The Urology Nurse-NP/PA | FEBRUARY 2018 | VOL 9 | NO 1 by The Lynx Group

FEBRUARY 2018 VOL 9 NO 1

Precision Medicine and Immunotherapy Highlighted at ASH 2017 By Wayne Kuznar Atlanta, GA—More than 25,000 attendees converged on Atlanta during the middle of a rare winter snowstorm to attend ASH 2017, which featured nearly 5000 scientific abstract presentations ranging from cutting-edge advances in gene therapy and personalized medicine to practice-changing discoveries in immunotherapies. Featured topics included the use of combination therapies in hematologic malignancies and 2 ASH-FDA symposia on new drug approvals for the treatment of acute lymphoid leukemia, non-Hodgkin lymphoma (NHL), and acute myeloid leukemia, as well as a Continued on page 7

Including ASH 2017 Highlights*

CAR T-Cell Therapy Makes Significant Inroads in Lymphoma: Kymriah and Yescarta Show Durable Remissions By Phoebe Starr Atlanta, GA—CD19-directed chimeric antigen receptor (CAR) T-cell therapy continues to show excellent and dura-

Kenneth C. Anderson, MD

Photo credit: © Phil McCarten 2017

PAYERS’ PERSPECTIVES IN ONCOLOGY

Stephen J. Schuster, MD

ble responses in patients with lymphoma who have no other treatment options. Two studies presented at ASH Continued on page 13

Mogamulizumab, Anti-CCR4 Antibody, Improves Survival in Patients with Advanced Cutaneous T-Cell Lymphoma By Charles Bankhead

ASH Recaps “Phenomenal” Year for Acute Myeloid Leukemia Drug Approvals By Chase Doyle Atlanta, GA—Although there have been major advancements in the treatment of hematologic malignancies in recent years, according to Richard Pazdur, MD, Direc-

tor, FDA’s Oncology Center of Excellence, the number of agents approved in 2017 for acute myeloid leukemia (AML) was nothing short of “phenomenal.” Continued on page 20

*This publication is neither endorsed by nor associated with the American Society of Hematology.

Atlanta, GA—Mogamulizumab, a monoclonal antibody targeting CC chemokine receptor type 4 (CCR4), significantly reduced the risk for disease progression or death in patients with untreated cutaneous T-cell lymphoma (CTCL) compared with vorinostat (Zolinza), reported Youn H. Kim, MD,

Continued on page 10

INSIDE EMERGING THERAPIES . . . . . . . . Sotatercept improves outcomes in anemic patients with myelofibrosis Novel TKI shows promise in CML

IMMUNOTHERAPY . . . . . . . . . . . . 12 CAR T-cell therapy shows impressive results in multiple myeloma Combination immunotherapies: when and which to use? VALUE-BASED CARE . . . . . . . . . . 15 Oral multiple myeloma drug decreases productivity loss

Director, Multidisciplinary Cutaneous Lymphoma Program, Stanford Medicine, California, at ASH 2017. Patients receiving mogamulizumab had a median progression-free survival (PFS) of 7.7 months versus 3.1 months in patients who received vorinostat. This difference represents a 47% reduc-

LEUKEMIA HIGHLIGHTS . . . . . . . 19 Ibrutinib plus venetoclax combo shows impressive results in relapsed CLL MULTIPLE MYELOMA . . . . . . . . . . 22 Lenalidomide-elotuzumab maintenance improves responses Daratumumab extends progression-free survival for SMM LYMPHOMA HIGHLIGHTS . . . . . . 23 New combo for first-line treatment of advanced Hodgkin lymphoma High response with 3-drug regimen in follicular lymphoma

#1 PRESCRIBED THERAPY IN FRONTLINE* AND PREVIOUSLY TREATED CLL1†

TAKE CONTROL OF CLL/SLL WITH YOUR FIRST STEP: IMBRUVICA® (ibrutinib) Proven results across key efficacy endpoints: PFS and OS2

Based on market share data from IMS from November 2016 to April 2017. Based on market share data from IMS from May 2014 to April 2017.

* †

CLL SLL

IMBRUVICA® (ibrutinib) is a kinase inhibitor indicated for the treatment of adult patients with: • Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)2 • CLL/SLL with 17p deletion2

IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA®. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and postprocedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA®. The mechanism for the bleeding events is not well understood. IMBRUVICA® may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding IMBRUVICA® for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding. Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA® therapy. Grade 3 or greater infections occurred in 14% to 29% of patients. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA®. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections. Monitor and evaluate patients for fever and infections and treat appropriately. Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 13 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA®. Monitor complete blood counts monthly.

Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA® therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0 to 1% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 0 to 6% of patients. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias. Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA® treatment and follow dose modification guidelines. Hypertension: Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA® with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA®. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate. Second Primary Malignancies: Other malignancies (range, 3 to 16%) including non-skin carcinomas (range, 1 to 4%) have occurred in patients treated with IMBRUVICA®. The most frequent second primary malignancy was non-melanoma skin cancer (range, 2 to 13%). Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA® therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate.

RESONATETM-2 FRONTLINE DATA RESONATETM-2 was a multicenter, randomized 1:1, open-label, Phase 3 trial of IMBRUVICA® vs chlorambucil in frontline CLL/SLL patients ≥65 years (N=269)2,3 Patients with 17p deletion were excluded3

EXTENDED OVERALL SURVIVAL2

PROLONGED PROGRESSION-FREE SURVIVAL2,3

SECONDARY ENDPOINT: OS IMBRUVICA® vs CHLORAMBUCIL

PRIMARY ENDPOINT: PFS IMBRUVICA® vs CHLORAMBUCIL

84% statistically significant reduction in risk of progression or death2,3

Reduced risk of death by more than half

Estimated PFS at 18 months

90% IMBRUVICA®

100

56%

IMBRUVICA®

(95% CI: 89, 97)

90 80 70

95%

PFS (%)

Statistically significant reduction in risk of death

Estimated survival rates at 24 months

HR=0.44 (95% CI: 0.21, 0.92)

60 50 40 30

41%

of patients crossed over to IMBRUVICA® upon disease progression

chlorambucil (95% CI: 77, 90)

84%

Estimated PFS at 18 months

52% Chlorambucil

HR=0.16 (95% CI: 0.09, 0.28); P<0.0001

0 0

• Median follow-up was 28 months2 • Fewer deaths with IMBRUVICA® were observed; 11 (8.1%) in the IMBRUVICA® arm vs 21 (15.8%) in the chlorambucil arm2

Months

N at risk IMB

136

133

130

126

122

CLB

133

121

• Median follow-up was 18 months3 • With IMBRUVICA®, median PFS was not reached vs 18.9 months (95% CI: 14.1, 22.0) with chlorambucil2 • PFS and ORR (CR and PR) were assessed by an IRC according to the revised 2008 iwCLL criteria3

RESONATE™-2 Adverse Reactions ≥15% • Diarrhea (42%) • Musculoskeletal pain (36%) • Cough (22%)

• Rash (21%) • Bruising (19%) • Peripheral edema (19%)

Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA® can cause fetal harm when administered to a pregnant woman. Advise women to avoid becoming pregnant while taking IMBRUVICA® and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Advise men to avoid fathering a child during the same time period.

ADVERSE REACTIONS The most common adverse reactions (≥20%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were thrombocytopenia (62%)*, neutropenia (61%)*, diarrhea (43%), anemia (41%)*, musculoskeletal pain (30%), bruising (30%), rash (30%), fatigue (29%), nausea (29%), hemorrhage (22%), and pyrexia (21%). The most common Grade 3 or 4 adverse reactions (≥5%) in patients with B-cell malignancies (MCL, CLL/SLL, WM and MZL) were neutropenia (39%)*, thrombocytopenia (16%)*, and pneumonia (10%). Approximately 6% of patients discontinued IMBRUVICA® due to adverse reactions. Adverse reactions leading to discontinuation included hemorrhage (1.3%), pneumonia (1.1%), atrial fibrillation (0.8%), neutropenia (0.7%)*, rash (0.7%), diarrhea (0.6%), bruising (0.2%), interstitial lung disease (0.2%), and thrombocytopenia (0.2%)*. Seven percent of patients had a dose reduction due to adverse reactions. *Treatment-emergent decreases (all grades) were based on laboratory measurements and adverse reactions.

To learn more, visit

IMBRUVICAHCP.com

• Pyrexia (17%) • Dry eye (17%) • Arthralgia (16%)

• Skin infection (15%)

DRUG INTERACTIONS CYP3A Inhibitors: Dose adjustments may be recommended. CYP3A Inducers: Avoid coadministration with strong CYP3A inducers.

SPECIFIC POPULATIONS Hepatic Impairment (based on Child-Pugh criteria): Avoid use of IMBRUVICA® in patients with severe baseline hepatic impairment. In patients with mild or moderate impairment, reduce IMBRUVICA® dose. Please see the Brief Summary on the following pages.

CI=confidence interval, CLL=chronic lymphocytic leukemia, HR=hazard ratio, IRC=Independent Review Committee, iwCLL=International Workshop on CLL, OS=overall survival, PFS=progression-free survival, SLL=small lymphocytic lymphoma.

References: 1. Data on file. Pharmacyclics LLC. 2. IMBRUVICA® (ibrutinib) Prescribing Information. Pharmacyclics LLC 2017. 3. Burger JA, Tedeschi A, Barr PM, et al; for the RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437.

Brief Summary of Prescribing Information for IMBRUVICA® (ibrutinib) IMBRUVICA® (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information INDICATIONS AND USAGE Mantle Cell Lymphoma: IMBRUVICA is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Accelerated approval was granted for this indication based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial [see Clinical Studies (14.1) in Full Prescribing Information]. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) [see Clinical Studies (14.2) in Full Prescribing Information]. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma with 17p deletion: IMBRUVICA is indicated for the treatment of adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with 17p deletion [see Clinical Studies (14.2) in Full Prescribing Information]. Waldenström’s Macroglobulinemia: IMBRUVICA is indicated for the treatment of adult patients with Waldenström’s macroglobulinemia (WM) [see Clinical Studies (14.3) in Full Prescribing Information]. Marginal Zone Lymphoma: IMBRUVICA is indicated for the treatment of adult patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20based therapy. Accelerated approval was granted for this indication based on overall response rate [see Clinical Studies (14.4) in Full Prescribing Information]. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. Chronic Graft versus Host Disease: IMBRUVICA is indicated for the treatment of adult patients with chronic graft-versus-host disease (cGVHD) after failure of one or more lines of systemic therapy [see Clinical Studies (14.5) in Full Prescribing Information]. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hemorrhage: Fatal bleeding events have occurred in patients treated with IMBRUVICA. Grade 3 or higher bleeding events (intracranial hemorrhage [including subdural hematoma], gastrointestinal bleeding, hematuria, and post procedural hemorrhage) have occurred in up to 6% of patients. Bleeding events of any grade, including bruising and petechiae, occurred in approximately half of patients treated with IMBRUVICA. The mechanism for the bleeding events is not well understood. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant therapies and patients should be monitored for signs of bleeding. Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery depending upon the type of surgery and the risk of bleeding [see Clinical Studies (14) in Full Prescribing Information]. Infections: Fatal and non-fatal infections (including bacterial, viral, or fungal) have occurred with IMBRUVICA therapy. Grade 3 or greater infections occurred in 14% to 29% of patients [see Adverse Reactions]. Cases of progressive multifocal leukoencephalopathy (PML) and Pneumocystis jirovecii pneumonia (PJP) have occurred in patients treated with IMBRUVICA. Consider prophylaxis according to standard of care in patients who are at increased risk for opportunistic infections. Monitor and evaluate patients for fever and infections and treat appropriately. Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias including neutropenia (range, 13 to 29%), thrombocytopenia (range, 5 to 17%), and anemia (range, 0 to 13%) based on laboratory measurements occurred in patients with B-cell malignancies treated with single agent IMBRUVICA. Monitor complete blood counts monthly. Cardiac Arrhythmias: Fatal and serious cardiac arrhythmias have occurred with IMBRUVICA therapy. Grade 3 or greater ventricular tachyarrhythmias occurred in 0 to 1% of patients, and Grade 3 or greater atrial fibrillation and atrial flutter occurred in 0 to 6% of patients. These events have occurred particularly in patients with cardiac risk factors, hypertension, acute infections, and a previous history of cardiac arrhythmias. Periodically monitor patients clinically for cardiac arrhythmias. Obtain an ECG for patients who develop arrhythmic symptoms (e.g., palpitations, lightheadedness, syncope, chest pain) or new onset dyspnea. Manage cardiac arrhythmias appropriately, and if it persists, consider the risks and benefits of IMBRUVICA treatment and follow dose modification guidelines [see Dosage and Administration (2.3) in Full Prescribing Information]. Hypertension: Hypertension (range, 6 to 17%) has occurred in patients treated with IMBRUVICA with a median time to onset of 4.6 months (range, 0.03 to 22 months). Monitor patients for new onset hypertension or hypertension that is not adequately controlled after starting IMBRUVICA. Adjust existing anti-hypertensive medications and/or initiate anti-hypertensive treatment as appropriate. Second Primary Malignancies: Other malignancies (range, 3 to 16%) including non-skin carcinomas (range, 1 to 4%) have occurred in patients treated with IMBRUVICA. The most frequent second primary malignancy was non-melanoma skin cancer (range, 2 to 13%). Tumor Lysis Syndrome: Tumor lysis syndrome has been infrequently reported with IMBRUVICA therapy. Assess the baseline risk (e.g., high tumor burden) and take appropriate precautions. Monitor patients closely and treat as appropriate. Embryo-Fetal Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when administered to a pregnant woman. Administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis caused embryo-fetal toxicity including malformations at exposures that were 2-20 times higher than those reported in patients with hematologic malignancies. Advise women to avoid becoming pregnant while taking IMBRUVICA and for 1 month after cessation of therapy. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations]. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: • Hemorrhage [see Warnings and Precautions] • Infections [see Warnings and Precautions] • Cytopenias [see Warnings and Precautions] • Cardiac Arrhythmias [see Warnings and Precautions] • Hypertension [see Warnings and Precautions] • Second Primary Malignancies [see Warnings and Precautions] • Tumor Lysis Syndrome [see Warnings and Precautions] Clinical Trials Experience: Because clinical trials are conducted under widely variable conditions, adverse event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA in a clinical trial (Study 1104) that included 111 patients with previously treated MCL treated with 560 mg daily with a median treatment duration of 8.3 months. The most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, anemia, fatigue, musculoskeletal pain, peripheral edema, upper respiratory tract infection, nausea, bruising, dyspnea, constipation, rash, abdominal pain, vomiting and decreased appetite (see Tables 1 and 2). The most common Grade 3 or 4 non-hematological adverse reactions (≥ 5%) were pneumonia, abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. Fatal and serious cases of renal failure have occurred with IMBRUVICA therapy. Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 9% of patients. Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560 mg daily occurring at a rate of ≥ 10% are presented in Table 1.

IMBRUVICA® (ibrutinib) capsules Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111) Body System Adverse Reaction All Grades (%) Grade 3 or 4 (%) Gastrointestinal Diarrhea 51 5 disorders Nausea 31 0 Constipation 25 0 Abdominal pain 24 5 Vomiting 23 0 Stomatitis 17 1 Dyspepsia 11 0 Infections and Upper respiratory tract infection 34 0 infestations Urinary tract infection 14 3 Pneumonia 14 7 Skin infections 14 5 Sinusitis 13 1 General disorders Fatigue 41 5 and administration Peripheral edema 35 3 site conditions Pyrexia 18 1 Asthenia 14 3 Skin and Bruising 30 0 subcutaneous tissue Rash 25 3 disorders Petechiae 11 0 Musculoskeletal and Musculoskeletal pain 37 1 connective tissue Muscle spasms 14 0 disorders Arthralgia 11 0 Respiratory, thoracic Dyspnea 27 4 and mediastinal Cough 19 0 disorders Epistaxis 11 0 Metabolism and Decreased appetite 21 2 nutrition disorders Dehydration 12 4 Nervous system Dizziness 14 0 disorders Headache 13 0 Table 2: Treatment-Emergent* Hematologic Laboratory Abnormalities in Patients with MCL (N=111) Percent of Patients (N=111) All Grades Grade 3 or 4 (%) (%) Platelets Decreased 57 17 Neutrophils Decreased 47 29 Hemoglobin Decreased 41 9 * Based on laboratory measurements and adverse reactions Ten patients (9%) discontinued treatment due to adverse reactions in the trial (N=111). The most frequent adverse reaction leading to treatment discontinuation was subdural hematoma (1.8%). Adverse reactions leading to dose reduction occurred in 14% of patients. Patients with MCL who develop lymphocytosis greater than 400,000/mcL have developed intracranial hemorrhage, lethargy, gait instability, and headache. However, some of these cases were in the setting of disease progression. Forty percent of patients had elevated uric acid levels on study including 13% with values above 10 mg/dL. Adverse reaction of hyperuricemia was reported for 15% of patients. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: The data described below reflect exposure in one single-arm, open-label clinical trial (Study 1102) and three randomized controlled clinical trials (RESONATE, RESONATE-2, and HELIOS) in patients with CLL/SLL (n=1278 total and n=668 patients exposed to IMBRUVICA). Study 1102 included 51 patients with previously treated CLL/SLL, RESONATE included 391 randomized patients with previously treated CLL or SLL who received single agent IMBRUVICA or ofatumumab, RESONATE-2 included 269 randomized patients 65 years or older with treatment naïve-CLL or SLL who received single agent IMBRUVICA or chlorambucil, and HELIOS included 578 randomized patients with previously treated CLL or SLL who received IMBRUVICA in combination with bendamustine and rituximab or placebo in combination with bendamustine and rituximab. The most commonly occurring adverse reactions in Studies 1102, RESONATE, RESONATE-2, and HELIOS in patients with CLL/SLL receiving IMBRUVICA (≥ 20%) were neutropenia, thrombocytopenia, anemia, diarrhea, musculoskeletal pain, nausea, rash, bruising, fatigue, pyrexia and hemorrhage. Four to 10 percent of patients receiving IMBRUVICA in Studies 1102, RESONATE, RESONATE-2, and HELIOS discontinued treatment due to adverse reactions. These included pneumonia, hemorrhage, atrial fibrillation, rash and neutropenia (1% each). Adverse reactions leading to dose reduction occurred in approximately 6% of patients. Study 1102: Adverse reactions and laboratory abnormalities from the CLL/SLL trial (N=51) using single agent IMBRUVICA 420 mg daily in patients with previously treated CLL/SLL occurring at a rate of ≥ 10% with a median duration of treatment of 15.6 months are presented in Tables 3 and 4. Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL/SLL (N=51) in Study 1102 Body System Adverse Reaction All Grades (%) Grade 3 or 4 (%) Gastrointestinal Diarrhea 59 4 disorders Constipation 22 2 Nausea 20 2 Stomatitis 20 0 Vomiting 18 2 Abdominal pain 14 0 Dyspepsia 12 0 Infections and Upper respiratory tract infection 47 2 infestations Sinusitis 22 6 Skin infection 16 6 Pneumonia 12 10 Urinary tract infection 12 2 General disorders and Fatigue 33 6 administration site Pyrexia 24 2 conditions Peripheral edema 22 0 Asthenia 14 6 Chills 12 0 Skin and Bruising 51 2 subcutaneous tissue Rash 25 0 disorders Petechiae 16 0 Respiratory, thoracic Cough 22 0 and mediastinal Oropharyngeal pain 14 0 disorders Dyspnea 12 0 Musculoskeletal and Musculoskeletal pain 25 6 connective tissue Arthralgia 24 0 disorders Muscle spasms 18 2 Nervous system Dizziness 20 0 disorders Headache 18 2 Metabolism and Decreased appetite 16 2 nutrition disorders Neoplasms benign, Second malignancies* 12* 0 malignant, unspecified Vascular disorders Hypertension 16 8 * One patient death due to histiocytic sarcoma.

