ASH Clinical News August 2017 v3

Peer Review Week September 11 – 17, 2017 Peer Review Week is an annual global event celebrating the essential role that peer review plays in maintaining scientific quality. The theme “Transparency in Review” will be explored in virtual events, such as webinars and social media activities, and in-person panel discussions that coincide with the Peer Review Congress in Chicago, IL. Advanced Practice Providers Oncology Summit The goal of this summit is to foster collaboration, share best practices, and provide a forum for peer-to-peer interaction among advanced practice providers who are actively engaged in caring for oncology patients. Upcoming Dates and Locations: September 15 – 16, 2017 Denver, CO 7th International Symposium on Acute Promyelocytic Leukemia September 24 – 27, 2017 Rome, Italy In addition to advances in biology and treatment of acute promyelocytic leukemia, the meeting includes updates on diagnostics, management, and minimal residual disease assessment. October 13 – 14, 2017 Portland, OR ” G:.5” S:6.75” Adverse Reactions (10% or Greater) in Patients with CML in Study 1 (cont’d) Chronic Phase CML N=406 Back pain Asthenia Pruritus Dizziness Dyspnea Advanced Phase CML N=140 All Grades (%) Grade 3/4 (%) All Grades (%) Grade 3/4 (%) 12 11 11 10 10 1 1 1 0 1 7 10 8 13 19 1 1 0 1 6 Advanced phase (AdvP) CML includes patients with accelerated phase and blast phase CML a. Abdominal pain includes the following preferred terms: abdominal pain, upper abdominal pain, lower abdominal pain, abdominal tenderness, gastrointestinal pain, abdominal discomfort b. Rash includes the following preferred terms: rash, macular rash, pruritic rash, generalized rash, papular rash, maculo-papular rash c. Fatigue includes the following preferred terms: fatigue, malaise d. Edema includes the following preferred terms: edema, peripheral edema, localized edema, face edema e. Respiratory tract infection includes the following preferred terms: respiratory tract infection, upper respiratory tract infection, lower respiratory tract infection, viral upper respiratory tract infection, viral respiratory tract infection In the single-arm, Phase 1/2 clinical trial, one patient (0.2%) experienced QTcF interval of greater than 500 ms. Patients with uncontrolled or significant cardiovascular disease, including QT interval prolongation, were excluded by protocol. Number (%) of Patients with Clinically Relevant or Severe Grade 3/4 Laboratory Test Abnormalities in Patients with CML in Study 1, Safety Population Chronic Phase CML N=406 n (%) 102 (25) 74 (18) 52 (37) 126 (23) 53 (13) 49 (35) 102 (19) 39 (10) 17 (4) 33 (8) 8 (6) 4 (3) 4 (3) 47 (9) 21 (4) 37 (7) 30 (7) 10 (7) 40 (7) 3 (1) 2 (1) 5 (1) Additional Adverse Reactions from Multiple Clinical Trials: The following adverse reactions were reported in patients in clinical trials with BOSULIF (less than 10% of BOSULIF-treated patients). They represent an evaluation of the adverse reaction data from 870 patients with Ph+ leukemia who received at least 1 dose of single-agent BOSULIF. These adverse reactions are presented by system organ class and are ranked by frequency. These adverse reactions are included based on clinical relevance and ranked in order of decreasing seriousness within each category. Blood and Lymphatic System Disorders: 1% and less than 10% - febrile neutropenia Cardiac Disorders: 1% and less than 10% - pericardial effusion; 0.1% and less than 1% - pericarditis Ear and Labyrinth Disorders: 1% and less than 10% - tinnitus Gastrointestinal Disorders: 1% and less than 10% - gastritis; 0.1% and less than 1% - acute pancreatitis, gastrointestinal hemorrhage a General Disorders and Administrative Site Conditions: 1% and less than 10% - chest pain, b pain Hepatobiliary Disorders: 1% and less than 10% - hepatotoxicity, c abnormal hepatic function d ; 0.1% and less than 1% - liver injury Immune System Disorders: 1% and less than 10% - drug hypersensitivity; 0.1% and less than 1% - anaphylactic shock Infections and Infestations: 1% and less than 10% - pneumonia, e influenza, bronchitis Investigations: 1% and less than 10% - electrocardiogram QT prolonged, increased blood creatine phosphokinase, increased blood creatinine Metabolism and Nutrition Disorder: 1% and less than 10% - hyperkalemia, dehydration Musculoskeletal and Connective Tissue Disorder: 1% and less than 10% - myalgia Nervous System Disorders: 1% and less than 10% - dysgeusia Renal and Urinary Disorders: 1% and less than 10% - acute renal failure, renal failure Respiratory, Thoracic, and Mediastinal Disorders: 1% and less than 10% - pleural effusion; 0.1% and less than 1% - acute pulmonary edema, respiratory failure, pulmonary hypertension Skin and Subcutaneous Disorders: 1% and less than 10% - urticaria, pruritus, acne; 0.1% and less than 1% - erythema multiforme, exfoliative rash, drug eruption a. Gastrointestinal hemorrhage includes the following preferred terms: gastrointestinal hemorrhage, gastric hemorrhage, upper gastrointestinal hemorrhage b. Chest pain includes the following preferred terms: chest pain, chest discomfort c. Hepatotoxicity includes the