence varies widely Ruxolitinib is associated with dose-dependent risks of thrombocytopenia and anemia – Expected from its mechanism of action – These do not indicate a worsening of underlying disease – Reduced starting dose for patients with pre-existing thrombocytopenia Dose titration can effectively manage cytopenias without compromising efficacy – Frequent monitoring and management (esp. first 8-12 weeks) are necessary to ensure patients are able to attain stable doses that are safe and provide maximum benefit – Avoid interruptions of therapy (due to return of symptoms within 10 days)