IMBRUVICA® (ibrutinib) capsules Table 4: Treatment-Emergent* Hematologic Laboratory Abnormalities in Patients with CLL/SLL (N=51) in Study 1102 Percent of Patients (N=51) All Grades (%) Grade 3 or 4 (%) Platelets Decreased 69 12 Neutrophils Decreased 53 26 Hemoglobin Decreased 43 0 * Based on laboratory measurements per IWCLL criteria and adverse reactions. RESONATE: Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect exposure to IMBRUVICA with a median duration of 8.6 months and exposure to ofatumumab with a median of 5.3 months in RESONATE in patients with previously treated CLL/SLL. Table 5: Adverse Reactions Reported in ≥ 10% of Patients and at Least 2% Greater in the IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE IMBRUVICA Ofatumumab (N=195) (N=191) Body System All Grades Grade 3 or 4 All Grades Grade 3 or 4 Adverse Reaction (%) (%) (%) (%) Gastrointestinal disorders Diarrhea 48 4 18 2 Nausea 26 2 18 0 Stomatitis* 17 1 6 1 Constipation 15 0 9 0 Vomiting 14 0 6 1 General disorders and administration site conditions Pyrexia 24 2 15 1 Infections and infestations Upper respiratory tract infection 16 1 11 2 Pneumonia* 15 10 13 9 Sinusitis* 11 1 6 0 Urinary tract infection 10 4 5 1 Skin and subcutaneous tissue disorders Rash* 24 3 13 0 Petechiae 14 0 1 0 Bruising* 12 0 1 0 Musculoskeletal and connective tissue disorders Musculoskeletal Pain* 28 2 18 1 Arthralgia 17 1 7 0 Nervous system disorders Headache 14 1 6 0 Dizziness 11 0 5 0 Injury, poisoning and procedural complications Contusion 11 0 3 0 Eye disorders Vision blurred 10 0 3 0 Subjects with multiple events for a given ADR term are counted once only for each ADR term. The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms Table 6: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with CLL/SLL in RESONATE IMBRUVICA Ofatumumab (N=195) (N=191) All Grades Grade 3 or 4 All Grades Grade 3 or 4 (%) (%) (%) (%) Neutrophils Decreased 51 23 57 26 Platelets Decreased 52 5 45 10 Hemoglobin Decreased 36 0 21 0 RESONATE-2: Adverse reactions described below in Table 7 reflect exposure to IMBRUVICA with a median duration of 17.4 months. The median exposure to chlorambucil was 7.1 months in RESONATE-2. Table 7: Adverse Reactions Reported in ≥ 10% of Patients and at Least 2% Greater in the IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE-2 IMBRUVICA Chlorambucil (N=135) (N=132) Body System All Grades Grade 3 or 4 All Grades Grade 3 or 4 Adverse Reaction (%) (%) (%) (%) Gastrointestinal disorders Diarrhea 42 4 17 0 Stomatitis* 14 1 4 1 Musculoskeletal and connective tissue disorders Musculoskeletal pain* 36 4 20 0 Arthralgia 16 1 7 1 Muscle spasms 11 0 5 0 Eye Disorders Dry eye 17 0 5 0 Lacrimation increased 13 0 6 0 Vision blurred 13 0 8 0 Visual acuity reduced 11 0 2 0 Skin and subcutaneous tissue disorders Rash* 21 4 12 2 Bruising* 19 0 7 0 Infections and infestations Skin infection* 15 2 3 1 Pneumonia* 14 8 7 4 Urinary tract infections 10 1 8 1

IMBRUVICA® (ibrutinib) capsules Table 7: Adverse Reactions Reported in ≥ 10% of Patients and at Least 2% Greater in the IMBRUVICA Treated Arm in Patients with CLL/SLL in RESONATE-2 (continued) IMBRUVICA Chlorambucil (N=135) (N=132) Body System All Grades Grade 3 or 4 All Grades Grade 3 or 4 Adverse Reaction (%) (%) (%) (%) Respiratory, thoracic and mediastinal disorders Cough 22 0 15 0 General disorders and administration site conditions Peripheral edema 19 1 9 0 Pyrexia 17 0 14 2 Vascular Disorders Hypertension* 14 4 1 0 Nervous System Disorders Headache 12 1 10 2 Subjects with multiple events for a given ADR term are counted once only for each ADR term. The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms HELIOS: Adverse reactions described below in Table 8 reflect exposure to IMBRUVICA + BR with a median duration of 14.7 months and exposure to placebo + BR with a median of 12.8 months in HELIOS in patients with previously treated CLL/SLL. Table 8: Adverse Reactions Reported in at Least 10% of Patients and at Least 2% Greater in the IMBRUVICA Arm in Patients with CLL/SLL in HELIOS Ibrutinib + BR Placebo + BR (N=287) (N=287) All Grades Grade 3 or 4 All Grades Grade 3 or 4 Body System (%) (%) (%) (%) Adverse Reaction Blood and lymphatic system disorders Neutropenia* 66 61 60 55 Thrombocytopenia* 34 16 26 16 Skin and subcutaneous tissue disorders Rash* 32 4 25 1 Bruising* 20 <1 8 <1 Gastrointestinal disorders Diarrhea 36 2 23 1 Abdominal Pain 12 1 8 <1 Musculoskeletal and connective tissue disorders Musculoskeletal pain* 29 2 20 0 Muscle spasms 12 <1 5 0 General disorders and administration site conditions Pyrexia 25 4 22 2 Vascular Disorders Hemorrhage* 19 2 9 1 Hypertension* 11 5 5 2 Infections and infestations Bronchitis 13 2 10 3 Skin infection* 10 3 6 2 Metabolism and nutrition disorders Hyperuricemia 10 2 6 0 The body system and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. * Includes multiple ADR terms <1 used for frequency above 0 and below 0.5% Atrial fibrillation of any grade occurred in 7% of patients treated with IMBRUVICA + BR and 2% of patients treated with placebo + BR. The frequency of Grade 3 and 4 atrial fibrillation was 3% in patients treated with IMBRUVICA + BR and 1% in patients treated with placebo +BR. Waldenström’s Macroglobulinemia and Marginal Zone Lymphoma: The data described below reflect exposure to IMBRUVICA in open-label clinical trials that included 63 patients with previously treated WM (Study 1118) and 63 patients with previously treated MZL (Study 1121). The most commonly occurring adverse reactions in Studies 1118 and 1121 (≥ 20%) were thrombocytopenia, diarrhea, neutropenia, fatigue, bruising, hemorrhage, anemia, rash, musculoskeletal pain, and nausea. Nine percent of patients receiving IMBRUVICA across Studies 1118 and 1121 discontinued treatment due to adverse reactions. The most common adverse reactions leading to discontinuation were interstitial lung disease, diarrhea and rash. Adverse reactions leading to dose reduction occurred in 10% of patients. Study 1118: Adverse reactions and laboratory abnormalities described below in Tables 9 and 10 reflect exposure to IMBRUVICA with a median duration of 11.7 months in Study 1118. Table 9: Non-Hematologic Adverse Reactions in ≥ 10% in Patients with WM in Study 1118 (N=63) Body System Adverse Reaction All Grades (%) Grade 3 or 4 (%) Gastrointestinal disorders Diarrhea 37 0 Nausea 21 0 Stomatitis* 16 0 Gastroesophageal reflux disease 13 0 Skin and subcutaneous tissue Rash* 22 0 disorders Bruising* 16 0 Pruritus 11 0 General disorders and Fatigue 21 0 administrative site conditions Musculoskeletal and Muscle spasms 21 0 connective tissue disorders Arthropathy 13 0

IMBRUVICA® (ibrutinib) capsules

Table 9: Non-Hematologic Adverse Reactions in ≥ 10% in Patients with WM in Study 1118 (N=63) (continued) Body System Adverse Reaction All Grades (%) Grade 3 or 4 (%) Infections and infestations Upper respiratory tract infection 19 0 Sinusitis 19 0 Pneumonia* 14 6 Skin infection* 14 2 Respiratory, thoracic and Epistaxis 19 0 mediastinal disorders Cough 13 0 Nervous system disorders Dizziness 14 0 Headache 13 0 Neoplasms benign, malignant, Skin cancer* 11 0 and unspecified (including cysts and polyps) The body system and individual ADR preferred terms are sorted in descending frequency order. * Includes multiple ADR terms. Table 10: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with WM in Study 1118 (N=63) Percent of Patients (N=63) All Grades (%) Grade 3 or 4 (%) Platelets Decreased 43 13 Neutrophils Decreased 44 19 Hemoglobin Decreased 13 8 Study 1121: Adverse reactions and laboratory abnormalities described below in Tables 11 and 12 reflect exposure to IMBRUVICA with a median duration of 11.6 months in Study 1121. Table 11: Non-Hematologic Adverse Reactions in ≥ 10% in Patients with MZL in Study 1121 (N=63) Body System Adverse Reaction All Grades Grade 3 or 4 (%) (%) Gastrointestinal Diarrhea 43 5 disorders Nausea 25 0 Dyspepsia 19 0 Stomatitis* 17 2 Abdominal pain 16 2 Constipation 14 0 Abdominal pain Upper 13 0 Vomiting 11 2 General disorders and Fatigue 44 6 administrative site Peripheral edema 24 2 conditions Pyrexia 17 2 Skin and subcutaneous Bruising * 41 0 tissue disorders Rash* 29 5 Pruritus 14 0 Musculoskeletal and Musculoskeletal pain* 40 3 connective tissue Arthralgia 24 2 disorders Muscle spasms 19 3 Infections and Upper respiratory tract infection 21 0 infestations Sinusitis* 19 0 Bronchitis 11 0 Pneumonia* 11 10 Metabolism and nutrition Decreased appetite 16 2 disorders Hyperuricemia 16 0 Hypoalbuminemia 14 0 Hypokalemia 13 0 Vascular Disorders Hemorrhage* 30 0 Hypertension* 14 5 Respiratory, thoracic and Cough 22 2 mediastinal disorders Dyspnea 21 2 Nervous system Dizziness 19 0 disorders Headache 13 0 Psychiatric disorders Anxiety 16 2 The body system and individual ADR preferred terms are sorted in descending frequency order. * Includes multiple ADR terms. Table 12: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with MZL in Study 1121 (N=63) Percent of Patients (N=63) Platelets Decreased Hemoglobin Decreased Neutrophils Decreased

All Grades (%) 49 43 22

Grade 3 or 4 (%) 6 13 13

Chronic Graft versus Host Disease: The data described below reflect exposure to IMBRUVICA in an open-label clinical trial (Study 1129) that included 42 patients with cGVHD after failure of first line corticosteroid therapy and required additional therapy. The most commonly occurring adverse reactions in the cGVHD trial (≥ 20%) were fatigue, bruising, diarrhea, thrombocytopenia, stomatitis, muscle spasms, nausea, hemorrhage, anemia, and pneumonia. Atrial fibrillation occurred in one patient (2%) which was Grade 3. Twenty-four percent of patients receiving IMBRUVICA in the cGVHD trial discontinued treatment due to adverse reactions. The most common adverse reactions leading to discontinuation were fatigue and pneumonia. Adverse reactions leading to dose reduction occurred in 26% of patients. Adverse reactions and laboratory abnormalities described below in Tables 13 and 14 reflect exposure to IMBRUVICA with a median duration of 4.4 months in the cGVHD trial. Table 13: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with cGVHD (N=42) Body System

Adverse Reaction

General disorders and Fatigue administration site conditions Pyrexia Edema peripheral Skin and subcutaneous tissue Bruising* disorders Rash* Gastrointestinal disorders Diarrhea Stomatitis* Nausea Constipation Musculoskeletal and Muscle spasms connective tissue disorders Muscoloskeletal pain* Vascular disorders Hemorrhage* Infections and infestations Pneumonia* Upper respiratory tract infection Sepsis*

All Grades (%)

Grade 3 or 4 (%)

57 17 12 40 12 36 29 26 12 29 14 26 21 19 10

12 5 0 0 0 10 2 0 0 2 5 0 10 0 10

Table 13: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with cGVHD (N=42) (continued) Body System

Adverse Reaction

All Grades (%)

Grade 3 or 4(%)

Nervous system disorders Headache 17 5 Injury, poisoning and Fall 17 0 procedural complications Respiratory, thoracic and Cough 14 0 mediastinal disorders Dyspnea 12 2 Metabolism and nutrition Hypokalemia 12 7 disorders The system organ class and individual ADR preferred terms are sorted in descending frequency order. * Includes multiple ADR terms. Table 14: Treatment-Emergent Hematologic Laboratory Abnormalities in Patients with cGVHD (N=42)

Platelets Decreased Neutrophils Decreased Hemoglobin Decreased

Percent of Patients (N=42) All Grades (%) Grade 3 or 4 (%) 33 0 10 10 24 2

Additional Important Adverse Reactions: Cardiac Arrhythmias: In randomized controlled trials (n=1227; median treatment duration of 13.1 months for patients treated with IMBRUVICA and 9.0 months for patients in the control arm), the incidence of ventricular tachyarrhythmias (ventricular extrasystoles, ventricular arrhythmias, ventricular fibrillation, ventricular flutter, and ventricular tachycardia) of any grade was 1.0% versus 0.2% and of Grade 3 or greater was 0.2% versus 0% in patients treated with IMBRUVICA compared to patients in the control arm. In addition, the incidence of atrial fibrillation and atrial flutter of any grade was 7% versus 1.5% and for Grade 3 or greater was 2.8% versus 0.3% in patients treated with IMBRUVICA compared to patients in the control arm. Diarrhea: Diarrhea of any grade occurred at a rate of 43% (range, 36% to 59%) of patients treated with IMBRUVICA. Grade 2 diarrhea occurred in 9% (range, 3% to 14%) and Grade 3 in 3% (range, 0 to 5%) of patients treated with IMBRUVICA. The median time to first onset of any grade diarrhea was 10 days (range, 0 to 627), of Grade 2 was 39 days (range, 1 to 719) and of Grade 3 was 74 days (range, 3 to 627). Of the patients who reported diarrhea, 82% had complete resolution, 1% had partial improvement and 17% had no reported improvement at time of analysis. The median time from onset to resolution or improvement of any grade diarrhea was 5 days (range, 1 to 418), and was similar for Grades 2 and 3. Less than 1% of patients discontinued IMBRUVICA due to diarrhea. Visual Disturbance: Blurred vision and decreased visual acuity of any grade occurred in 10% of patients treated with IMBRUVICA (9% Grade 1, 2% Grade 2). The median time to first onset was 85 days (range, 1 to 414 days). Of the patients with visual disturbance, 61% had complete resolution and 38% had no reported improvement at time of analysis. The median time from onset to resolution or improvement was 29 days (range, 1 to 335 days). Postmarketing Experience: The following adverse reactions have been identified during postapproval use of IMBRUVICA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Hepatobiliary disorders: hepatic failure • Respiratory disorders: interstitial lung disease • Metabolic and nutrition disorders: tumor lysis syndrome [see Warnings & Precautions] • Immune system disorders: anaphylactic shock, angioedema, urticaria • Skin and subcutaneous tissue disorders: Stevens-Johnson Syndrome (SJS), onychoclasis • Infections: hepatitis B reactivation DRUG INTERACTIONS Effect of CYP3A Inhibitors on Ibrutinib: The coadministration of IMBRUVICA with a strong or moderate CYP3A inhibitor may increase ibrutinib plasma concentrations [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Increased ibrutinib concentrations may increase the risk of drug-related toxicity. Dose modifications of IMBRUVICA are recommended when used concomitantly with posaconazole, voriconazole and moderate CYP3A inhibitors [see Dosage and Administration (2.4) in Full Prescribing Information]. Avoid concomitant use of other strong CYP3A inhibitors. Interrupt IMBRUVICA if these inhibitors will be used short-term (such as anti-infectives for seven days or less) [see Dosage and Administration (2.4) in Full Prescribing Information]. Examplesa of strong CYP3A inhibitors include: boceprevir, clarithromycin, cobicistat conivaptan, danoprevir and ritonavir, diltiazem, elvitegravir and ritonavir, idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), ritonavir, saquinavir and ritonavir, tipranavir and ritonavir, and troleandomycin. Examplesa of moderate CYP3A inhibitors include: aprepitant, cimetidine, ciprofloxacin, clotrimazole, crizotinib, cyclosporine, dronedarone, erythromycin, fluconazole, fluvoxamine, imatinib, tofisopam, and verapamil. Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain strong or moderate inhibitors of CYP3A. Effect of CYP3A Inducers on Ibrutinib: The coadministration of IMBRUVICA with strong CYP3A inducers may decrease ibrutinib concentrations. Avoid coadministration with strong CYP3A inducers [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Examplesa of strong CYP3A inducers include: carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, and St. John’s wortb. a These examples are a guide and not considered a comprehensive list of all possible drugs that may fit this category. The healthcare provider should consult appropriate references for comprehensive information. b The induction potency of St. John’s wort may vary widely based on preparation. USE IN SPECIFIC POPULATIONS Pregnancy: Risk Summary: IMBRUVICA, a kinase inhibitor, can cause fetal harm based on findings from animal studies. There are no available data on IMBRUVICA use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, administration of ibrutinib to pregnant rats and rabbits during the period of organogenesis at exposures up to 2-20 times the clinical doses of 420-560 mg daily produced embryofetal toxicity including structural abnormalities (see Animal Data). If IMBRUVICA is used during pregnancy or if the patient becomes pregnant while taking IMBRUVICA, the patient should be apprised of the potential hazard to the fetus. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Animal Data: Ibrutinib was administered orally to pregnant rats during the period of organogenesis at doses of 10, 40 and 80 mg/kg/day. Ibrutinib at a dose of 80 mg/kg/day was associated with visceral malformations (heart and major vessels) and increased resorptions and post-implantation loss. The dose of 80 mg/kg/day in rats is approximately 14 times the exposure (AUC) in patients with MCL or

IMBRUVICA® (ibrutinib) capsules

Active ingredient made in China. Distributed and Marketed by: Pharmacyclics LLC Sunnyvale, CA USA 94085 and Marketed by: Janssen Biotech, Inc. Horsham, PA USA 19044 Patent http://www.imbruvica.com IMBRUVICA® is a registered trademark owned by Pharmacyclics LLC © Pharmacyclics LLC 2017 © Janssen Biotech, Inc. 2017 PRC-03737

VOL. 9

NO. 1

INTRODUCTION

Precision Medicine... late-breaking abstracts session that featured 6 studies with new data related to novel drugs with high clinical impact. “With precision medicine being a major theme this year, we are excited to highlight the cross-cutting areas of genomics and immunology and the promise they offer to transform the way we care for our patients,” said ASH President Kenneth C. Anderson, MD, Program Director, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, Boston. Targeted Therapies

Several studies highlighted novel targeted cancer therapies being used to improve outcomes and quality of life for patients with rare, advanced, or difficult-to-treat hematologic malignancies. These included a phase 3 comparison of the investigational agent mogamuliz umab with standard-of-care vorinostat (Zolinza) in patients with previously treated cutaneous T-cell lymphoma (see page 10). Median progression-free survival was 7.7 months for patients receiving mogamulizumab versus 3.1 months with vorinostat. Also, patients with advanced Hodg kin lymphoma who received a multidrug regimen that included brentuximab vedotin (Adcetris) had a 23% reduction in the risk of disease progression, death, or the need for additional therapy, compared with patients who received the standard 4-drug first-line regimen for advanced Hodgkin lymphoma (see page 23). These results represent the first successful effort in more than 30 years to improve outcomes of first-line treatment in patients with advanced Hodgkin lymphoma, without escalating chemotherapy to cause unacceptable toxicity. In another important study, one-third of patients with previously treated chronic lymphocytic leukemia (CLL) had no detectable disease after 6 months of therapy with the combination of ibrutinib (Imbruvica) and venetoclax (Venclexta)—both of which are approved for CLL as monotherapies— with no increase in the occurrence of tumor lysis syndrome (see page 19).