following preferred terms: hepatotoxicity, toxic hepatitis, cytolytic hepatitis d. Abnormal hepatic function includes the following preferred terms: abnormal hepatic function, liver disorder e. Pneumonia includes the following preferred terms: pneumonia, bronchopneumonia, lobar pneumonia, primary atypical pneumonia DRUG INTERACTIONS Drugs That May Increase Bosutinib Plasma Concentrations: CYP3A inhibitors: Avoid the concomitant use of strong or moderate CYP3A inhibitors with BOSULIF as an increase in bosutinib plasma concentration is expected. In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant ketoconazole (strong CYP3A inhibitor) increased bosutinib C max 5.2-fold and AUC 8.6-fold compared to BOSULIF alone. Drugs That May Decrease Bosutinib Plasma Concentrations: CYP3A Inducers: Avoid the OVERDOSAGE Experience with BOSULIF overdose in clinical studies was limited to isolated cases. There were no reports of any serious adverse events associated with the overdoses. Patients who take an overdose of BOSULIF should be observed and given appropriate supportive treatment. PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling. Dosing and Administration: Instruct patients to take BOSULIF exactly as prescribed, not to change their dose or to stop taking BOSULIF unless they are told to do so by their doctor. If patients miss a dose beyond 12 hours, they should be advised to take the next scheduled dose at its regular time. A double dose should not be taken to make up for any missed dose. Advise patients to take BOSULIF with food. Patients should be advised: “Do not crush or cut tablet. Do not touch or handle crushed or broken tablets.” Gastrointestinal Problems: Advise patients that they may experience diarrhea, nausea, vomiting, abdominal pain, or blood in their stools with BOSULIF and to seek medical attention promptly for these symptoms. Low Blood Cell Counts: Advise patients of the possibility of developing low blood cell counts and to immediately report fever, any suggestion of infection, or signs or symptoms suggestive of bleeding or easy bruising. Liver Problems: Advise patients of the possibility of developing liver function abnormalities and to immediately report jaundice. Fluid Retention: Advise patients of the possibility of developing fluid retention (swelling, weight gain, or shortness of breath) and to seek medical attention promptly if these symptoms arise. Renal Problems: Advise patients of the possibility of developing renal problems and to immediately report frequent urination, polyuria, or oliguria. Other Adverse Reactions: Advise patients that they may experience other adverse reactions such as respiratory tract infections, rash, fatigue, loss of appetite, headache, dizziness, back pain, arthralgia, or pruritus with BOSULIF and to seek medical attention if symptoms are significant. There is a possibility of anaphylactic shock. Pregnancy and Breast-feeding: Advise patients that BOSULIF can cause fetal harm when administered to a pregnant woman. Advise women of the potential hazard to the fetus and to avoid becoming pregnant. If BOSULIF is used during pregnancy, or if the patient becomes pregnant while taking BOSULIF, the patient should be apprised of the potential hazard to the fetus. Because a potential risk to the nursing infant cannot be excluded, women that are taking BOSULIF should not breast-feed or provide breast milk to infants. Counsel females of reproductive potential to use effective contraceptive measures to prevent pregnancy during and for at least 30 days after completing treatment with BOSULIF. Instruct patients to contact their physicians immediately if they become pregnant during treatment. Advise patients not to take BOSULIF treatment while pregnant or breast-feeding. If a patient wishes to restart breast-feeding after treatment, advise her to discuss the appropriate timing with her physician. Drug Interactions: Advise patients that BOSULIF and certain other medicines, including over-the-counter medications or herbal supplements (such as St. John’s wort), can interact with each other and may alter the effects of BOSULIF. October 5 – 6, 2017 Buenos Aires, Argentina The InterAmerican Oncology Conference focuses on translational advances in the treatment of cancer, as well as provides updates on targeted therapies, immunotherapies, and emerging treatments in early development. American Association of Blood Banks Annual Meeting October 7 – 10, 2017 San Diego, CA The AABB Annual Meeting brings together transfusion specialists, laboratory supervisors, cellular therapy and blood banking professionals, medical technologists, donor recruiters, physicians, and nurses to advance transfusion and cellular therapies worldwide. CAP17: The Pathologists’ Meeting October 8 – 11, 2017 National Harbor, MD The College of American Pathologists’ 2017 meeting brings together pathology and laboratory medicine experts from around the world. Towards Transformative Therapies for Sickle Cell Disease October 24, 2017 New York, NY This one-day symposium discusses recent developments in sickle cell disease, highlighting key biological mechanisms of disease and reviewing relevant clinical science, while also underscoring the importance of the patient experience. Clinical Application of CAR T Cells November 16 – 17, 2017 New York, NY Memorial Sloan Kettering faculty and national and international experts will discuss clinical and translational aspects of chimeric antigen receptors (CARs), both for hematologic malignancies and solid tumors. 