Immunotherapy

Three studies spotlighted the emerging role of immunotherapy with chimeric antigen receptor (CAR) T-cell therapies to achieve remissions in NHL, diffuse large B-cell lymphoma (DLBCL), and multiple myeloma. Among 108 patients with refractory aggressive NHL, more than 50% were still alive at least 1 year after receiving a

FEBRUARY 2018

Continued from the cover

MZL and 20 times the exposure in patients with CLL/SLL or WM administered the dose of 560 mg daily and 420 mg daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased fetal weights. The dose of 40 mg/kg/day in rats is approximately 6 times the exposure (AUC) in patients with MCL administered the dose of 560 mg daily. Ibrutinib was also administered orally to pregnant rabbits during the period of organogenesis at doses of 5, 15, and 45 mg/kg/day. Ibrutinib at a dose of 15 mg/kg/day or greater was associated with skeletal variations (fused sternebrae) and ibrutinib at a dose of 45 mg/kg/day was associated with increased resorptions and post-implantation loss. The dose of 15 mg/kg/day in rabbits is approximately 2.0 times the exposure (AUC) in patients with MCL and 2.8 times the exposure in patients with CLL/SLL or WM administered the dose of 560 and 420 mg daily, respectively. Lactation: Risk Summary: There is no information regarding the presence of ibrutinib or its metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. The development and health benefits of breastfeeding should be considered along with the mother’s clinical need for IMBRUVICA and any potential adverse effects on the breastfed child from IMBRUVICA or from the underlying maternal condition. Females and Males of Reproductive Potential: Pregnancy Testing: Verify the pregnancy status of females of reproductive potential prior to initiating IMBRUVICA therapy. Contraception Females: Advise females of reproductive potential to avoid pregnancy while taking IMBRUVICA and for up to 1 month after ending treatment. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be informed of the potential hazard to a fetus. Males: Advise men to avoid fathering a child while receiving IMBRUVICA, and for 1 month following the last dose of IMBRUVICA. Pediatric Use: The safety and effectiveness of IMBRUVICA in pediatric patients has not been established. Geriatric Use: Of the 905 patients in clinical studies of IMBRUVICA, 62% were ≥ 65 years of age, while 21% were ≥75 years of age. No overall differences in effectiveness were observed between younger and older patients. Anemia (all grades) and Grade 3 or higher pneumonia occurred more frequently among older patients treated with IMBRUVICA. Hepatic Impairment: Avoid use of IMBRUVICA in patients with severe hepatic impairment (ChildPugh class C). The safety of IMBRUVICA has not been evaluated in patients with mild to severe hepatic impairment by Child-Pugh criteria. Dose modifications of IMBRUVICA are recommended in patients with mild or moderate hepatic impairment (Child-Pugh class A and B). Monitor patients for adverse reactions of IMBRUVICA closely [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) in Full Prescribing Information]. Plasmapheresis: Management of hyperviscosity in WM patients may include plasmapheresis before and during treatment with IMBRUVICA. Modifications to IMBRUVICA dosing are not required. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). • Hemorrhage: Inform patients of the possibility of bleeding, and to report any signs or symptoms (severe headache, blood in stools or urine, prolonged or uncontrolled bleeding). Inform the patient that IMBRUVICA may need to be interrupted for medical or dental procedures [see Warnings and Precautions]. • Infections: Inform patients of the possibility of serious infection, and to report any signs or symptoms (fever, chills, weakness, confusion) suggestive of infection [see Warnings and Precautions]. • Cardiac Arrhythmias: Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, shortness of breath, and chest discomfort [see Warnings and Precautions]. • Hypertension: Inform patients that high blood pressure has occurred in patients taking IMBRUVICA, which may require treatment with anti-hypertensive therapy [see Warnings and Precautions]. • Second primary malignancies: Inform patients that other malignancies have occurred in patients who have been treated with IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions]. • Tumor lysis syndrome: Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation [see Warnings and Precautions]. • Embryo-fetal toxicity: Advise women of the potential hazard to a fetus and to avoid becoming pregnant during treatment and for 1 month after the last dose of IMBRUVICA [see Warnings and Precautions]. • Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions and that the capsules should be swallowed whole with a glass of water without being opened, broken, or chewed at approximately the same time each day [see Dosage and Administration (2.1) in Full Prescribing Information]. • Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon as possible on the same day with a return to the normal schedule the following day. Patients should not take extra capsules to make up the missed dose [see Dosage and Administration (2.6) in Full Prescribing Information]. • Advise patients of the common side effects associated with IMBRUVICA [see Adverse Reactions]. Direct the patient to a complete list of adverse drug reactions in PATIENT INFORMATION. • Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products [see Drug Interactions]. • Advise patients that they may experience loose stools or diarrhea, and should contact their doctor if their diarrhea persists. Advise patients to maintain adequate hydration [see Adverse Reactions].

“With precision medicine being a major theme this year, we are excited to highlight the cross-cutting areas of genomics and immunology and the promise they offer to transform the way we care for our patients.” —Kenneth C. Anderson, MD

single infusion of the CAR T-cell therapy axicabtagene ciloleucel (Yescarta), which targets the CD-19 protein frequently found on lymphoma cells. More than 1 year after infusion of CAR T-cells, 42% of patients remain in remission and 40% have no evidence of cancer (see page 13). And in a 6-month interim analysis of the JULIET trial, the overall response rate (ORR) was 37% and the complete response rate was 30% after a single infusion of tisagenlecleucel (Kymriah), another CAR T-cell therapy directed at CD-19, in adult patients with relapsed or refractory DLBCL. Twenty-six percent of patients had therapy on an outpatient basis, noted lead investigator Stephen J. Schuster, MD, Director, Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia. Responders remain relapse-free without additional therapy, and median overall survival has yet to be reached (see page 13). Finally, a 1-time infusion of an investigational CAR T-cell therapy that targets BCMA—a protein found on most multiple myeloma cells—elicited an 86% ORR in 21 patients with relapsed or refractory disease after a median of 7 previous treatments, according to results from a phase 1 study. Among 18 patients who received higher, active doses of infused CAR T-cells, the response rate improved to 94%, with manageable adverse effects (see page 12). s

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EDITORIAL BOARD SECTION EDITORS EDITOR-IN-CHIEF EMERGING THERAPIES

Burt Zweigenhaft, BS Managing Director, BioPharma Partners, LLC, President, National Association Specialty Pharmacy, Co-Chairman, Association Value, Based Cancer Care, Chairman, CureVax, LLC

Ray Tancredi, RPh, MBA, CSP Divisional Vice President Specialty Pharmacy Development Walgreens Boots Alliance Deerfield, IL

BIG DATA & HEALTH INFORMATION EXCHANGE Bruce S. Pyenson, FSA, MAAA Principal & Healthcare Consultant Milliman, Inc. New York, NY

CLINICAL EVIDENCE, GUIDELINES, & VALUE William McGivney, PhD Managing Partner McGivney Global Advisors Philadelphia, PA

HEMATOLOGY & ONCOLOGY COMMUNITY PRACTICE John D. Sprandio, MD, FACP Chief Physician, Consultants in Medical Oncology and Hematology Chairman, Oncology Management Services Drexel Hill, PA

REIMBURSEMENT Matthew Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth Salt Lake City, UT

EMPLOYERS

PATIENT ADVOCACY

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F. Randy Vogenberg, PhD, RPh, FASHP Partner, National Institute of Collaborative Healthcare, and Access Market Intelligence Greenville, SC

Robert Goldberg, PhD President and Co-Founder Center for Medicine in the Public Interest Springfield, NJ

Eric Sredzinski, PharmD, AAHIVP EVP Clinical and Quality Assurance Avella Specialty Pharmacy Phoenix, AZ

GOVERNMENT & POLICY

PERSONALIZED MEDICINE

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Jayson Slotnik, JD, MPH Partner Health Policy Strategies, Inc. Bethesda, MD

Sanjiv S. Agarwala, MD Professor of Medicine Chief, Oncology & Hematology St. Luke’s University Hospital and Temple University Philadelphia, PA

Julie Silver, MD Associate Professor and Associate Chair for Strategic Initiatives Department of Physical Medicine and Rehabilitation, Harvard Medical School, Boston, MA

EDITORS-AT-LARGE

Al B. Benson III, MD, FACP, FASCO Professor of Medicine Associate Director for Clinical Investigations, Robert H. Lurie Comprehensive Cancer Center of Northwestern University Chicago, IL

Arlene A. Forastiere, MD Senior Vice President Medical Affairs eviti, Inc Philadelphia, PA

Jennifer Malin, MD, PhD Medical Director Oncology and Care Management Anthem, Inc

Ed Pezalla, MD, MPH National Medical Director of Pharmacy Policy and Strategy Aetna Hartford, CT

Linda D. Bosserman, MD, FACP Clinical Assistant Professor Medical Oncology and Hematology City of Hope Medical Group Rancho Cucamonga, CA

Philip E. Johnson, MS, RPh, FASHP Pharmacy, Oncology, Healthcare, and School Health Consulting Tampa, FL

John L. Marshall, MD Chief, Hematology and Oncology and Director, Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center Washington, DC

Denise K. Pierce DK Pierce & Associates Zionsville, IN

Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield New York, NY

Kevin B. Knopf, MD, MPH Medical Oncology California Pacific Medical Center, Sutter Health Care San Francisco, CA

Barbara L. McAneny, MD Chief Executive Officer New Mexico Oncology Hematology Consultants, Ltd Albuquerque, NM

Jatin J. Shah, MD M.D. Anderson Cancer Center Houston, TX

Gena Cook Co-Founder & CEO Navigating Cancer Seattle, WA

Michael Kolodziej, MD National Medical Director Managed Care Strategy Flatiron Health New York, NY

Lee Newcomer, MD, MHA UnitedHealthcare Group Minnetonka, MN

Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA

Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA

Mark J. Krasna, MD Corporate Medical Director of Oncology Jersey Shore University Medical Center Neptune, NJ

Lynn Nishida, RPh Director, Clinical Services Catamaran Center of Excellence Northwest Region Portland, OR

G. Rhys Williams, ScD, MS Amgen Thousand Oaks, CA

Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers Pittsburgh, PA

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Washington, DC

Ted Okon, BS, MBA Executive Director Community Oncology Alliance Washington, DC

VALUE-BASED CANCER CARE

FEBRUARY 2018

VOL. 9

NO. 1

IN THIS ISSUE

ENGAGE

HEALTHCARE COMMUNICATIONS, LLC

Senior Vice President/Group Publisher Russell Hennessy rhennessy@the-lynx-group.com Senior Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Associate Editor Drew Amorosi Editorial Assistant Cara Guglielmon Production Manager Cara Nicolini

EMERGING THERAPIES ogamulizumab improves survival in M advanced cutaneous T-cell lymphoma

SH recaps “phenomenal” year for AML A drug approvals

otatercept improves hemoglobin levels in S anemic patients with myelofibrosis

I brutinib plus venetoclax combo elicits impressive responses in relapsed CLL

More…

IMMUNOTHERAPY President/CEO Brian Tyburski Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Senior Vice President/Group Publisher John W. Hennessy jhennessy2@the-lynx-group.com Senior Vice President, Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Vice President, Finance Andrea Kelly Director, Human Resources Mara Castellano Director, Strategy & Program Development John Welz Chief Nursing Officer Senior Director, Strategic Planning & Initiatives Danelle Johnston, RN, MSN, ONN-CG, OCN, CBCN Senior Vice President, Group Operations Marion Murray Director, Quality Control Barbara Marino Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Director, Digital Marketing Samantha Weissman

LEUKEMIA HIGHLIGHTS

AR T-cell therapy makes significant inroads C in lymphoma

enetoclax plus rituximab new V chemotherapy-free combo for CLL More…

MULTIPLE MYELOMA

AR T-cell therapy shows impressive results C in multiple myeloma

enalidomide plus elotuzumab maintenance L regimen improves responses

hich combination immunotherapies to use, W and when?

aratumumab for smoldering multiple D myeloma extends progression-free survival

More…

LYMPHOMA HIGHLIGHTS VALUE-BASED CARE ral multiple myeloma drug linked to O decreased productivity loss ML treatment episodes linked to significant A economic burden

MYELOPROLIFERATIVE NEOPLASMS rofound symptom burden highlighted in new P studies

new combination as first-line regimen in A advanced Hodgkin lymphoma? igh response rate with 3-drug combination H for untreated follicular lymphoma More…

CONFERENCE CORRESPONDENT MCL: US patients face substantial economic burden of treatment ML: Enasidenib monotherapy well-tolerated A in older patients with untreated mIDH2 AML More…

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MISSION STATEMENT Value-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the costvalue issues particular to cancer treatments. This unique focus is achieved through news coverage from major hematology/oncology meetings and the cancer literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Copyright © 2018 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Cancer Care is a registered trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Value-Based Cancer Care, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. E-mail: editorial@valuebasedcancer.com. Phone: 732-992-1891. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Engage Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. POSTMASTER: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. YEARLY SUBSCRIPTION RATES: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

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EMERGING THERAPIES

tion in the hazard ratio for disease progression or death in favor of the anti-CCR4 antibody, stated Dr Kim. “Mogamulizumab demonstrated convincing clinical activity, not just in skin but also in clearing malignant T-cells in the blood and lymph nodes. PFS and overall global response outcomes are clearly superior,” said Dr Kim. “The side effects are tolerable, and we see measurable improvements in quality of life with mogamulizumab compared with vorinostat. Taken together, these findings represent a durable and clinically meaningful benefit for patients with CTCL,” she added. The findings came from the randomized, phase 3 clinical trial MAVORIC, which compared mogamulizumab and the histone deacetylase inhibitor, vorin ostat, in patients with CTCL who received ≥1 previous systemic regimens. The trial’s key entry criteria mirrored the indication for which the FDA granted priority review to mogamu lizumab in November 2017. The trial involved 372 patients with 1 of 2 predominant subtypes of CTCL— mycosis fungoides or Sézary syndrome. Patients received mogamulizumab 1

Mogamulizumab, Anti-CCR4 Antibody...

“Mogamulizumab demonstrated convincing clinical activity, not just in skin but also in clearing malignant T-cells in the blood and lymph nodes.” —Youn H. Kim, MD

mg/kg weekly for 4 weeks and then every 2 weeks thereafter, or vorinostat at a dose of 400 mg daily. Patients allocated to vorinostat could cross over to mogamulizumab at disease progression

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or in the event of intolerable toxicity. The primary end point was investigator- assessed PFS. The study population had a median age of 64 to 65 years, and more than 99% of the patients had an Eastern Cooperative Oncology Group performance status 0 or 1. Approximately 67% of the patients had stage III or IV disease. The median number of previous regimens was 3. CCR4 expression level was not included in the eligibility criteria. The primary analysis yielded a statistically significant hazard ratio of 0.53 in favor of the anti-CCR4 antibody (95% confidence interval [CI], 0.41-0.69; P <.0001). Independent review of the primary end point was consistent with investigator assessment, as patients randomized to mogamulizumab had a median PFS of 6.7 months versus 3.8 months for the vorinostat arm (hazard ratio, 0.64; 95% CI, 0.49-0.84; P = .0007). The advantage for mogamu lizumab was consistent across all prespecified subgroups. The objective response rate was 28% with mogamulizumab and 4.8% with vorinostat (P <.0001). Response rates favored the monoclonal antibody

among patients with mycosis fungoides or Sézary syndrome, and among patients with stage III or IV disease. The median duration of response was 14.1 months with mogamulizumab and 9.1 months with vorinostat, and did not vary substantially between patients with mycosis fungoides or Sézary syndrome. Patients who crossed over from vorinostat to mogamulizumab had an objective response rate of 30.1%. “The response data represent global composite responses in all of the compartments, including skin, lymph nodes, and blood. Responses in all the compartments were integrated into a global response, so the responses were not just in skin,” said Dr Kim. Grade 1/2 treatment-emergent adverse events occurred in 54.9% of patients treated with the anti-CCR4 antibody, and grade 3/4 adverse events occurred in 42.4%. Treatment-emergent adverse events that occurred substantially more often (>15% difference) with mogamulizumab than with vorinostat were infusion-related reactions (33.2% vs 0.5%, respectively) and skin eruptions (23.9% vs 0.5%, respectively). s

First-in-Class Sotatercept Improves Hemoglobin Levels in Anemic Patients with Myelofibrosis By Wayne Kuznar Atlanta, GA—Sotatercept, an investigational activin receptor IIA ligand trap, when used alone or in combination with ruxolitinib (Jakafi), safely increases hemoglobin levels in patients with myeloproliferative neoplasm–associated myelofibrosis, according to data from a phase 2, investigator-initiated clinical trial, data presented at ASH 2017. Ruxolitinib is the only medication approved by the FDA for the treatment of myelofibrosis, but it causes an initial decline in hemoglobin levels before they recover to a new and lower baseline. This anemia can prevent optimal dosing of ruxolitinib, or lead to its discontinuation. “This is important, because spleen responses to ruxolitinib are dose-dependent; therefore, optimization of the dose is important, and they also correlate with survival,” said Prithviraj Bose, MD, Assistant Professor, Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX. Patients with primary polycythemia vera, post–polycythemia vera, or post-

essential thrombocythemia myelofibrosis and hemoglobin levels persistently <10 g/dL were enrolled in the study that Dr Bose presented. A monotherapy cohort was given sotatercept subcutaneously every 3 weeks at 0.75 mg/kg or 1 mg/kg. A second cohort received 0.75 mg/kg of sotatercept in combination with ruxolitinib; patients in that cohort had been receiving ruxolitinib for ≥6 months. To be evaluable for response, patients had to be in the study for ≥84 days. The overall response rate was a composite of the rate of transfusion independence, as defined by the International Working Group-Myeloproliferative Neoplasms Research and Treatment 2013 criteria, and the hemoglobin response, defined as a hemoglobin increase from baseline of ≥1.5 g/dL consecutively over ≥84 days without red blood cell transfusions. To date, 35 patients have received treatment—24 in the monotherapy cohort and 11 in the ruxolitinib combination cohort. Among all patients, 3 had grade 3 hypertension, 2 had grade 2

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hypertension, and 2 reported bilateral lower-limb pain. Monotherapy: 39% Response Rate

Of the 24 patients receiving sotatercept monotherapy, 20 had primary myelofibrosis. Their median baseline hemoglobin level was 7.5 g/dL. A JAK2 driver mutation was detected in 16 patients. All 24 patients had intermediate-2 or high risk on the Dynamic International Prognostic Scoring System (DIPSS). Bone marrow fibrosis was grade 3 in 15 patients, and grade 2 in 9 patients. Overall, 7 of 18 evaluable patients in the monotherapy cohort had a response, 4 of which were hemoglobin responses and 3 transfusion-independent responses. Responses occurred at both doses evaluated. Two patients who were not evaluable because of insufficient time in the study had an increase from baseline in their hemoglobin level ≥1.5 g/dL. The median time to response was 7 days, and the median duration of response was 12 months. Two patients continuing in the

study have received 35 cycles each. A total of 22 patients in the monotherapy cohort have discontinued therapy. Combination: 27% Response Rate

Of the 11 patients in the combination cohort, most had primary myelofibrosis, and their median baseline hemoglobin level was 7.2 g/dL. Most had JAK2 mutations. All had DIPSS intermediate-2 or high risk, and most had grade ≥2 bone marrow fibrosis. Of the 11 patients, 10 were evaluable, and 3 were responders. “All of the responses [in the combination cohort] were in anemic subjects; we did not actually see responses in transfusion-dependent subjects in this cohort,” said Dr Bose. There were 3 responders: responses began at 7, 14, and 140 days. Response durations are 3, 4, and 15 months, and the responses are ongoing. Five patients, including the 3 responders, continue in the study. Six patients discontinued— 3 because of lack of response, and 3 because they had allogeneic transplants. s

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Ivosidenib, New IDH1 Inhibitor, Elicits Complete Response in Relapsed Acute Myeloid Leukemia By Wayne Kuznar Atlanta, GA—Treatment with ivosidenib, an IDH1 inhibitor, resulted in an objective response rate (ORR) of 41.6% in a phase 1 dose-escalation and expansion clinical trial in patients with relapsed or refractory acute myeloid leukemia (AML) and IDH1 mutation. Ivosidenib induced a complete response (CR) or a CR with a partial hematologic recovery (CRh) in 30.4% of the study population. The results were presented by Courtney D. DiNardo, MD, MSCE, Assistant Professor, Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX, at ASH 2017. Ivosidenib demonstrates “impressive single-agent efficacy, with durable responses in these high-risk patients with relapsed or refractory AML,” said Dr DiNardo. “Important measures of clinical benefit for patients treated with ivosidenib were also observed, and include increases in transfusion independence, and a decrease in the frequency of comorbidities, such as febrile neutropenia and infections in responding patients,” she said. In this study, patients with hematologic malignancies and IDH1 mutation

were enrolled in a dose-escalation stage in which ivosidenib was given at 100 mg twice daily, or in doses ranging from 200 mg to 1200 mg once daily. A subsequent dose-expansion cohort was treated with 500 mg daily of ivosidenib. The dose-expansion cohort consisted of 4 arms—(1) 126 patients who had a second relapse after stem-cell transplantation, had disease refractory to previous therapy, or had AML with IDH1 mutation that relapsed within 1 year; (2) 25 patients with untreated AML; (3) 11 patients with non-AML relapsed or refractory hematologic malignancies and IDH1 mutation; and (4) 18 patients with IDH1 mutation and relapsed or refractory AML who were not eligible for arm 1. Study Results

The ORR in the primary analysis was 41.6%, with a CR rate of 21.6% and a CRh rate of 8.8%. The median duration of response was 9.3 months for patients who achieved a CR, 8.2 months for those who achieved a CR/ CRh, and 6.5 months for all responders. The median time to first response was 1.9 months, median time to CR

Ivosidenib demonstrates “impressive single-agent efficacy, with durable responses in these high-risk patients with relapsed or refractory AML.” —Courtney D. DiNardo, MD, MSCE

was 2.8 months, and the median time to CR/CRh was 2.7 months. At the time of data cut-off (14.8 months of follow-up), the median over-

all survival (OS) was not yet reached for patients who achieved a CR/CRh. For responders who did not achieve a CR/ CRh, the median OS was 9.3 months. All patients who were transfusion-dependent at baseline and achieved a CR became independent of platelet transfusions, and 84.6% became independent of red blood cell (RBC) transfusions during any 56-day postbaseline. Of those who were transfusion-dependent at baseline and achieved a CRh, 71.4% became independent of platelet transfusions, and 75% became independent of RBC transfusions. Among the entire study cohort, 39.1% and 39.7% of patients, respectively, were independent of platelet transfusions and RBC transfusions. In arm 2, 34 patients with AML had responses, including a 55.9% ORR and 20.6% CR. In arm 3, 12 patients with myelodysplastic syndrome achieved a 91.7% ORR and 41.7% CR. The most common adverse events were diarrhea (33.3%), elevated levels of white blood cells (30.2%), nausea (29.5%), fatigue (28.7%), and febrile neutropenia (25.2%); 10 (8%) of 125 patients had grade 3 QT prolongation. s

Quizartinib Combinations Show High Activity in Newly Diagnosed Acute Myeloid Leukemia with FLT3 Mutation Atlanta, GA—The combination of the investigational drug quizartinib plus azacitidine (Vidaza) or low-dose cytarabine has substantial activity in patients with myeloid leukemias and FLT3 mutations. The composite complete response (CRc) with the combinations was approximately 83% in previously untreated patients and 59% in patients with relapsed disease in an interim report of a phase 1/2 clinical trial presented by Mahesh Swaminathan, MD, Leukemia Fellow, M.D. Anderson Cancer Center, Houston, at ASH 2017. The response rates and the duration of remission were higher than expected with each agent alone, “although this needs to be confirmed in more patients in a randomized trial,” he said. FLT3 is expressed in hematopoietic progenitor cells. Activating mutations are present in 25% to 40% of patients with acute myeloid leukemia (AML), and are associated with poor prognosis.

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Quizartinib, an oral FLT3 receptor tyrosine kinase inhibitor, inhibits wildtype FLT3 and FLT3-ITD. Single- agent quizartinib induced CRs in approximately 50% of patients with AML and FLT3-ITD mutations in phase 1 and 2 studies. Doses as low as 30 mg and 60 mg have shown activity, with higher response rates and overall survival (OS) with the 60-mg dose. Based on these results, quizartinib 60 mg was combined with either azacitidine or low-dose cytarabine in the phase 1/2 clinical trial of 61 patients with myelodysplastic syndrome, chronic myelomonocytic leukemia, or AML. Quizartinib was administered daily in 28-day cycles, uninterrupted, with azacitidine 75 mg/m2 for 7 days per cycle, or with cytarabine 20 mg twice daily for 10 days per cycle. In all, 8% of patients in the azacitidine arm and 25% in the lowdose cytarabine arm had previous exposure to FLT3 inhibitors. Approximately 24% and 13% of pa-

“The treatment was associated with a low rate of early deaths, with a 60-day mortality rate of only 5% in the azacitidine arm and 0% in the lowdose cytarabine arm.” —Mahesh Swaminathan, MD

tients in the azacitidine and low-dose cytarabine arms, respectively, had not received previous therapy. Overall, >90% of patients had FLT3-ITD mutations at baseline. The total CRc rate was 64%, with 68% in the azacitidine arm and 58% in the low-dose cytarabine arm. “The treatment was associated with a low rate of early deaths, with a 60-day mortality rate of only 5% in the azacitidine arm and 0% in the low-dose cytarabine arm,” said Dr Swaminathan. The

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median OS was 14.8 months and 7.4 months, respectively; the median relapse-free survival rates were 6.93 months and 4.37 months, respectively. Among the newly diagnosed patients, the median OS was 21 months in the azacytidine, arm and was not reached in the low-dose cytarabine arm; the median relapse-free survival was 17.7 months and was not reached, respectively. The CRc rates were 78% and 100%, respectively. “These results remain unchanged when you consider patients who have not been previously exposed to FLT3 inhibitors,” Dr Swaminathan said. In the 12 patients who received stem-cell transplant, the median OS was 5.12 months in the azacitidine arm and was not reached in the low-dose cytarabine arm. QTc prolongation was reported in 9 patients. The most common grade 3/4 toxicities were infections, gastrointestinal hemorrhage, hypokalemia, and hyponatremia.—WK s

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CAR T-Cell Therapy Shows “Impressive” Results in Multiple Myeloma By Wayne Kuznar had at least 50% BCMA expression on plasma cells.

Prolonged Duration of Response

Study Details

The study enrolled 24 patients, 21 of whom had received bb2121. The study’s objective was to identify the maximum tolerated dose. Overall, 29% of patients had disease that was refractory to 5 common multiple myeloma therapies, including bortezomib (Velcade), lenalidomide (Revlimid), carfilzomib (Kyprolis), pomalidomide (Pomalyst), and daratumumab (Darzalex). After lymphodepletion with fludarabine and cyclophosphamide, patients received from 50 × 106 to 800 × 106 CAR T-cells. The median follow-up was 35 weeks, with the first response assessment at week 4. Overall, 43% of the study cohort had high-risk cytogenetics. All patients had received previous autologous stemcell transplantation. “Generally, this was a very well-tolerated CAR T-cell product,” said Dr Kochenderfer. A total of 71% of patients had cytokine release syndrome (CRS), with 10% being grade ≥3. The 2 reported grade 3 CRS events resolved within 24 hours. Overall, 24% of patients had neurologic toxicity, but no grade ≥3

Photo credit: © Phil McCarten 2017

Atlanta, GA—Although chimeric antigen receptor (CAR) T-cell therapies directed against the CD19 protein garnered much attention at ASH 2017, CAR T-cells targeting B-cell maturation antigen (BCMA), a protein expressed nearly universally on multiple myeloma cells, were found to be remarkably effective in patients with heavily pretreated multiple myeloma. In the phase 1, dose-escalation clinical trial CRB-401 of 21 patients with multiple myeloma that relapsed after a median of 7 lines of therapy, the response to a single infusion of the CAR T-cell therapy called bb2121, which was engineered to target BCMA, was 86%. The response rate increased to 94% in 18 patients who had received higher active doses of the infused CAR T-cells, reported James N. Kochenderfer, MD, Investigator, Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD. The dose-escalation clinical trial of bb2121 was conducted in patients with relapsed or refractory multiple myeloma who received at least 3 previous lines of therapy, including a proteasome inhibitor and an immunomodulatory drug, or who were double-refractory, and who

“Our longest response has been going on 68 weeks at this point. In general, very impressive responses when compared to my previous experience.” —James N. Kochenderfer, MD

neurotoxicity, or dose-limiting toxicities were observed. Overall, 5 deaths occurred during the study, 3 because of disease progression at the 50 × 106 dose, which was deemed not to have clinical activity. Overall, 14 patients had ≥1 serious adverse events.

Among the 18 patients who received active doses of bb2121 (150 × 106 to 800 × 106 CAR T-cells), 17 (94%) had an objective response, with a complete response rate that improved from 27% in May 2017, to 56% at data lock in October 2017. After 40 weeks of follow-up, 9 of 10 evaluable patients had no minimal residual disease. Some responses have been ongoing for more than 1 year. “Our longest response has been going on 68 weeks at this point. In general, very impressive responses when compared to my previous experience treating multiple myeloma,” said Dr Kochenderfer. Responses continued to improve as late as month 15, and the duration of response has not yet been reached. Overall, 2 patients who received active doses of bb2121 were in complete remission at the time of their deaths. The median time to first response was 1.02 months, the median time to best response was 3.74 months, and the median time to complete response was 3.84 months. The median progression-free survival has not been reached in the active-dose cohorts. At 9 months, progression-free survival was 71%. s

Atlanta, GA—A novel, third-generation, oral tyrosine kinase inhibitor (TKI), PF-114 mesylate, has antileukemic activity in heavily pretreated patients with chronic myeloid leukemia (CML), including those with T315I mutation, said Jorge E. Cortes, MD, Deputy Chair, Department of Leukemia, M.D. Anderson Cancer Center, Houston, TX, at ASH 2017. In an ongoing, phase 1, dose-escalation clinical trial of patients with CML, 50% of whom had received ≥3 previous TKIs, major cytogenetic responses were achieved in 40% of patients with chronic-phase (CP) CML. Based on these results, a phase 2, multicenter, international study is planned for 2018, said Dr Cortes. PF-114 mesylate is an ATP competitive inhibitor of BCR-ABL kinases,

including the gatekeeper mutation T315I. It is designed to avoid interaction with off-target kinases, such as VEGF receptor-2 and BRAF, which could potentially lead to life-threatening toxicities. “That leads to a kinase inhibition profile that is much more selective… and very few are inhibited at potent concentrations, suggesting the possibility of a better toxicity profile,” Dr Cortes told attendees. Preclinical work supported the phase 1 clinical trial of PF-114 mesylate in patients with CP or accelerated-phase (AP) Philadelphia chromosome–positive CML who are resistant to ≥1 second-generation TKIs, intolerant to treatment with TKIs, or have T315I mutation in the BCR-ABL gene. The trial was a 3+3 design of dose escala-

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Novel TKI Leads to Responses in Heavily Pretreated Patients with Chronic Myeloid Leukemia

“There have been only 5 patients in total that have had at least 1 hematologic toxicity.” —Jorge E. Cortes, MD

tion until the maximum tolerated dose, followed by expanded cohorts planned for doses below the maximum tolerated dose. At data cut-off, 24 patients with a median time of 11.4 years since CML diagnosis had been enrolled. Of these patients, 21 had CP-CML, 2 had APCML, and 1 had blast-phase CML. Eleven patients had T315I mutation, 13 patients had received ≥3 previous TKIs, and 16 patients had no cytogenetic response at the time of enrollment. To date, 5 cohorts have been fully enrolled, at oral doses of 50 mg, 100 mg, 200 mg, 400 mg, and 500 mg once daily. A sixth cohort of 600 mg daily has started enrollment. Intra-patient dose escalation is permitted, allowing patients to move to the next dose level. The doses most thoroughly explored have been

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CAR T-Cell Therapy Makes Significant...

Updated results from the ZUMA-1 clinical trial show that patients with refractory DLBCL continue to have durable responses to the CD19-directed CAR T-cell therapy axicabtagene ciloleucel after >1 year. Furthermore, investigators identified 2 potential mechanisms of resistance—loss of CD19 and PD-L1 expression—paving the way for strategies to overcome resistance. Of the 108 patients enrolled in the clinical trial, 42% continued to have ongoing remission after just 1 CAR T-cell infusion, and 40% of patients had no evidence of cancer at a median follow-up of 15.4 months. These are remarkable responses in patients with aggressive disease who did not respond to other treatments. More than 50% of the patients were alive at 15.4 months; the median survival is only 4 to 6 months with existing therapy. “Long-term follow-up of ZUMA-1 confirms that these responses can be durable, and the ongoing responses at 24 months suggest that late relapses are uncommon. Patients who are in remis-

for all patients was 11.1 months; median duration of complete response has not yet been reached, and 3 of the 7 patients enrolled in the phase 1 portion of the study continued to have complete responses at 24 months. With longer follow-up, no new treatment-related CRS, neurologic events, or grade 5 adverse events have been reported. Tisagenlecleucel

Primary analysis of the JULIET study showed that a single infusion of the CAR T-cell therapy tisagenlecleucel achieved durable remissions in nearly 50% of adults with relapsed or refractory DLBCL.

“CAR T-cell therapy represents a breakthrough therapy in a setting with a large unmet need.” —Stephen J. Schuster, MD

late-onset cytokine release syndrome [CRS] or neurological toxicity due to treatment. Durable responses were observed with and without detectable CAR-T,” added Dr Neelapu. ZUMA-1 is the largest study to date with a CD19-directed CAR T-cell therapy (ie, axicabtagene ciloleucel). Patients received low-dose conditioning chemotherapy using fludarabine and cyclophosphamide for 3 days, followed by a single infusion of their own re-engineered T-cells through axicab tagene ciloleucel. “We confirmed the feasibility and reliability of centralized manufacturing and coordination of the leukapheresis procedures and shipping from multiple centers across the country,” said Dr Neelapu. At 15.4 months, the objective response rate (ORR) was 82%. The complete response rate was 58%. At the time of follow-up, 42% of patients remained responsive, and 40% of patients had a complete response. The median duration of response

Photo credit: © Phil McCarten 2017

Axicabtagene Ciloleucel

sion at 6 months tend to stay in remission,” said lead investigator Sattva S. Neelapu, MD, Deputy Department Chair ad interim, Department of Lymphoma/Myeloma, M.D. Anderson Cancer Center, Houston, TX. “We saw no

Photo credit: © Phil McCarten 2017

2017 provide encouraging news for 2 new drugs, including long-term follow-up of the pivotal ZUMA-1 study of the CAR T-cell therapy axicabtagene ciloleucel (Yescarta), and primary results from the JULIET study of tisagenlecleucel (Kymriah). Both drugs were approved by the FDA in 2017, and were the first 2 gene therapies approved in the United States. Tisagenlecleucel is indicated for pediatric patients with B-cell acute lymphocytic leukemia (ALL), and axicabtagene ciloleucel is indicated for adults with certain types of relapsed or refractory large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL). The JULIET study results suggest that tisagenlecleucel may receive a new FDA indication for lymphoma. The long-term results from ZUMA-1 were published online (Neelapu SS, et al. N Engl J Med. 2017;377:2531-2544) to coincide with the study’s presentation at the meeting.

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“The JULIET trial, along with ZUMA-1, shows striking responses that are remarkably similar, even though there are differences in the two products.” —Renier J. Brentjens, MD, PhD

“JULIET shows the feasibility of global distribution of CAR T-cell therapy using cryopreserved apheresis and central manufacturing. If this therapy is approved [for lymphoma], the sponsor is gearing up for large-scale production for DLBCL in 2018,” said lead investigator Stephen J. Schuster, MD, Director, Lymphoma Program, Abramson

Cancer Center, Philadelphia. JULIET was conducted at 27 sites in 10 countries. T-cells were manufactured at 2 sites, 1 in the United States and 1 in Germany, with a turnaround time of approximately 22 days. Of the 147 enrolled patients, 99 received the CAR T-cell infusion. Dr Schuster reported findings for 81 patients who received tisagenlecleucel manufactured in the United States. At 3 months, the best ORR was 53%, and the complete response was 40%. At 6 months, the ORR was 37%, and the complete response was 30%. Nearly 75% of patients were relapse-free at 6 months. The median duration of response and overall survival were not reached at that time. “The ORR at 3 months is important, because most of those patients will stay in remission for years. I anticipate that we will continue to see durable responses at 3 years,” said Dr Schuster. “This is in the context of an expected median survival of 4 months in relapsed or refractory DLBCL, showing that CAR T-cell therapy represents a breakthrough therapy in a setting with a large unmet need,” he added. No treatment-related deaths, CRS, or cerebral edema were reported. Overall, 26% of patients received CAR T-cell therapy on an outpatient basis, and 77% of them remained outpatients for ≥3 days after the infusion. “This suggests that it is possible to give CAR T-cell therapy on an outpatient basis,” said Dr Schuster. “The JULIET trial, along with ZUMA-1, shows striking responses that are remarkably similar, even though there are differences in the two products,” said Renier J. Brentjens, MD, PhD, Director, Cellular Therapeutics, Memorial Sloan Kettering Cancer Center, New York, who moderated a press conference at the meeting. “The initial hoopla was about the high response rates in B-[cell] ALL, but the lingering question was, ‘how durable are these responses, and can they be extrapolated to other B-cell malignancies?’ These trials show that the answer is affirmative,” added Dr Brentjens. s

Novel TKI Leads to Responses in Heavily Pretreated Patients with... Continued from page 12 200 mg and 400 mg, with a median number of cycles of 9 and 5, respectively. The maximum tolerated dose has not yet been reached. In a preliminary analysis for efficacy (maximum 9 cycles of therapy), major cytogenetic responses have been

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achieved in 4 patients, all with CPCML and T315I mutation. Four patients in chronic phase, 1 in accelerated phase, and 1 in blast phase have had hematologic responses. Hematologic toxicity was modest. “There have been only 5 patients in

total that have had at least 1 hematologic toxicity, and this represents 1 patient in the blast phase that had anemia and thrombocytopenia, and 4 patients with chronic-phase CML; all of them had a history of cytopenias grades 1 to 4, and all of them had received at least 2

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prior TKIs,” said Dr Cortes. The most common nonhematologic adverse event has been skin toxicity, mostly dry skin and psoriasiform skin lesions. Overall, 13 patients had grade 2, and 4 had grade 3 skin toxicity, 1 of which was a dose-limiting toxicity.—WK s

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IMMUNOTHERAPY

Which Combination Immunotherapies to Use, and When? High Response Rates, but Serious Toxicity Remains a Concern By Chase Doyle Atlanta, GA—As single-agent immunotherapies continue to show promising results, the challenge is now to determine which combination regimens with immunotherapies can improve outcomes. According to data presented at ASH 2017, 3 approaches are currently being explored, which include: 1. Using immunotherapies to replace nonspecific cytotoxic agents to increase efficacy and reduce toxicity 2. Combining an immunotherapy with a targeted drug for chemotherapy- free regimens 3. Revitalizing T-cells by using checkpoint inhibitors in combination with other immune-mediated agents. Although preliminary research has shown early success with all 3 approaches, Donna Przepiorka, MD, PhD, Cross-Discipline Team Lead, FDA’s Division of Hematology Products, urged caution in interpreting single-arm clinical trials to avoid unpredictable and potentially fatal toxicities. According to Dr Przepiorka, lessons learned from the era of cytotoxic drugs can still be applied to immunotherapies in combinations today. “The main rationale from the cytotoxic era is to increase efficacy by combining agents that have different mechanisms and nonoverlapping toxicities. The question is whether we can replace nonspecific cytotoxic agents with a specific, more effective immunotherapeutic,” she emphasized. Brentuximab Vedotin plus Standard of Care?

One such immunotherapy is brentuximab vedotin (Adcetris), which consists of an antibody drug conjugate linked to monomethyl auristatin E. In a single-arm trial of brentuximab vedotin monotherapy for patients with relapsed or refractory Hodgkin lymphoma, 73% of patients achieved a complete response (CR) plus partial response, with modest toxicity. Although this response rate is “substantial,” said Dr Przepiorka, the investigators wanted to know whether this drug could be added to the standard-ofcare chemotherapy regimen known as ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), or should it

replace bleomycin in this regimen. In the ECHELON-1 study of 1334 patients with advanced-stage Hodgkin lymphoma, patients were randomized to the replacement regimen of brentuximab vedotin plus ABVD instead of bleomycin or to the standard-of-care ABVD regimen. The replacement regimen showed surperior results, with a hazard ratio (HR) of 0.77.

“The main rationale from the cytotoxic era is to increase efficacy by combining agents that have different mechanisms and nonoverlapping toxicities. The question is whether we can replace nonspecific cytotoxic agents with a specific, more effective immunotherapeutic.” —Donna Przepiorka, MD, PhD

Nevertheless, despite the modest benefit in progression-free survival (PFS), different toxicity profiles for these combinations should be taken into account, Dr Przepiorka noted. “Less pulmonary toxicity was clearly confirmed in this study, with less than 1% of patients having a grade 3 or higher pulmonary event, but we still need to be vigilant for this toxicity,” said Dr Przepiorka. “Moreover, although there is less pulmonary toxicity in the BV [brentuximab vedotin] arm, there is far more neurotoxicity, as well as more febrile neutropenia and infection. Safe use of this regimen appears to require additional use of filgrastim prophylaxis,” she added. Blinatumomab plus Standard Chemotherapy?

The efficacy of blinatumomab (Blincyto), a first-in-class immunotherapy known as a T-cell engager, was demon-

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strated in the randomized clinical trial TOWER, which compared monotherapy with blinatumomab versus standard chemotherapy for patients with relapsed or refractory Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL). The CR rate for the blinatumomab arm was nearly double that of conventional chemotherapy, and survival analysis showed evident superiority for blinatumomab, with an HR of 0.71. Although the safety profile of blinatumomab differs from that of usual cytotoxic chemotherapies used for ALL, there is concern that ALL drugs would counteract the effects of blinatumomab. However, if blinatumomab were combined with a targeted agent that spared T-cells, Dr Przepiorka explained, this may be less of a problem. Assi and colleagues looked at the efficacy of blinatumomab plus a tyrosine kinase inhibitor (TKI) in patients with Ph-positive ALL. Although the study included a small number of patients, the updated data showed a 54% CR rate, said Dr Przepiorka, and currently 2 single-arm trials of chemotherapy-free blinatumomab plus TKI are ongoing. “It’s encouraging to think that this may open the door to chemotherapy-free treatment of ALL by using a T-cell engager with targeted therapy,” Dr Przepiorka said. “However, only a randomized trial with long-term follow up will be able to tell us whether this combination is effective,” she added. Immunomodulatory Drug plus Checkpoint Inhibitor?