182 (33) 7th InterAmerican Oncology Conference 80 (57) USE IN SPECIFIC POPULATIONS Pregnancy Category D: Based on its mechanism of action and findings in animals, BOSULIF can cause fetal harm when administered to a pregnant woman. Studies in animals showed reproductive toxicities. If BOSULIF is used during pregnancy, or if the patient becomes pregnant while taking BOSULIF, the patient should be apprised of the potential hazard to the fetus. Fetal exposure to bosutinib-derived radioactivity during pregnancy was demonstrated in a placental-transfer study in pregnant rats. Bosutinib was administered orally to pregnant rats during the period of organogenesis at doses of 1, 3, and 10 mg/kg/day. This study did not expose pregnant rats to enough bosutinib to fully evaluate adverse outcomes. In a study conducted in rabbits, bosutinib was administered orally to pregnant animals during the period of organogenesis at doses of 3, 10, and 30 mg/kg/day. At the maternally-toxic dose of 30 mg/kg/day of bosutinib, there were fetal anomalies (fused sternebrae, and two fetuses had various visceral observations), and an approximate 6% decrease in fetal body weight. The dose of 30 mg/kg/day resulted in exposures (AUC) approximately 4 times those in humans at the 500 mg/day dose of bosutinib. Nursing Mothers: It is not known whether bosutinib is excreted in human milk. Bosutinib and/or its metabolites were excreted in the milk of lactating rats. Radioactivity was present in the plasma of suckling offspring 24 to 48 hours after lactating rats received a single oral dose of radioactive bosutinib. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from BOSULIF, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and efficacy of BOSULIF in patients less than 18 years of age have not been established. Geriatric Use: In the Phase 1/2 clinical trial of BOSULIF in patients with Ph+ CML, 20% were age 65 and over, and 4% were 75 and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Hepatic Impairment: Treat with a dose of 200 mg daily in patients with any baseline hepatic impairment. In a dedicated hepatic impairment trial, the exposure to bosutinib increased (C max increased 1.5- to 2.3-fold and the AUC increased 1.9- to 2.4-fold) in patients with hepatic impairment (Child-Pugh classes A, B, and C; N=18) compared to matched healthy volunteers (N=9). Renal Impairment: Reduce the BOSULIF starting dose in patients with severe (CrCL <30 mL/min) or moderate (CrCL 30-50 mL/min) renal impairment at baseline. For patients who have declining renal function while on BOSULIF who cannot tolerate a 500-mg dose, follow dose adjustment recommendations for toxicity. In a dedicated renal impairment trial, compared to subjects with normal renal function, the exposure (AUC) of bosutinib increased by 60% and 35% in subjects with CrCL <30 mL/min and CrCL 30-50 mL/min, respectively, compared to subjects with normal renal function. BOSULIF has not been studied in patients undergoing hemodialysis. September 24 – 27, 2017 San Diego, CA The 58th ASTRO Annual Meeting creates a forum for global collaboration on issues in radiation oncology. Hematology Parameters Platelet Count (Low) less than 50 x 10 9 /L Absolute Neutrophil Count less than 1 x 10 9 /L Hemoglobin (Low) less than 80 g/L Biochemistry Parameters SGPT/ALT greater than 5.0 x ULN SGOT/AST greater than 5.0 x ULN Lipase greater than 2 x ULN Phosphorus (Low) less than 0.6 mmol/L Total Bilirubin greater than 3.0 x ULN Advanced Phase CML All CP and AdvP CML N=546 N=140 n (%) n (%) concomitant use of strong or moderate CYP3A inducers with BOSULIF as a large reduction in exposure is expected. In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant rifampin (strong CYP3A inducer) decreased bosutinib C max by 86% and AUC by 94% compared to BOSULIF alone. Proton Pump Inhibitors: In a dedicated cross-over drug-interaction trial in healthy volunteers (N=24), concomitant lansoprazole (PPI) decreased bosutinib C max by 46% and AUC by 26% compared to BOSULIF alone. Consider using short-acting antacids or H2 blockers instead of PPIs to avoid a r eduction in bosutinib exposure. Separate antacid or H2 blocker dosing and BOSULIF dosing by more than 2 hours. American Society for Radiation Oncology Annual Meeting 2017 American Society of Hematology Annual Meeting December 9 – 12, 2017 Atlanta, GA The 59th ASH Annual Meeting and Exposition will provide an invaluable educational experi- ence and the opportunity to review thousands of scientific abstracts highlighting updates in the hottest topics in hematology. Rx only This brief summary is based on BOSULIF Prescribing Information LAB-0443-6.0, revised April 2016. © 2016 Pfizer Inc. All rights reserved. May 2016 ASH Clinical News 3

ASH Clinical News August 2017 v3 | Page 5