In the meantime, researchers are still trying to understand why not all patients respond to this treatment. One possible explanation for this failure, said Dr Przepiorka, is T-cell exhaustion, which occurs when T-cells are persistently stimulated by antigens in patients with chronic infections and in those with cancer. Although checkpoint inhibitors have been proposed as a way to revitalize exhausted effector T-cells, response rates for checkpoint inhibitors in hematologic malignancies are generally low. One possible solution is to use an immuno-

modulatory drug (IMiD) to enhance the effect of the checkpoint inhibitor. In a single-arm, phase 2 clinical trial, Badros and colleagues used pembroliz umab (Keytruda) in combination with pomalidomide (Pomalyst) and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma. In 48 patients tested, the overall response rate was 60%, and the median PFS was 17.4 months. However, 42% of patients had grade ≥3 adverse events, and 13% had pneumonitis; still, only 11% discontinued treatment because of toxicity. “It is clearly difficult to assess the benefits of this combination in a single-arm setting,” said Dr Przepiorka, adding that 2 studies with pembro lizumab, KEYNOTE-183 and KEYNOTE-185, were terminated early because of increased deaths in the pembrolizumab arms, with a 61% increase in the relative risk for death in the pembrolizumab arm in patients with relapsed or refractory disease, and a doubling of the risk for death in patients with newly diagnosed disease.

“It’s encouraging to think that this may open the door to chemotherapyfree treatment of ALL by using a T-cell engager with targeted therapy.” —Donna Przepiorka, MD, PhD

“We’ve learned from this experience that single-arm trials of combinations can be difficult to interpret, so we should consider randomized trials, even in the early stages. Moreover, we still do not understand the biological reasons for increased toxicity in the KEYNOTE studies,” said Dr Przepiorka. “Additional randomized trials with other IMiDs and checkpoint inhibitors are ongoing, with frequent assessments of safety, but until we understand why this toxicity occurred, all such trials are being watched closely,” she concluded. s

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Oral Multiple Myeloma Medication Linked to Decreased Productivity Loss By Chase Doyle Atlanta, GA—A recent analysis of a commercial claims database suggests that oral therapy for multiple myeloma may help decrease the economic burden for patients and healthcare systems. According to data presented at ASH 2017, patients with multiple myeloma who received injectable therapy used significantly more disability benefits and incurred higher productivity costs than patients who received oral medications. “The use of novel multiple myeloma drugs has been associated with improved therapeutic outcomes and survival, but the disease continues to pose a significant economic burden. Evaluating the economic implications and outcomes of available treatments is important to improve efficiency of care,” said David Merola, PharmD candidate, Bernard J. Dunn School of Pharmacy, Shenandoah University, Winchester, VA. Productivity loss is common in patients with multiple myeloma, including lost days from work or inability to work because of symptoms or treatment, Mr Merola explained. Although the direct costs of illness have been well- described in the literature, he noted, the indirect costs associated with multiple myeloma are understudied. For this study, Mr Merola and colleagues analyzed the extent of work-

place productivity loss in the United States among adults with multiple myeloma and its associated costs. These outcomes were compared among patients who received injectable versus oral multiple myeloma therapy. Mr Merola and colleagues used the Truven Health Analytics MarketScan Commercial Claims and Encounters with Medicare Supplemental Coordination of Benefits and Health and Productivity Management databases. Patients aged ≥18 years who were diagnosed with multiple myeloma between January 1, 2008, and December 31, 2014, were included in the study and were followed until December 31, 2015. The patients were analyzed 1 year before and 1 year after their first diagnosis. Mr Merola and colleagues evaluated productivity loss using several key variables found in workplace absenteeism, short-term disability, and long-term disability claim files. The cost of productivity loss was calculated for each patient by multiplying the number of days lost to absenteeism by the average daily wage for all occupations in accordance with the US Bureau of Labor Statistics. Fewer Workdays Missed

The study included 299 patients with newly diagnosed multiple myeloma; 73

“The use of novel multiple myeloma drug agents has been associated with improved therapeutic outcomes and survival, but the disease continues to pose a significant economic burden.” —David Merola, PharmD candidate

patients received oral therapy and 226 received injectable agents. A regression analysis showed that treatment type was a significant predictor of productivity loss. Patients who received injectable

therapy missed an average of 110 workdays in the 1 year postdiagnosis compared with 87 days (P <.001) for patients receiving only oral therapy. Treatment type was also a significant predictor of the cost of lost productivity. The lost productivity cost was $18,315 for patients who received injectable therapy and $14,429 for patients who only received oral drug therapy. The difference in valuated productivity losses between the study groups was also statistically significant at $3886 (P <.001). According to Mr Merola and colleagues, an interrupted time-series analysis showed a significant increase in missed workdays per month after the initial diagnosis of multiple myeloma for both treatment groups. Patients who received injectable therapy experienced an immediate increase of 6.9 lost productivity days per month (P <.001) compared with 4.4 days per month in patients who received oral therapy alone (P <.001). The difference in these values was not statistically significant, said Mr Merola, although a strong trend was observed (2.5 days per month; P = .057). Further studies are needed to elucidate the differences in outcome between patients receiving oral and injectable chemotherapies, Mr Merola and colleagues concluded. s

Acute Myeloid Leukemia Treatment Episodes Linked to Significant Economic Burden By Chase Doyle Atlanta, GA—A retrospective analysis of a large commercial payer database has demonstrated a link between various treatment episodes of acute myeloid leukemia and substantial economic burden. According to data presented at ASH 2017, healthcare resource use and direct healthcare costs were associated with high-intensity chemotherapy induction, hematopoietic stem-cell transplantation (HSCT), and episodes of relapsed or refractory disease in a US commercially insured population. “Clearly, new therapeutic strategies associated with less economic burden are needed,” said Bruno C. Medeiros, MD, Director, Inpatient Hematology Service, Stanford University School of Medicine, CA, who noted that hospi-

“Clearly, new therapeutic strategies associated with less economic burden are needed.” —Bruno C. Medeiros, MD

talization was a major cost driver across all episodes. Although the incidence of acute myeloid leukemia has risen 3.1% each year over the past 10 years, detailed real-world cost estimates and comparisons of key acute myeloid leukemia treatment episodes are rare and are challenging to assemble, Dr Medeiros explained. For this study, he and his colleagues used a healthcare claims database (PharMetrics Plus) and linked charge detail master hospital data to search for adults with acute myeloid leukemia and ≥2 outpatient claims or ≥1 inpatient claims between January 2008 and March 2016. Dr Medeiros and colleagues evaluated the treatment episodes, including

high-intensity chemotherapy induction (evidence of inpatient high-dose cytarabine plus anthracycline use within 3 months of diagnosis), high-intensity chemotherapy consolidation (evidence of cytarabine use with or without an thracycline within 2 months of high- intensity chemotherapy), low-intensity chemotherapy (evidence of low-intensity cytarabine, anthracycline, 5-azacy tidine, decitabine, clofarabine, hydroxyurea, or gemtuzumab ozogamicin use in the outpatient setting within 3 months of diagnosis), HSCT (record of transplant-specific diagnosis or procedure codes), and patients with relapsed or refractory disease (record of an International Classification of Diseases, Ninth Revision diagnosis code [205.02] for reContinued on page 18

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Highlights from 2017 American Society of Hematology CLL & OTHER B-CELL MALIGNANCIES

Phase 2 Study of Brentuximab Vedotin plus Ibrutinib for Patients with Relapsed/Refractory Hodgkin Lymphoma Brentuximab vedotin (BV), an antibody drug conjugate, selectively delivers the antitubulin agent, monomethyl auristatin E, to CD30+ cells.1 In a multicenter phase 2 trial in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL), BV showed an overall response rate (ORR) of 75%, a complete response (CR) rate of 34%, and a median duration of response (DOR) of 6.7 months.1 Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, has demonstrated antitumor activity in B-cell lymphomas.2 As a single agent at standard dose, ibrutinib does not have antitumor activity in the HL cell line. However, standard-dose ibrutinib is synergistic with BV in L428, an HL cell line. Based on this preclinical model, it can be hypothesized that ibrutinib may enhance the antitumor activity of BV in patients with HL. At ASH 2017, the authors reported on an interim analysis of efficacy and safety from a phase 2 trial using the combination of ibrutinib plus BV in patients with R/R HL.3 This was a prospective, multicenter phase 2 trial in patients with R/R HL. Patients were treated with 1.8 mg/kg of BV intravenously every 3 weeks and oral ibrutinib 560 mg daily. Patients could have received prior BV. The primary end point was the CR rate. Secondary end points were toxicities, ORR (CR + partial response [PR]),

DOR, BTK/IL-2 inducible T-cell kinase receptor occupancy, and changes in T-cell/B-cell/natural killer–cell subsets in peripheral blood. At the time of the presentation, 16 patients were evaluable for toxicity, and 13 patients were evaluable for efficacy. At baseline, 50% of the patients were stage III/IV at diagnosis, 50% were primary refractory to induction, 37% were refractory to last therapy, and 4 patients had prior BV (25%). The overall best response (CR+PR) rate was 69% (CR rate, 46%). Stable disease (SD) was noted in 31%, resulting in a disease control rate (CR+PR+SD) of 100%. Treatment with ibrutinib plus BV was well-tolerated, and there were no grade 4 adverse events (AEs). Grade 3 possibly related AEs included neutropenia and hypokalemia. Grade 1 AEs included diarrhea, nausea, fatigue, rash, and thrombocytopenia. The authors concluded that the combination of BV and ibrutinib is well-tolerated. Although the ORR of 69% may be similar to BV alone, the CR of 46% and disease control rate of 100% appear promising. The study has met its interim analysis end point and warrants further accrual to investigate the final CR rate. l References: 1. Younes A, et al. J Clin Oncol. 2012;30:2183-2189. 2. Aw A, Brown JR. Drugs Aging. 2017;34:509-527. 3. Chen RW, et al. ASH 2017. Abstract 738.

Preliminary Results of Prophylactic Tocilizumab After Axicabtagene Ciloleucel (axi-cel; KTE-C19) Treatment for Patients with Relapsed/ Refractory, Aggressive NHL ZUMA-1 is a pivotal, multicenter trial of axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, for the treatment of patients with refractory, aggressive non-Hodgkin lymphoma (NHL).1 The objective response rate (ORR) was 82% with a 54% rate of complete response (CR), and 44% of responses were ongoing at the time of the primary analysis.2 Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 13% and 28% of patients, respectively. At ASH 2017, the authors presented the results of a safety management study (SMS) that was added to ZUMA1 to further characterize mechanisms underlying CRS and NEs associated with CAR T-cell therapy. The SMS was also designed to evaluate the impact of prophylactic use of tocilizumab and levetiracetam on the rates of these adverse events (AEs).3 In the SMS, patients with relapsed or refractory transplant-ineligible NHL received low-dose conditioning of 500 mg/m2 of cyclophosphamide and 30 mg/m2 of fludarabine for 3 days, followed by axi-cel at a target dose of 2 × 106 CAR T-cells/kg. Patients also received prophylactic treatment with 750 mg of levetiracetam twice daily on day 0, and 8 mg/kg of tocilizumab on day 2 after axi-cel infusion. A total of

34 patients were included in the SMS analysis (59% had stage III-IV disease, 74% were refractory to ≥second-line therapy, and 24% relapsed ≤12 months after autologous stem-cell transplant). Most patients in the SMS experienced at least 1 grade ≥3 AE. The most common grade ≥3 AEs were neutropenia/decreased neutrophil count (74%), anemia (50%), thrombocytopenia/decreased platelet count (50%), leukopenia/decreased white blood cell count (32%), febrile neutropenia (29%), encephalopathy (26%), and hypotension (24%). One patient experienced grade 4 CRS, while grade 3 and 4 NEs occurred in 1 patient each. There was 1 death due to AEs: a patient died of cerebral edema. Among the 34 patients in the SMS, the preliminary ORR was 62%, including a CR rate of 44%. Follow-up duration, however, is currently limited. The authors concluded that tociliz umab use on day 2 may reduce the incidence of severe CRS but not the incidence of severe NEs in patients treated with CAR T-cell therapy. These data provide evidence that the underlying pathophysiology of NEs differs from that of CRS, which may help to further improve the benefit–risk profile for CAR T-cell therapy. l References: 1. Locke FL, et al. Mol Ther. 2017;25:285-295. 2. Locke FL, et al. AACR 2017. Abstract 9986. 3. Locke FL, et al. ASH 2017. Abstract 1547.

Median 3.5-Year Follow-Up of Ibrutinib Treatment in Patients with Relapsed/ Refractory Mantle-Cell Lymphoma: A Pooled Analysis Ibrutinib (ibr) is a first-in-class oral inhibitor of Bruton’s tyrosine kinase approved for relapsed/refractory (R/R) mantle-cell lymphoma (MCL). The results of a pooled analysis of 370 patients with R/R MCL treated with ibr in the SPARK, RAY, and PCYC-1104 studies were previously reported (median follow-up, 24 months).1 At ASH 2017, the authors presented median 3.5-year fol-

low-up in these patients, including additional exposure and follow-up of 87 patients across the 3 studies who enrolled in the long-term access study, CAN3001.2 Patients enrolled in SPARK, RAY, and PCYC-1104 received ibr 560 mg orally once daily until progressive disease or unacceptable toxicity. Study inclusion and exclusion criteria were similar, except that patients in SPARK were

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required to have received both rituximab and bortezomib, and in RAY, prior rituximab. Patients who continued to benefit from ibr therapy at the end of the study were eligible to enroll in CAN3001, an open-label phase 3b study providing continued access to ibr. The pooled analysis presented at ASH 2017 was limited to patients receiving ibr therapy, excluding crossover patients.

Investigator-assessed tumor response, progression-free survival (PFS), and overall survival (OS) were evaluated. Of 370 patients, 111 were enrolled in PCYC-1104, 120 in SPARK, and 139 in RAY; 87 of the 370 patients subsequently enrolled in CAN3001. The median duration of follow-up in the pooled data set was 41 months, with a median treatment exposure of 11 months.

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CLL & Other B-Cell Malignancies CLL & OTHER B-CELL MALIGNANCIES

Adverse Events, Resource Use, and Economic Burden in Patients with Mantle-Cell Lymphoma in the United States In patients with mantle-cell lymphoma (MCL), adverse events (AEs) can impair patient adherence to planned therapeutic regimens, and moderate-to-severe AEs generally require medical attention and are often associated with increased healthcare resource use (HRU) and costs. At ASH 2017, the authors presented the results of a retrospective cohort analysis designed to assess HRU and direct costs of MCL, examine variation in costs across treatment types, and document the economic burden associated with MCL treatment-related AEs.1 The study was performed using MarketScan databases containing employer- and health-plan–sourced administrative claims data for more than 60 million privately insured individuals across the United States. Cost information included patient copay, coinsurance, charges, and the actual amounts paid by the payers. Patients were included in the analysis if they had ≥2 medical claims on separate dates with a diagnosis code for MCL and were continuously enrolled in medical and drug plans for ≥12 months before the date of first MCL diagnosis (ie, study index date). A total of 783 patients with MCL met the study selection criteria. Mean (standard deviation [SD]) all-cause and MCL-related monthly costs were $8393 ($16,276) and $6730 ($14,779), respectively. Inpatient admission costs ($4817 [$14,267]) and office visit costs ($1493 [$3250]) were the largest drivers of total all-cause costs. Among patients receiving systemic

therapies, mean all-cause monthly costs were highest for rituximab, cyclophosphamide, doxorubicin, and vincristine (R-CHOP), followed by ibrutinib monotherapy, bendamustine plus rituximab (BR), and rituximab alone (including rituximab maintenance therapy). The median length of stay per allcause inpatient admission was 3.0 days (range, 2-4 days) among patients with no AEs, which increased to 5.2 days (range, 1-50 days) among those with ≥6 AEs. A corresponding increase in the length of stay per admission with increasing numbers of AEs was also observed. The mean (SD) all-cause monthly costs were $4298 ($10,082) among those with no AEs and more than 2-fold higher ($10,335 [$16,868]) among those with ≥6 AEs during follow-up. This was the largest series of patients with MCL in which real-world economic burden data have been reported. The authors concluded that the economic burden of MCL is substantial, with mean monthly costs varying considerably by treatment regimen and care setting. Inpatient admissions and office visits were the largest drivers of total costs for patients treated with R-CHOP, BR, and rituximab, whereas prescription drug costs were the largest component of total costs for patients receiving ibrutinib. Patients experiencing more AEs were observed to have higher monthly costs than those experiencing few AEs. l Reference: 1. Karve S, et al. ASH 2017. Abstract 3442.

Ibrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (GA101) for FirstLine Treatment of Patients with CLL with Mutated IGHV and without TP53 Aberrations The combination of fludarabine, cyclophosphamide, and rituximab (FCR) has been the standard first-line treatment for young patients with chronic lymphocytic leukemia (CLL), with a complete remission (CR) rate after 6 cycles of 40% to 72%, and an undetectable bone marrow (BM) minimal residual disease (MRD) rate after 6 cycles of 43% to 58%.1 However, there is a 5% risk for therapy-related myelodysplastic syndromes/acute myelogenous leukemia in these patients.2 Patients with mutated IGHV (IGHV-M) have favorable long-term outcomes (10-year progression-free survival >60%) after receiving first-line FCR. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, is approved for patients with CLL/small lymphocytic lymphoma, and obinutuz umab, a glycoengineered type II CD20 monoclonal antibody, was shown to be superior to rituximab in older adults when combined with chlorambucil in the CLL11 trial.3 Emerging data (HELIOS trial) indicated that the combination of ibrutinib with chemoimmunotherapy is safe and effective.4 At ASH 2017, the authors reported on an investigator-initiated phase 2 trial with ibrutinib, fludarabine, cy clophosphamide, and obinutuzumab (iFCG) for untreated patients with IGHV-M CLL and no TP53 aberrations.5 In this study, patients received 3 courses of iFCG, with a primary end point of CR/CR with incomplete blood count recovery (CRi) with undetect-

able BM MRD after 3 courses of iFCG. Patients meeting the primary end point received ibrutinib with obinutuzumab (iG) for cycles 4 through 6, then ibrutinib for cycles 7 through 12. Patients not achieving the primary end point received iG for cycles 4 through 12. A total of 32 patients initiated treatment. After 3 cycles of iFCG, all patients responded and 28 (87%) achieved BM MRD–negative remission. Fourteen (44%) achieved CR/ CRi with undetectable MRD at 3 months. Nineteen patients have reached the 12-month time point (all 19 were MRD-negative); 16 (84%) CR/CRi, 3 (16%) partial responses, and all have stopped treatment per protocol design. All remain MRD-negative at a median follow-up of 5.5 months after stopping ibrutinib. In the first 3 cycles of therapy, grade 3/4 neutropenia occurred in 68% of the patients. Grade 3/4 thrombocytopenia occurred in 42% of the patients. Atrial fibrillation occurred in 4 (11%) patients. The authors concluded that iFCG achieves a high rate of undetectable MRD after 3 courses. All 19 patients who have reached the 1-year time point are MRD-negative and have stopped all therapy, including ibrutinib. l References: 1. Fischer K, et al. Blood. 2016;127:208-215. 2. Benjamini O, et al. Leuk Lymphoma. 2015;56:16431650. 3. Goede V, et al. N Engl J Med. 2014;370:1101-1110. 4. Chanan-Khan A, et al. Lancet Oncol. 2016;17:200211. 5. Jain N, et al. ASH 2017. Abstract 495.

Median 3.5-Year Follow-Up of Ibrutinib Treatment in Patients with... At 2 and 3 years, respectively, 36% and 26% of patients were progression-free, and the median PFS was 13.0 months. Median PFS in patients with 1 prior line of therapy was 33.6 (19.442.1) months, and in patients achieving complete response (CR) was 46.2 (42.1not estimable) months. Overall, 53%, 45%, and 37% of patients were alive at

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2, 3, and 5 years, respectively. Median OS was 26.7 months. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 295 (79.7%) patients, with the new-onset events decreasing after year 1 (67.8%, 47.8%, 34.8%, 36.1%, and 20.0% for years 1, 2, 3, 4, and >4, respectively). The most common (incidence ≥5%) grade ≥3

TEAEs were neutropenia (17.0%), thrombocytopenia (12.2%), pneumonia (11.9%), anemia (9.5%), atrial fibrillation (5.9%), and hypertension (5.1%). Most of these were more common during the first year of ibr treatment. The authors concluded that in this pooled analysis of ibr-treated patients with R/R MCL with a median 3.5 years

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of follow-up, more than a quarter of patients remained progression-free and nearly half were alive at 3 years. Clinical outcomes were best for patients who achieved CR and those who were treated with ibr at first relapse/progression. l References: 1. Rule S, et al. Br J Haematol. 2017;179:430-438. 2. Rule S, et al. ASH 2017. Abstract 151.

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MYELOPROLIFERATIVE NEOPLASMS

Profound Symptom Burden of Myeloproliferative Neoplasms Highlighted in New Studies By Chase Doyle Atlanta, GA—A pair of recent studies from the Mayo Clinic underscore the serious symptom burden experienced by patients diagnosed with myeloproliferative neoplasms (MPNs), according to data presented at ASH 2017. Specifically, patients with MPNs are at high risk for depression, and those with Philadelphia chromosome–negative disease are afflicted with sleep and psychiatric disturbance as well. “The presence of significant depressive symptoms is not uncommon in patients with MPNs,” said Leslie Padrnos, MD, Hematology Oncologist, Seattle Cancer Care Alliance, WA, and lead investigator of the first study. “Mood disturbances were not associated with MPN-related therapy options, but were associated with worse systemic symptoms. These findings indicate depressive symptomatology may be intrinsic to the condition, and not a result of treatment side effects.” Krisstina L. Gowin, DO, Professor of Hematology, Mayo Clinic Arizona, Fife, WA, and lead investigator of the second study, emphasized “the prevalence and potential undertreatment of sleep and psychiatric disturbance in those afflicted with MPN.” Study 1

For the first study, Dr Padrnos and colleagues surveyed 1389 patients with MPNs in the United States, using the self-reported Patient Health Ques-

tionnaire-2 (PHQ-2). Among the PHQ-2 survey responders, 318 (23%) had scores of ≥3, indicating symptoms of depression.

“Mood disturbances were not associated with MPNrelated therapy options, but were associated with worse systemic symptoms. These findings indicate depressive symptomatology may be intrinsic to the condition, and not a result of treatment side effects.” —Leslie Padrnos, MD

The self-reported diagnoses among the total 1389 patients with MPNs included 550 (40%) patients with polycythemia, 445 (32%) with essential thrombocythemia, 349 (25%) with myelofibrosis, and 41 (3%) with other conditions. Although no differences were found in the use of particular MPN-directed treatments between the depression symptom groups, a history of thrombosis was found to be associated with increased depressive symptoms, according to the investigators.

Depression was also associated with younger age and a more recent MPN diagnosis, said Dr Padrnos, suggesting that patients with a relatively new diagnosis may have the highest risk for depression. Finally, patients with PHQ-2 scores of ≥3 used drugs to treat mood problems more often than patients without symptoms of depression (87% vs 77%, respectively). “Given that almost one-fourth of the patients endorsed having symptoms of depression, a better understanding of the mood disturbances impacting patients with MPN is warranted,” Dr Padrnos said. “Comprehensive healthcare for patients with MPNs should include an investigation into interventions targeting mood disturbances that may improve health-related quality of life and may prove to mitigate the severity of MPN-related symptoms, specifically fatigue.”

tients reported difficulty falling asleep, whereas 268 (31.2%) and 159 (18.5%) patients, respectively, reported insomnia and sleeping too much. The investigators also noted that only 20.9% of the population received mental health treatment, including medication use, counseling, and/or group therapy.

“Patients self-reported depression more often than revealed by the PHQ-2. Clearly, more studies are needed to understand optimal screening and treatment strategies in the MPN patient population.” —Krisstina L. Gowin, DO

Study 2

In the second study, Dr Gowin and colleagues recruited 1087 patients from around the world via social media to complete similar self-report surveys. The self-reported diagnoses included 338 patients with essential thrombocytosis, 188 patients with myelofibrosis, 315 with polycythemia vera, and 17 with other conditions. Difficulty staying asleep was reported by 447 (52.1%) patients, Dr Gowin reported. In addition, 289 (33.7%) pa-

Of 172 patients who received mental health treatment in the past 6 months, 131 received medications, 74 received counseling, and 6 participated in group therapy. “Patients self-reported depression more often than revealed by the PHQ2,” said Dr Gowin. “Clearly, more studies are needed to understand optimal screening and treatment strategies in the MPN patient population.” s

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lapsed acute myeloid leukemia after high-intensity chemotherapy, low-intensity chemotherapy, or HSCT).

oldest (mean age, 64.9 years), and patients receiving high-intensity chemotherapy were the youngest (mean age, 47.0 years). Hospitalizations Drive Cost of On average, the total episode cost Treatment Episodes was highest for HSCT ($329,621) with The final study sample consisted of a mean follow-up of 6.4 months. For 1542 treatment episodes of high-inten- patients undergoing HSCT, the hospisity chemotherapy induction, 591 epi- talization costs averaged $244,801, sodes of high-intensity chemotherapy whereas physician office visits and outconsolidation, 628 episodes of low- patient pharmacy costs were $6017 and intensity chemotherapy, 1000 cases of $11,398, respectively. According to Dr HSCT, and 119 patients with relapsed Medeiros and colleagues, 26.9% of paor refractory disease. Patients receiving tients who had HSCT had ≥1 emergenlow-intensity chemotherapy were the cy department visits that did not lead

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to hospital admission, at an average cost of $1037. High-intensity chemotherapy induction had the second-highest average episode cost ($198,528, with a mean follow-up of 2.1 months). As Dr Medeiros reported, all high-intensity chemotherapy induction required hospitalization, and accounted for most of the high-intensity chemotherapy costs ($178,891), with $2843 attributed to physician office visits and $2868 to outpatient pharmacy costs. Relapsed or refractory episodes were also associated with high economic bur-

den, with a cost of $145,634 and a mean follow-up of 7.6 months. Hospitalization occurred in 74.8% of patients with relapsed or refractory disease at a cost of $101,420, whereas physician office visits and outpatient pharmacy costs were $3340 and $6108, respectively. On the other hand, the cost was lowest with treatment episodes involving low-intensity chemotherapy ($53,081, with a 2-month follow-up). High-intensity chemotherapy consolidation costs $73,304 on average, with a mean follow-up of 1.5 months, Dr Medeiros and colleagues noted. s

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LEUKEMIA HIGHLIGHTS

Ibrutinib plus Venetoclax Combo Elicits Impressive Responses in Relapsed Chronic Lymphocytic Leukemia By Wayne Kuznar ibrutinib monotherapy followed by the addition of weekly venetoclax escalation therapy, starting at 20 mg, until the full 400-mg dose.

adding venetoclax because of toxicity; 49 patients successfully passed through venetoclax escalation. Overall, 8% of the patients had bulky disease (defined as lymph nodes ≥5 cm); 20% had 17p deletions; and 25% had 11q deletions without 17p deletions. The median number of previous therapies was 1, with a maximum of 6. The

Ibrutinib plus venetoclax led to an objective response rate of 100% in patients with relapsed or refractory CLL. —Peter Hillmen, MBChB, PhD, FRCP, FRCPath

Treatment was stopped at 14 months if the 8-month bone marrow assessment was negative for MRD. Treatment was stopped at 26 months if the 14-month bone marrow assessment was MRD-negative. Ibrutinib alone was continued if the bone marrow was MRD-positive at 26 months. MRD was defined as <0.01% CLL cells in the bone marrow. In all, 4 patients stopped taking ibrutinib before

Atlanta, GA—Ibrutinib (Imbruvica) plus venetoclax (Venclexta) led to an objective response rate of 100% in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), with 47% in complete remission at 6 months. These high response rates were achieved with only 1 case of laboratory tumor lysis syndrome, said Peter Hillmen, MBChB, PhD, FRCP, FRCPath, Leader, Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, United Kingdom, at ASH 2017. Data from the CLARITY clinical trial showed that approximately 33% of 38 patients evaluable for efficacy had minimal residual disease (MRD) in their bone marrow 6 months after receiving this combination. Ibrutinib improves overall survival and progression-free survival in patients with relapsed or treatment-naïve CLL, “However, ibrutinib does not eradicate residual disease as a single agent in many patients,” said Dr Hillmen. Venetoclax also elicits good responses in patients with CLL, leading to rare instances of tumor lysis syndrome that necessitate a slow dose increase in the first month. “However, this tumor lysis does translate into the eradication of detectable disease in a small proportion of patients,” Dr Hillmen told attendees. These observations led to the design of the CLARITY study, in which 54 patients with relapsed or refractory CLL were enrolled; of these, 50 patients received the daily combination of ibrutinib 420 mg plus venetoclax 400 mg. Patients received 8 weeks of

The results of CLARITY were impressive and herald “an era where we can use these targeted therapies to replace some of the toxic agents.” —Laurie Sehn, MD, MPH

most common previous therapies were fludarabine, cyclophosphamide, and ri tuximab (FCR) or bendamustine and rituximab (BR) in 81% of patients. Approximately 44% of patients had re-

lapsed within 3 years of receiving BR or FCR. Twenty percent of patients had previously received idelalisib (Zydelig). “The vast majority of adverse events were grade 1 and did not lead to stopping the treatment,” said Dr Hillmen. The most common adverse event of interest was bruising, in 33 patients. Of 25 cases of neutropenia, 6 were grade 3 and 6 were grade 4. The 1 patient who had tumor lysis syndrome was managed by delaying venetoclax, which was rapidly re-escalated with no further tumor lysis syndrome. All 38 patients who were evaluable for efficacy experienced at least a partial response. There were 15 (38%) patients with a complete response, and 3 (8%) with a complete response with incomplete hematologic recovery. At 8 months, 15 (37%) patients were negative for MRD in the peripheral blood, and 12 (32%) patients were MRD negative in the bone marrow. The remainder (53%) of the patients had a partial response. Among the patients who relapsed with FCR or BR treatment in <36 months, the MRD rates in the peripheral blood and bone marrow were 52% and 41%, respectively. A phase 3 clinical trial of ibrutinib plus venetoclax combination as first line for CLL is currently enrolling patients. Laurie Sehn, MD, MPH, Medical Oncologist, British Columbia Cancer Agency, Vancouver, Canada, said that the results of CLARITY were impressive and herald “an era where we can use these targeted therapies to replace some of the toxic agents used to treat hematological disorders.” s

Recent FDA Approvals for ALL a “Watershed” Moment Atlanta, GA—The past few years have witnessed significant progress in the treatment of several hematologic malignancies, and truly paradigm-changing therapies have recently emerged in acute lymphoblastic leukemia (ALL). At ASH 2017, Crystal L. Mackall, MD, Co-Director, Immunology & Immunotherapy of Cancer Program, Stanford University, CA, discussed the FDA approvals of 2 important treatments for patients with B-cell precursor ALL. Besponsa for B-Cell ALL in Adults

In August 2017, the FDA approved inotuzumab ozogamicin (Besponsa), a

CD22-directed antibody drug conjugate for the treatment of relapsed or refractory B-cell precursor ALL in adults. In a study of relapsed or refractory B-ALL in adults, inotuzumab ozogamicin showed an impressive single-agent remission induction rate of 81% versus 29% with standard chemotherapy (Kantarjian HM, et al. N Engl J Med. 2016;375:740-753). Despite these “very promising” results, said Dr Mackall, excitement has been tempered by liver toxicity. A related compound, gemtuzumab ozogamicin (Mylotarg, now approved for actute myelod leukemia), had

demonstrated similar activity in ALL, but its benefit was diminished by veno-occlusive disease (VOD), which required hematopoietic stem-cell transplant in many patients. “A similar pattern emerged with inotuzumab ozogamicin,” said Dr Mackall. VOD occurred in 11% of patients receiving this drug versus 1% in those who received chemotherapy. “These results further implicate ozogamicin as a risk factor for VOD, and suggest that these patients will be at heightened risk when they undergo consolidation therapy if it comes in the form of hematopoietic stem-cell transplant.”

Kymriah First FDA-Approved CAR T-Cell Therapy

In August 2017, the FDA approved tisagenlecleucel (Kymriah), the first chimeric antigen receptor (CAR) T-cell therapy, for B-cell precursor ALL that is refractory or in second or later relapse in young patients <25 years. Although incremental advances have yielded big payoffs in pediatric ALL in the past 50 years, chemoresistance has prevented further improvements, said Dr Mackall. The substantial incidence of late effects, especially central nervous system (CNS) toxicity, is a major problem facing clinicians. The FDA approvContinued on page 20

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LEUKEMIA HIGHLIGHTS

ASH Recaps “Phenomenal” Year for... At ASH 2017, clinical reviewers from the FDA highlighted 4 major drug approvals for the treatment of patients with AML, and discussed their safety and efficacy issues.

or AML with myelodysplasia- related changes,” said Dr Krauss. Mylotarg

Rydapt

In April 2017, midostaurin (Rydapt) was approved for the treatment of adults with newly diagnosed FLT3-positive AML in combination with standard intensive induction consolidation chemotherapy. The approval of the drug, which inhibits multiple kinases with nanomolar potency, was based on the results of the RATIFY trial, in which 717 patients with treatment-naïve FLT3 mutation–positive AML were randomized 1:1 to receive standard induction and consolidation chemotherapy in combination with midostaurin (50 mg orally twice daily on days 8-21 of each cycle) or placebo. Ashley F. Ward, MD, Medical Officer, FDA’s Division of Hematology Products, reported that RATIFY met its primary end point of overall survival (hazard ratio [HR], 0.77 favoring midostaurin). Despite a trial design that included maintenance, the FDA determined that the study did not support an indication of maintenance therapy.

Vyxeos

Daunorubicin plus cytarabine (Vyxeos) is a liposomal combination of cytarabine, a nucleoside metabolic inhibitor, and daunorubicin, an anthracycline topoisomerase inhibitor, and is indicated for the treatment of adults with newly diagnosed therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-

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The number of agents approved in 2017 was nothing short of “phenomenal.” —Richard Pazdur, MD

MRC). The drug was approved in August 2017, based on data from a phase 3 clinical trial of 309 patients with t-AML or AML-MRC. Aviva C. Krauss, MD, Medical Officer, FDA’s Division of Hematology Products, reported that the study exclusively enrolled patients with AML who have traditionally been excluded from clinical trials as a result of their poor prognosis. With a median follow-up of 20.7 months, patients receiving the combination therapy had a median overall survival of 9.6 months compared with 5.9 months for patients receiving the 2 drugs separately. “This drug is the first chemotherapy to demonstrate an overall survival advantage over the standard of care in a phase 3 randomized study of older adults with newly diagnosed therapy-related AML

In September 2017, the FDA approved gemtuzumab ozogamicin (Mylotarg) for the treatment of adults with newly diagnosed CD33-positive AML. The FDA also approved the drug for the treatment of patients aged ≥2 years with relapsed or refractory CD33-positive AML. Although the drug originally received accelerated approval in May 2000 as a stand-alone treatment for older patients with CD33-positive AML who relapsed, it was withdrawn from the market after subsequent trials did not verify a clinical benefit and showed safety concerns, including early death. Kelly J. Norsworthy, MD, of the FDA reported that the most recent approval includes a lower recommended dose, a different schedule in combination with chemotherapy or alone, and a new patient population. The drug’s safety and efficacy in combination with chemotherapy were studied in 271 adults with newly diagnosed CD33-positive AML. The patients were randomized to gemtuzumab ozogamicin plus daunoru bicin and cytarabine, or to daunorubicin and cytarabine without gemtuzu mab ozogamicin. The addition of gemtuzumab ozogamicin to the standard “7 + 3” chemotherapy improved the median event-free survival by 4.8 months (HR, 0.68). In a separate, single-arm study, 57 patients with CD33-positive AML who had 1 relapse of disease received a single course of gemtuzumab ozogamicin. Patients with relapsed AML who received the drug had durable remis-

sions, and 26% of patients achieved complete remission that lasted a median of 11.6 months. Idhifa

In August 2017, the FDA approved enasidenib (Idhifa) for the treatment of adults with relapsed/refractory AML and an isocitrate dehydrogenase-2 (IDH2) mutation as detected by an FDA-approved test. “This is the first FDA approval for relapsed or refractory AML specifically with an IDH2 mutation,” said Dr Ward, noting that this is a rare cancer with high unmet need. The approval of enasidenib was based on an open-label, single-arm, multicenter clinical trial that included 199 adults with relapsed or refractory AML with an IDH2 mutation as detected by the aforementioned assay. Patients received enasidenib (100 mg orally daily), and after a median follow-up of 6.6 months, 23% had a complete response (CR) or a CR with partial hematologic recovery (CRh) lasting a median of 8.2 months. A total of 19% of patients had a median CR of 8.2 months, and 4% had a median CRh of 9.6 months. Of the 157 patients who needed transfusions at the trial’s start, 34% no longer required them during at least one 56-day time period while receiving enasidenib. Of the 42 patients who did not require transfusions at the start of the trial, 76% maintained transfusion independence. “This study demonstrated compelling evidence of disease palliation,” said Dr Ward. “Although enasidenib is not curative, the short-term benefit is clinically meaningful for patients seeking quality of life.” s

Recent FDA Approvals for ALL a “Watershed”... al of tisagenlecleucel, the first gene therapy approved in the United States, represents a “watershed moment in cancer immunotherapy,” she said. “This is clearly some kind of therapeutic that we’ve never seen before,” she added. Reacting to this approval, Scott Gott lieb, MD, FDA Commissioner, said, “We’re witnessing a new frontier in medical innovation with the ability to reprogram a patient’s own cells to attack a deadly cancer. New technologies such as gene and cell therapies have the potential to transform medicine.” Dr Mackall emphasized that despite their complexity and cost, CAR T-cell therapies are poised for a major impact

in B-ALL. This impact will lead to eradication of chemoresistant leukemia; improve cell manufacturing to provide these drugs to all patients with cancer; reduce chronic toxicity for B-cell ALL; and reduce late adverse effects from CNS-directed therapies. Several studies using CAR T-cells have demonstrated that CD-19 CAR T-cells yield high remission rates in children with B-cell ALL. “What’s exciting to me is that the highest-risk patients—those with primary refractory, Philadelphia chromosome–positive, or ALL-rearranged disease—continually see high rates of remission,” she said. “The important

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point is that chemoresistance does not equate with immune resistance. Therefore, CARs provide a potent new tool to add to the multiagent treatment regimen for chemoresistant B-ALL.” Clinical Questions

A major question facing clinicians is how best to integrate CAR T-cell therapy with allogeneic stem-cell transplant. “When is it appropriate to recommend or defer allogeneic stem-cell transplant to patients rendered into remission with CAR therapy?” Dr Mackall asked. “There are many different answers to that question, and we’re going to need more data to figure that out.”

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Integrating CAR T-cell therapies with recently approved monoclonal antibodies, such as blinatumomab (Blincyto) and inotuzumab ozogamicin, is another issue. “Emerging clinical experience strongly suggests that previous blinatumomab increases the risk of CD19-negative relapse following CD19-CAR therapy, and similar results are emerging with inotuzumab ozogamicin and CD22CAR therapy,” she said. “Rather than these therapies synergizing with each other…clinicians may be reducing the power of a CAR T-cell by pretreating patients with an antibody targeting the same antigen.” s

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LEUKEMIA HIGHLIGHTS

New BTK Inhibitor Leads to Durable Responses in Relapsed or Refractory Chronic Lymphocytic Leukemia By Charles Bankhead Atlanta, GA—More than 90% of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) achieved objective responses with the new Bruton’s tyrosine kinase (BTK) inhibitor acalabrutinib (Calquence), updated data from an ongoing study showed. In most cases, the responses were durable, reported John C. Byrd, MD, Director, Division of Hematology, the Ohio State University Comprehensive Cancer Center, Columbus, at ASH 2017. Including partial response with lymphocytosis, 93% of 134 treated patients had objective responses to single- agent acalabrutinib. Complete responses accounted for 3% of the total response rate. “This updated analysis of an ongoing phase 1/2 showed that acalabrutinib is associated with a high response rate and durable remissions in patients with relapsed or refractory CLL or small-lymphocytic lymphoma” (SLL), said Dr Byrd. “The reported adverse events are consistent with a tolerable safety profile, including a low rate of grade 3 or higher

bleeding or cardiac events.” Acalabrutinib received FDA approval on October 31, 2017, for patients with mantle-cell lymphoma but not for patients with CLL. It is only the second BTK inhibitor to receive approval by the FDA. Ibrutinib (Imbruvica), the first BTK inhibitor approved by the FDA, is approved for several indications, including CLL, SLL, and mantle-cell lymphoma, among others. Ibrutinib has resulted in objective responses in a high percentage of patients with CLL. Acalabrutinib exhibits greater selectivity and potency of BTK inhibition. Preliminary data from a phase 1/2 trial involving 61 patients with relapsed or refractory CLL/SLL showed an objective response rate (ORR) of 95% and stable disease in the remaining 5%. A safety analysis showed that most adverse events were grade 1 or 2 in severity (Byrd JC, et al. N Engl J Med. 2016;374:323-332). Dr Byrd presented findings from an updated analysis of the phase 1/2 trial, which included more than twice as many

patients as the original report. Eligible patients had CLL/SLL that relapsed after or proved refractory to at least 1 previous therapy. Treatment started with acalabrutinib 100 to 400 mg once daily or 100 to 200 mg twice daily during the dose-escalation phase, and 100 mg twice daily during the expansion phase. Treatment continued until disease progression or unacceptable toxicity. Safety was the study’s primary objective, and investigator-assessed ORR was a key secondary end point. The updated analysis showed an ORR of 87%, including complete responses in 2% of patients. Including response with lymphocytosis pushed the ORR to 93%. A subgroup analysis showed consistent efficacy, including in high-risk groups, such as in 23 of 27 (85%) patients with deletion 17(p13.1), 18 of 21 (86%) patients with del(11) (q22.3), and 71 of 81 (88%) patients with immunoglobulin VH without mutation. The median progression-free survival (PFS) had not yet been reached; the 18-month PFS was 88%.

Similarly, the median PFS had not yet been reached in high-risk subgroups; the 18-month PFS rates for del(11) (q22.3) and del(17)(p13.1) were 100% and 78%, respectively. “The response rate and progression-free survival were consistent across all subgroups, including high-risk subgroups,” said Dr Byrd. “The 18-month PFS was above 80% in all subgroups.” The responses tended to be durable, which was reflected in the median response duration of 24.5 months. Consistent with the earlier report, most adverse events were grade 1/2 in severity. The most common events (all grades) were headache (46%), diarrhea (43%), upper respiratory tract infection (28%), fatigue (27%), nausea (27%), arthralgia (23%), pyrexia (23%), contusion (22%), petechiae (21%), and weight gain (21%). The most common grade 3/4 adverse events were neutropenia (11%) and pneumonia (11%). Based on these results, 3 phase 3 clinical trials of acalabrutinib in CLL/SLL have begun to enroll patients. s

Atlanta, GA—Venetoclax (Venclexta) plus rituximab (Rituxan) achieved superior progression-free survival (PFS) and overall survival (OS) compared with standard-of-care bendamustine (Treanda/Bendeka) plus rituximab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). PFS improved by 81% and OS by 52% with venetoclax plus rituximab, and the depth of response was impressive— complete response and complete response with incomplete platelet recovery was 26.8%, and minimal residual disease negativity in peripheral blood was 83.5%. These findings from an interim analysis of the phase 3 clinical trial MURANO were reported at ASH 2017. “This is the first randomized trial comparing any of the new agents targeted to treat CLL against a standard chemoimmunotherapy program, and it has proved the superiority of the chemotherapy-free approach,” said lead investigator John F. Seymour, MBBS, PhD, FRACP, Director, Haematology

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Venetoclax plus Rituximab New Chemotherapy-Free Option for Chronic Lymphocytic Leukemia

“Venetoclax/rituximab will be practicechanging.” —Robert A. Brodsky, MD

Department, Peter MacCallum Cancer Centre, Melbourne, Australia. “These findings suggest that venetoclax plus rituximab could be a standard option for relapsed or refractory CLL. There is also evidence of eradication of detectable disease that opens the prospect of time-limited therapy in this set-

ting,” Dr Seymour continued. A total of 389 patients were randomized to oral venetoclax 400 mg once daily, given until disease progression or unacceptable toxicity, for a maximum of 2 years, plus rituximab for 6 cycles versus 6 cycles of bendamustine plus rituximab. In the venetoclax arm, the dose was gradually increased to 400 mg daily over 4 to 5 weeks to reduce the likelihood of tumor lysis syndrome. All patients had 1 to 3 previous lines of therapy. Approximately 27% of patients in both arms had deletion 17p. The median PFS was not yet reached in the venetoclax arm versus 17 months in the bendamustine arm at a median follow-up of 23.8 months, representing an 83% risk reduction for disease progression favoring the experimental arm (P <.0001). The PFS results were consistent across subgroups, with responses seen in patients with poor-risk cytogenetics, as well as in those with good or intermediate risk. The secondary end points favored the venetoclax arm, including OS.

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Patients who received venetoclax plus rituximab had a 52% reduced mortality risk. At 2 years of follow-up, the median OS was not reached in either arm. Serious adverse events were reported in 46% of patients receiving venetoclax plus rituximab versus in 43% of those receiving bendamustine plus rituximab. Grades 3 and 4 adverse events were reported in 82% and 70% of patients, respectively. The causes of death were balanced between the 2 arms. Grades 3 and 4 neutropenia were more common in the venetoclax arm than in the bendamustine arm (58% vs 39%, respectively). Infections were relatively infrequent. Tumor lysis syndrome occurred in 3% of patients in the venetoclax arm versus in 1% of patients in the bendamustine arm. “Today’s phase 3 MURANO study suggests that venetoclax/rituximab will be practice-changing. We are getting away from chemotherapy and avoiding alkylating agents,” said ASH Secretary Robert A. Brodsky, MD, who moderated the press briefing. s

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MULTIPLE MYELOMA

Lenalidomide plus Elotuzumab Maintenance Regimen Improves Responses in Multiple Myeloma By Wayne Kuznar Atlanta, GA—A maintenance regimen of lenalidomide (Revlimid) and elotuzumab (Empliciti) after autologous stem-cell transplant (ASCT) improved the quality of responses achieved with induction therapy in patients with multiple myeloma. In a phase 2 study, 36% of patients receiving the combination as maintenance showed an improvement in response, and 20% of patients converted to either a complete response (CR) or stringent CR (sCR). The study is ongoing, with a planned accrual of 100 patients. The study’s data and results were reported by Sheeba K. Thomas, MD, MS, Associate Professor, Department of Lymphoma/Myeloma, M.D. Anderson Cancer Center, Houston, at ASH 2017. “The number of patients achieving CR may in fact be underestimated due to elotuzumab interference with electrophoretic measurements,” said Dr Thomas. “Nineteen of 33 patients not achieving CR had GK paraproteins, and 17 of the 19 were in VGPR [very good partial response].” After the enrollment of 68 patients who have been followed for a median of 23 months, the median progression-free survival (PFS) had not been reached. The 2-year estimated PFS was 88%. The median overall survival also had not been reached.

The study evaluated elotuzumab plus lenalidomide as maintenance therapy after myeloablative ASCT in patients treated with ≤2 lines of systemic therapy before ASCT. The first 28 patients received elotuzumab 10 mg/kg weekly

“Nineteen of 33 patients not achieving CR had GK paraproteins, and 17 of the 19 were in VGPR.” —Sheeba K. Thomas, MD, MS

for cycles 1 and 2, bimonthly for cycles 3 through 6, and 20 mg/kg monthly from cycle 7 forward. The study was amended for patients to receive elotuzumab 20 mg/kg monthly during cycles 3 through 6. Patients aged <75 years were instructed to take dexamethasone 28 mg before infusion for cycles 1 and 2. The dose was reduced to 8 mg for patients aged ≥75 years in an effort to optimize tolerability. All patients received 4 to 10 mg of intravenous dexamethasone immediately before each infusion. Patients received lenalidomide 10 mg daily for cycles 1 through 3, which could be increased to 15 mg daily from cycle 4 forward in the absence of signif-

icant cytopenias and nonhematologic toxicity. In all, 44% of patients required dose reductions of lenalidomide “so that most of our patients are currently dosed at 10 mg on days 1 through 21 of the 28-day cycle due to intolerability,” Dr Thomas said. Overall, 71% of the patients received 1 line of induction therapy before ASCT and 29% received 2 lines. A 3-drug induction regimen was used in all but 2 patients, with the most common (72%) being a proteasome inhibitor plus lenalidomide and dexamethasone. The me-

The majority (75%) of patients were in ≥very good partial response at study entry. “This has improved to 91% based on best response estimates on study, including 51% who have achieved CR or sCR.” —Sheeba K. Thomas, MD, MS

dian time from ASCT to the start of study treatment was 158 days. A total of 31% of pateints had highrisk cytogenetics according to Interna-

tional Myeloma Working Group criteria. The high-risk cytogenetic features included deletion 17p in 10% and t(4;14) in 7%. Of the 68 enrolled patients, 25 (36%) had an improvement in their quality of response. Among the patients whose responses were upgraded from study entry, the median number of cycles to best response was 3.5. Of the 13 patients in CR who were tested for minimum residual disease (MRD), 10 were MRD negative at study entry and 3 converted from VGPR to MRD negative. The majority (75%) of patients were in VGPR or better at study entry. “This has improved to 91% based on best response estimates on study, including 51% who have achieved CR or sCR,” said Dr Thomas. A total of 3 patients died, 2 with progressive disease while receiving salvage therapy, and 1 with acute encephalopathy and refractory status epilepticus in VGPR. Anemia (6%), neutropenia (31%), and thrombocytopenia (7%) were the most common grade ≥3 hematologic toxicities. The most common nonhematologic adverse events were fatigue (76%), myalgias (71%), diarrhea (69%), respiratory infections (57%), nausea/vomiting (57%), and dizziness (56%). s

Daratumumab Therapy for Smoldering Myeloma Extends Progression-Free Survival Atlanta, GA—Single-agent daratum umab (Darzalex) shows significant activity in smoldering multiple myeloma (SMM). The 12-month progression-free survival (PFS) rate with a long dosing schedule of daratumumab was 95%, and the median PFS was not yet reached in any of the 3 dosing schedules studied, announced Craig C. Hofmeister, MD, MPH, Associate Professor, Division of Hematology, the Ohio State University, Columbus, at ASH 2017. These results from the phase 2 clinical trial CENTAURUS support a long dosing schedule of 16 mg/kg intravenously in 8-week cycles from the phase 3 study, AQUILA. Current guidelines recommend only

monitoring patients with SMM every 3 to 6 months for progression to active multiple myeloma before initiating treatment. However, a previous phase 3 study

“From a clinical efficacy perspective, this supports the long dosing schedule for a subsequent phase 3 trial.” —Craig C. Hofmeister, MD, MPH

(QuiRedex) enhanced survival with lenalidomide (Revlimid) and pulsed

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dexamethasone in patients with highrisk SMM. “Hence, it’s appealing to try to treat patients with intermediate- and high-risk SMM to try to get some clinical benefit,” said Dr Hofmeister. Daratumumab acts through multiple mechanisms, he said. It has direct on- tumor activity that may contribute to rapid response and its immunomodulatory actions, including modulation of the tumor microenvironment and depletion of CD38-positive immunosuppressive cells, may promote deep and durable responses. CENTAURUS randomized 123 patients with a diagnosis of SMM of less than 5 years, bone marrow plasma cells ≥10% to <60%, and at least 1 high-risk

criterion. Patients with ≥1 multiple myeloma–defining events by SLiM-CRAB criteria were excluded. The patients were randomized to 1 of 3 dosing schedules: 1. A long regimen with the weekly administration of daratumumab in cycle 1, every other week in cycles 2 and 3, every 4 weeks in cycles 4 through 7, and every 8 weeks up to cycle 20 2. An intermediate schedule in which daratumumab was given weekly in cycle 1, and every 8 weeks up to cycle 20 3. A short, intense dosing schedule in which daratumumab was given weekly for 1 cycle. Serologic monitoring using International Myeloma Working Group

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LYMPHOMA HIGHLIGHTS

A New Combination as First-Line Regimen in Advanced Hodgkin Lymphoma? By Phoebe Starr pulmonary toxicity, and causes sterility in males and compromised fertility in females. The removal of bleomycin and addition of brentuximab vedotin rep-

Atlanta, GA—Adding brentuximab vedotin (Adcetris) to doxorubicin, vinblastine, and dacarbazine (A+AVD) instead of the standard regimen with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as frontline treatment for advanced Hodgkin lymphoma reduced the risk for disease progression, death, or the need for additional therapy by 23%, according to new data presented at ASH 2017. Lead investigator Joseph M. Connors, MD, FRCPC, Clinical Director, Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, Canada, reported the results of the phase 3 ECHELON-1 clinical trial, which were also published online (Connors JM, et al. N Engl J Med. 2018;378:331-344) to coincide with the ASH meeting. The A+AVD regimen improved the chances of cure with the first round of chemotherapy, obviating the need for additional, more intensive therapy, and reducing the odds of toxicity. Overall, 33% fewer patients who received A+AVD as frontline therapy required subsequent salvage therapy or high-dose chemotherapy and transplant compared with those who received standard therapy with ABVD. ABVD has been the standard-of-care regimen for approximately 40 years. Although the majority of patients with Hodgkin lymphoma are cured, an estimated 25% to 33% require additional therapy. The new regimen replaces bleomycin with brentuximab vedotin. “Many of these patients are younger. Bleomycin can cause life-threatening

“About 25% of patients who would otherwise fail [treatment] were successfully treated with the new combination. If this new regimen is widely adopted, it will change first-line treatment of advanced Hodgkin lymphoma.” —Joseph M. Connors, MD, FRCPC

resents a major step forward for the Hodgkin lymphoma community,” said Dr Connors. “About 25% of patients who would otherwise fail [treatment] were successfully treated with the new combina-

tion,” he said. “If this new regimen is widely adopted, it will change first-line treatment of advanced Hodgkin lymphoma,” added Dr Connors. ECHELON-1 was a randomized, open-label, multicenter, phase 3 clinical trial that was conducted at 218 sites in 21 countries. Overall, 1334 patients with histologically confirmed stage III or IV Hodgkin lymphoma were randomized to receive A+AVD (experimental arm) or standard treatment with ABVD. All patients received treatment for up to 6 cycles. For the primary end point, A+AVD achieved a significant 23% improvement in modified progression-free survival (PFS; including disease progression, death, or need for subsequent therapy) versus ABVD (P = .035); the 2-year modified PFS was 82.2% versus 77.2%, respectively, per independent review. The secondary end points also favored A+AVD over ABVD. The complete response rate was 73% in the A+AVD arm versus 70% in the ABVD arm, and the objective response rate was 86% versus 83%, respectively. Reduced Pulmonary Toxicity

The most common grade 3 or 4 adverse events with A+AVD were neutropenia, febrile neutropenia, and a reduction in neutrophil count. The use of growth factor support with granulocyte colony-stimulating factor (GCSF) reduced the rate of febrile neutropenia from 21% at baseline to 11% in the A+AVD arm. Primary prophylaxis with G-CSF is now recommended with A+AVD.

Daratumumab Therapy for Smoldering... (IMWG) criteria and magnetic resonance imaging was performed every 6 months for the first 3 years. The patients were followed until progressive disease or until the end of the study. Approximately 80% of patients in each arm had ≥2 high-risk factors at screening. The median time from the diagnosis of SMM to randomization was 6.47, 5.52, and 7.43 months in the long, intermediate, and short schedule arms, respectively. With a median follow-up of 15.8 months, 5 (12%) patients in the long

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arm discontinued treatment, with 2 (5%) resulting from adverse events and 2 (5%) from progressive disease. The discontinuation rates in the intermediate- and short-schedule arms were 10% and 5%, respectively. The 12-month PFS rates were 95% with the long schedule, 88% with an intermediate dosing schedule, and 81% with the short schedule of daratumu mab. A median PFS of ≥24 months was a coprimary end point and was achieved in each arm. More than half (54%) of the patients

Expert Input

George P. Canellos, MD, Medical Director, Network Development, Dana- Farber Cancer Institute, Boston, MA, was cautious about endorsing A+AVD as a new standard of care. “Should we now consider A+AVD as the new standard of care in advanced classical Hodgkin lymphoma? Not so quick! It is much too early to say that this is practice-changing, with only a small progression-free survival difference and a short duration of follow-up,” said Dr Canellos. He noted that the need for growth factor support will escalate treatment costs of the new regimen. “It is not clear whether these data will lead to approval of brentuximab vedotin for frontline treatment of advanced Hodgkin lymphoma,” stated Dr Canellos. s

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in the long-schedule arm and 49% in the intermediate-schedule arm had a partial response or better compared with 38% in the short arm. The other coprimary end point, a complete response of >15%, was not met. The complete response rates were 2% in the long-schedule arm, 5% in the intermediate-schedule arm, and 0% in the short-schedule arm. A modified PFS based on biochemical progression was added to the analysis. Biochemical progression was defined as a measurable disease increase from nadir by ≥25% in 2 subsequent assessments per

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“There was an excess in treatment-emergent peripheral neuropathy in the experimental arm [67% with A+AVD vs 43% with ABVD], but with appropriate changes in schedule and doses, two-thirds of patients reported peripheral neuropathy resolved or improved,” Dr Connors said. Pulmonary toxicity, which is a major concern with bleomycin therapy, was reported in 2% of patients in the A+AVD arm versus 7% of patients in the ABVD arm. Fewer than 1% of patients in each arm reported grade ≥3 pulmonary toxicity. Overall, 9 patients died in the A+AVD arm (7 in patients with neutropenia not treated with G-CSF) and 13 patients in the ABVD arm (11 in association with pulmonary toxicity).

the IMWG criteria. The 12-month modified PFS rates were 93%, 75%, and 56% in the long-, intermediate-, and short- schedule arms, respectively. “From a clinical efficacy perspective, this supports the long dosing schedule for a subsequent phase 3 trial,” said Dr Hofmeister. The safety profile was consistent with other single-agent daratumumab trials. The rate of hematologic treatment- emergent adverse events was <15% across all arms and the rates of grade 3 and 4 infections were ≤5% across all arms. s —WK

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LYMPHOMA HIGHLIGHTS

High Response Rate with 3-Drug Combination for Untreated Follicular Lymphoma By Charles Bankhead Atlanta, GA—Among patients with untreated follicular lymphoma, 75% achieved complete responses with the 3-drug combination of atezolizumab (Tecentriq), obinutuzumab (Gazyva), and bendamustine (Treanda), results of a small, preliminary clinical trial reported at ASH 2017 showed. The regimen achieved an overall response rate (ORR) of 85% in 40 evaluable patients. Although active, the regimen caused substantial toxicity, and more than 50% of the patients had grade 3 or 4 adverse events that led to treatment interruption. The 3-drug combination “resulted in encouraging end-of-induction activity in previously untreated patients,” said Anas Younes, MD, Chief, Lymphoma Service, Memorial Sloan Kettering Cancer Center, New York City. Acknowledging the preliminary nature of the study, he added, “Longer follow-up is needed to make a more comprehensive benefit–risk evaluation of this combination and to perform an analysis of biomarkers.” The response rate with the 3-drug combination was similar to that observed in the large, randomized, phase 3 GALLIUM trial that compared rituximab (Rituxan)-based induction chemotherapy with obinutuzumab-based induction in patients with untreated follicular lymphoma (Marcus R, et al. N Engl J Med. 2017;377:1331-1344). The ORRs in GALLIUM were 87% to 88% in both treatment groups. Despite the high initial response rates, including

complete responses, the disease eventually relapsed in most patients with follicular lymphoma, Dr Younes noted. As a result, investigators continue to evaluate therapies that may achieve more durable responses or offer effective options for relapsed disease. “Atezolizumab targets PD-L1 and has a complementary mechanism of action to obinutuzumab and has the potential to improve outcomes when added to obinutuzumab-based chemotherapy,” he said. Eligibility criteria for this preliminary study included untreated grade 1 to 3a follicular lymphoma or relapsed or refractory disease. Patients received induction therapy with all 3 drugs, and patients who achieved a complete or partial remission received maintenance therapy with obinutuzumab and atezo lizumab for as long as 24 months. The study included a 6-patient safety run-in phase, and patients with relapsed or refractory disease were eligible to participate only in the safety evaluation. The primary end point was complete response at the end of induction therapy, as determined by positron emission tomography or computed tomography assessment. The secondary end points included investigator-assessed complete response at the end of induction treatment using modified Lugano 2014 criteria and additional assessments of complete response, using different criteria to define complete response. The investigators enrolled 42 patients, 2 of whom had relapsed or refrac-

tory disease. The efficacy analysis included only the 40 patients with previously untreated follicular lymphoma. At data cutoff, 35 patients contin-

The 3-drug combination “resulted in encouraging end-of-induction activity in previously untreated patients….Longer followup is needed to make a more comprehensive benefit–risk evaluation of this combination and to perform an analysis of biomarkers.” —Anas Younes, MD

ued to use maintenance therapy, with median duration of 5.5 months, including 8 patients who received mainte-

nance therapy for at least 12 months. Overall, 93% of the patients had Ann Arbor stage III or IV disease. More than 70% of the patients had grade 2 or 3a disease, and Follicular Lymphoma International Prognostic Index risk status was low in 24%, intermediate in 43%, and high in 33% of patients. Approximately 20% of the patients had bulky disease (>7 cm), and approximately 50% had bone marrow infiltration. By modified Lugano criteria, the ORR at the end of induction was 85% by independent review and 95% by investigator assessment. In addition to a 57% rate of grade 3 or 4 adverse events, 29% of patients had serious adverse events, and 10% of patients discontinued treatment as a result. Furthermore, 10% of patients required dose reduction of bendamustine because of associated adverse events, and 57% required dose interruption. During induction, the most common grade 3 or 4 hematologic adverse events were neutropenia in 11 patients and thrombocytopenia in 2 patients. In addition, grade 3 or 4 lipase elevation occurred in 3 patients during induction. Seven patients had a total of 12 adverse events of special interest during induction therapy, including 3 with grade 1 or 2 and 1 case each of grade 4 increase in lipase, grade 2 rash, grade 4 myocarditis, and grade 1 bronchiolitis. Two patients died—1 from cardiac arrest associated with severe myocarditis and bronchiolitis and 1 from unknown cause. s

Brentuximab Vedotin plus Nivolumab Yields High Complete Responses in Relapsed or Refractory Hodgkin Lymphoma By Chase Doyle Atlanta, GA—Interim results from a phase 1/2 study of the combination of brentuximab vedotin (Adcetris) and nivolumab (Opdivo) have demonstrated a high overall response rate (ORR) in patients with relapsed or refractory Hodgkin lymphoma. According to data presented at ASH 2017, 83% of patients responded to the combination, which included a 62% rate among efficacy-evaluable patients.

“These data suggest the combination of brentuximab vedotin and nivolumab is a well-tolerated and active salvage therapy with a high rate of complete response that has no adverse impact on —Alex F. Herrera, MD stem-cell collection.” “These data suggest the combination of brentuximab vedotin and nivolumab

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is a well-tolerated and active salvage therapy with a high rate of complete

response that has no adverse impact on stem-cell collection,” said Alex F. Herrera, MD, Assistant Professor, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA. “The safety and activity of this novel combination support further exploration in an ongoing pivotal phase 3 trial in patients with relapsed or refractory Hodgkin lymphoma who have

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PET-Directed Approach Can Guide Radiation Therapy in Diffuse Large B-Cell Lymphoma By Phoebe Starr Atlanta, GA—A positron emission tomography (PET)-directed approach after standard chemotherapy can guide the need for consolidation radiation therapy in patients with diffuse large B-cell lymphoma (DLBCL). This approach can spare patients from further treatments, such as salvage chemotherapy and stem-cell transplant, as well as unnecessary radiation therapy, according to a study presented at ASH 2017. “Our experience shows that 18-F- fluorodeoxyglucose [FDG]-PET can be used to guide the administration of consolidative radiation therapy. This approach limits toxicity associated with radiation to those at greatest risk,” said lead investigator Ciara Louise Freeman, MD, MRCP, Lymphoma Fellow, Medical Oncology and Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, Canada, who presented the results. “We found that patients with bulky DLBCL who become PET-negative at end of therapy have excellent outcomes without radiation therapy. PET-positive

patients who did not progress…have favorable outcomes and appear to benefit from this approach,” she told listen-

“Patients with bulky DLBCL who become PETnegative at end of therapy have excellent outcomes without radiation therapy…. Almost 60% of those with bulky disease at diagnosis can be safely spared radiation therapy.” —Ciara Louise Freeman, MD, MRCP

ers. “Almost 60% of those with bulky disease at diagnosis can be safely spared radiation therapy.” To determine the benefit of FDG-

PET in selecting patients for radiation therapy after chemotherapy, this retrospective analysis included 723 patients with newly diagnosed advanced DLBCL who were listed in the British Columbia Cancer and Lymphoid Imaging databases between 2015 and 2017. Patients received treatment with curative intent using 6 cycles of the R-CHOP regimen, and then underwent posttreatment FDG-PET scans. Patients with PET-negative results went on to observation. Nonprogressing PET-positive patients had consolidative radiation therapy, when feasible. Patients enrolled in the study had stage III or IV (74%) or stage I or II disease, with B-cell symptoms and/or bulky disease (ie, ≥10 cm). At the end of chemo-immunotherapy, 72% were PET-negative and went on to observation. The remaining 206 (28%) patients were PET-positive. At a median of 3.3 years of follow-up from diagnosis, PET-negative patients were less likely to have disease progression: 83% of the PET-negative group

Brentuximab Vedotin plus Nivolumab... already received or are considered ineligible for autologous stem-cell transplant [ASCT].” Brentuximab vedotin and nivolumab are effective single-agent treatments for relapsed or refractory Hodgkin lymphoma. Brentuximab vedotin is believed to activate the patient’s immune system and initiate an antitumor immune response through the induction of immunogenic cell death, whereas nivolumab blocks the PD-1 receptor, inhibits binding of PD-1 ligands, and restores an effective antitumor immune response. “The encouraging activity The phase 1/2, open-label, multiof BV plus nivolumab will center trial enrolled 62 adults with relapsed or refractory classical Hodgkin be further evaluated in lymphoma. Patients were excluded if multiple settings.” they previously received salvage thera—Alex F. Herrera, MD py; brentuximab vedotin; immune- oncology therapy affecting the PD-1, CTLA4, or CD137 pathways; or stemcell transplant. The study’s primary end response rate after study completion. points were safety, the incidence and The patients received brentuximab severity of adverse events, and complete vedotin in combination with nivolu

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Continued from the page 24

mab every 3 weeks (1 cycle) for up to 12 weeks (4 cycles). After completion of the therapy, the patients were eligible to undergo ASCT. Overall, 60 (98%) patients had adverse events before undergoing ASCT or receiving salvage therapy after treatment. The majority (66%) of these adverse events were grade 1 or 2, but 19 (31%) were grade ≥3. Infusion-related reactions were reported by 27 (44%) patients, with 25 (41%) of these occurring during infusion with brentuximab vedotin, most often during cycle 2. “Pretreatment with low-dose steroid and antihistamine did not impact the frequency or severity of these reactions, which caused an interruption of infusion in 16 patients,” Dr Herrera said. “However, no patients discontinued treatment due to an infusion-related reaction.” Although 5 patients required systemic steroids for the treatment of an immune-related adverse event, no patients discontinued treatment because

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and 57% of the PET-positive group had not progressed, relapsed, or died from lymphoma. Of the 206 PET-positive patients, 47% did not receive radiation therapy and 109 received radiation. More than three-quarters (78%) of those with PET-positive disease who received radiation were free of disease progression at 3 years compared with 83% of the PET-negative patients, and 34% of the PET-positive patients who did not get radiation therapy. The 3-year overall survival was similar (86% and 84%) for the PET-negative and PET-positive cohorts of patients who received radiation therapy, respectively, compared with 44% of PET-positive patients who did not have radiation. The presence of bulky disease at baseline did not affect time to disease progression. The 3-year time to disease progression was 84% in the nonbulky PET-negative disease cohort and 82% in the bulky PET-negative disease cohort. s

of these events. The ORR with the combination treatment as first salvage therapy was 83%, and the complete response rate was 62%. “The combination of BV [brentuximab vedotin] and nivolumab did not appear to impact stem-cell mobilization and collection yields or engraftment,” said Dr Herrera. “Patients did not appear to have increased toxicity during or after the transplant period.” In addition, the combination resulted in increased numbers of circulating T-cells, increased innate and adaptive immune-activating cytokines and chemokines, and increased ability of memory T-cells to mount an immune response. “The encouraging activity of BV plus nivolumab will be further evaluated in multiple settings, including a pivotal phase 3 trial in patients with advanced Hodgkin lymphoma who are ineligible for ASCT or after failure of ASCT,” Dr Herrera concluded. s

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Highlights from 2017 American Society of Hematology ACUTE MYELOID LEUKEMIA

Nivolumab plus Azacitidine Shows Encouraging Activity in R/R AML or as Frontline Therapy in Elderly Patients with AML

Enasidenib Monotherapy Is Well-Tolerated and Active in Older Patients with Untreated mIDH2 AML

Available preclinical and clinical evidence suggests that inhibition of PD-1/ PD-L1 pathways increases antileukemic responses in acute myeloid leukemia (AML). Moreover, azacitidine treatment results in upregulation of PD-1 signaling, which is associated with azacitidine resistance. Based on this rationale, the current study evaluated the safety and efficacy of combination nivolumab plus azacitidine treatment in 2 patient cohorts: those with relapsed or refractory (R/R) AML with poor-risk features, and in elderly patients with untreated AML. In this single-institution, nonrandomized, phase 1b/2 trial, eligible patients were enrolled in 3 independent patient cohorts: cohort 1, comprised of patients with R/R AML who had adequate performance status (Eastern Cooperative Oncology Group ≤2) and organ function; cohort 2, comprised of AML patients ≥65 years and not suitable for induction therapy who received frontline nivolumab treatment; and cohort 3, comprised of patients in first and second salvage therapy for AML. All 3 cohorts received nivolumab (3 mg/kg on days 1 and 14) plus azacitidine (75 mg/m2 on days 1-7) every 4 to 5 weeks indefinitely, with cohort 3 receiving additional ipilimumab. The primary objective was best International Working Group response at any time on study; secondary objectives included progression-free survival, overall survival (OS), safety, and correlative studies.1 In the dose-escalation phase (n = 6), the dose-limiting toxicity was grade 3 pneumonia, with 75 mg/m2 established as the recommended phase 2 dose. A total of 70 eligible patients with R/R AML have been treated in cohort 1 and serve as the intent-to-treat population of the current analysis; 14 patients have been enrolled in cohort 2 (12 evaluable), and 12 in cohort 3 (not included in this analysis). The median age of patients in cohort 1 was 70 years (range, 22-90 years); 44% had secondary AML, 34% had poor-risk cytogenetics, and they had received a median of 2 salvage therapies (range, 1-7). Common mutations harbored by

Enasidenib (AG-221) is a novel, small-molecule oral inhibitor of mutated IDH2 (mIDH2) proteins that is currently indicated for the treatment of adult patients with mIDH-positive relapsed or refractory (R/R) acute myeloid leukemia (AML). The phase 1 AG221-C-001 study demonstrated the clinical efficacy of enasidenib in patients with mIDH2 R/R AML. Given the limited treatment options for older patients with untreated AML, the current analysis sought to evaluate the clinical outcomes for older patients with previously untreated mIDH2 AML who received enasidenib monotherapy in the AG221-C-001 study. 1 Both the dose-escalation and expansion cohorts included patients aged ≥60 years with previously untreated AML who were not candidates for standard treatment and had an Eastern Cooperative Oncology Group performance status of 0 to 2. In the dose-escalation phase, patients were treated with enasidenib 50 mg to 650 mg daily, whereas patients in the expansion phase received enasidenib 100 mg daily in continuous 28-day treatment cycles. The overall response rate (ORR) included complete remission (CR), CR with incomplete count recovery (CRi), CR with incomplete platelet recovery (CRp), and morphologic leukemia-free state (MLFS), per modified International Working Group 2003 response criteria for AML. Data cutoff for this analysis was October 14, 2016. A total of 239 patients received enasidenib monotherapy in the phase 1 dose-escalation and study expansion, of which 38 patients had previously untreated mIDH2 AML. The median age of analysis patient set was 77 years (range, 58-87 years); 19 patients had intermediate cytogenetic risk by National Comprehensive Cancer Network classification and 10 had poor-risk cytogenetics. The median number of enasidenib treatment cycles was 6.5 (range, 1-35), and median

evaluable patients (n = 28) included TP53 (23%), DNMT3A (17%), ASXL1 (16%), and TET2 (16%). At a median follow-up of 13.3 months, 16 (23%) patients achieved complete remission (CR), CR with insufficient recovery of counts (CRi) or partial response (PR); 7 (10%) showed hematologic improvement (HI), 17 (24%) had ≥50% bone marrow blast reduction, and 5 (7%) had stable disease >6 months. The response rate was similar in patients ≤65 years versus >65 years of age, and was higher in patients with diploid cytogenetics, in patients without prior therapy with a hypomethylating agent, and in patients with ASXL1 mutations. The median OS was 17.1 months in CR/CRi patients, 11.9 months in HI patients, and 5.6 months in nonresponders. The median OS associated with nivolumab plus azacitidine was found to be significantly higher than with hypomethylating agent– based salvage protocols from MD Anderson Cancer Center in similar settings (10.6 vs 3.9 months; P <.001). Grade 3/4 immune-related adverse events (irAEs) were observed in 8 (12%) patients, and grade 2 irAEs were seen in 8 (12%) patients; median time to onset was 6 weeks (range, 4 days-14 weeks). Common grade 2 to 4 irAEs included pneumonitis, colitis, nephritis, skin rash, and hypophysitis. At data cutoff, cohort 2 had enrolled 14 patients with frontline AML aged ≥65 years. Median age was 73 years (range, 68-82 years), 3 patients had secondary AML, and 7 patients had diploid cytogenetics. Of the 12 patients evaluable for response, 8 patients achieved CR/CRi/PR with insufficient recovery of counts (median follow-up was 5.9 months). Based on these results, it was concluded that combination therapy with nivolumab plus azacitidine yielded encouraging response rates, with improved OS compared with historical data in patients with R/R AML and poor-risk features. l

follow-up was 8.6 months (range, 0.534.3 months). In the efficacy analysis, an ORR of 32% (95% confidence interval [CI], 17.5-48.7) was reported, including 7 (18%) patients who achieved CR, 1 with CRi/CRp, 1 partial response, and 1 MLFS. Notably, 18 patients achieved stable disease. The median time to CR was 5.6 months (range, 3.4-12.9 months), the median duration of CR was not reached (NR; 95% CI, 3.7NR), and the median duration of any response was 12.2 months (95% CI, 2.9-NR). At data cutoff, 3 patients proceeded to transplant and remained in remission. In the overall cohort (n = 37), the median overall survival (OS) was 11.3 months (95% CI, 5.717.0) and median event-free survival was 5.7 months (95% CI, 3.1-16.0). The median OS in responders (n = 14) was not reached (95% CI, 10.4-NR). The most common treatment-emergent adverse events (TEAEs), regardless of grade, were fatigue (43%), nausea (41%), and decreased appetite (41%). The most frequent treatment-related TEAEs of any grade, occurring in ≥10% of patients, were hyperbilirubinemia (32%) and nausea (24%); grade 3/4 TEAEs occurred in 13% and 0%, respectively. Serious treatment-related TEAEs reported in >1 patient were IDH differentiation syndrome (n = 4; 11%) and tumor lysis syndrome (n = 4; 11%). Treatment-related TEAEs led to treatment discontinuation in 2 (3%) patients due to cardiac tamponade and thrombocytopenia. The safety profile was similar to that observed in the total study population of 239 patients. These results suggest that enasidenib monotherapy may improve clinical outcomes by inducing durable hematologic responses in older, difficult-to- treat patients with previously untreated mIDH2 AML who were not candidates for standard treatment. l Reference: 1. Pollyea DA, et al. 2017 ASH. Abstract 638.

Reference: 1. Daver N, et al. 2017 ASH. Abstract 1345.

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Acute Myeloid Leukemia ACUTE MYELOID LEUKEMIA

Safety and Tolerability of Midostaurin from Expanded Treatment Protocol in Patients with FLT3 Mutation–Positive, Newly Diagnosed AML

Encouraging Efficacy and Safety with Enasidenib or Ivosidenib plus Azacitidine in Patients with Newly Diagnosed AML

Midostaurin, a multikinase inhibitor targeting FLT3 and KIT, is indicated for the treatment of patients with newly diagnosed, FLT3 mutation–positive acute myeloid leukemia (AML) in combination with standard induction and consolidation chemotherapy, based on demonstrations of superior survival outcomes versus placebo in the randomized, double-blind, phase 3 RATIFY trial. The Radius-X open- label expanded treatment protocol (ETP) was designed to provide access to midostaurin and obtain additional insights into the safety and tolerability profile of midostaurin in adult patients with newly diagnosed, FLT3 mutation–positive AML. Patients eligible for enrollment into the ETP were adults with newly diagnosed, FLT3 mutation–positive AML (internal tandem duplication [ITD] or tyrosine kinase domain [TKD]) who were fit to receive intensive induction and consolidation chemotherapy. Patients received 1 to 2 cycles of induction therapy (cytarabine plus daunorubicin or idarubicin) and ≤4 cycles of cytarabine consolidation therapy in combination with midostaurin (50 mg twice daily on days 8-21 of each 28day cycle), followed by ≤12 months of single-agent midostaurin (50 mg twice daily on days 1-28). Patients could initiate midostaurin therapy at any point during standard chemotherapy prior to the completion of a second cycle of consolidation. At data cutoff, 103 patients were enrolled in the study, including 47 (46%) patients enrolled during induction and 56 (54%) during consolidation. Overall, 31 patients went on to receive maintenance therapy, 12 of whom remain on therapy. A total of 85 (83%) patients discontinued the study, mostly due to transplant (n = 52), adverse events (AEs; n = 7), relapse (n = 12), and not achieving complete response (CR)/CR with in-

Enasidenib and ivosidenib monotherapy have demonstrated induction of clinical responses in patients with mutant IDH (mIDH) relapsed/refractory acute myeloid leukemia (AML), whereas azacitidine (AZA) monotherapy prolongs survival in older patients with the newly diagnosed (ND) AML. Based on these results and coupled with preclinical evidence of synergy with combination of mIDH inhibitors plus AZA, an ongoing phase 1b/2 study evaluated the efficacy and safety of this combination in ND AML; results of the phase 1b portion were reported at ASH 2017. Eligible patients with mIDH ND AML were aged ≥18 years, were required to be ineligible for intensive chemotherapy per investigator assessment, and could have antecedent hematologic disorders but prior use of hypomethylating agents was not allowed. The treatment regimen included enasidenib in dose-escalation cohorts of 100 mg or 200 mg once daily for patients with mIDH2 AML, and ivosidenib 500 mg once daily for patients with mIDH1 AML in continuous 28-day cycles; all patients received AZA 75 mg/m2 daily for 7 days per cycle, administered subcutaneously. Efficacy was assessed per International Working Group criteria for AML; overall response rate (ORR) included complete remission (CR), CR with incomplete hematologic recovery, partial remission (PR), and morphologic leukemia-free state (MLFS). At data cutoff (September 1, 2017), a total of 17 patients had received ≥1 doses of combination therapy (enasidenib 100 mg + AZA, 3; enasidenib 200 mg + AZA, 3; ivosidenib 500 mg + AZA, 11). Eleven patients remained on study at data cutoff. The median age in the enasidenib + AZA cohort was 68 years (range, 64-79 years); in the ivosidenib + AZA cohort, it was 76 years (range, 72-88 years). Overall, the median number of enasidenib treatment cycles was 9 (range, 1-13), and

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complete hematologic recovery (CRi; n = 4). Among the FLT3 mutation– positive patients, 75 had ITD mutations and 23 had TKD. The median age was 58 years (range, 19-79 years); 45% of patients were aged ≥60 years. The median duration of midostaurin exposure was 29 days (range, 3-299 days); dose adjustments were needed in 42 patients. The majority (99%) of patients experienced ≥1 any-grade AEs that occurred mostly during induction (94%) and/or consolidation (85%). Grade 3/4 AEs were reported in 82% of patients. The most common any-grade nonhematologic AEs, occurring in ≥20% of patients, were nausea, diarrhea, anemia, fatigue, vomiting, headache, hypokalemia, and constipation; these were generally comparable between patients that received idarubicin and daunorubicin induction chemotherapy. Serious AEs were reported in 51% of patients, including febrile neutropenia (35%), cellulitis (6%), and pancytopenia. Eleven events of increases in corrected QT (QTc) intervals >30 ms occurred in 6 patients, none of which were >500 ms or considered clinically significant events. Midostaurin dose reduction to 50 mg once daily normalized the QTc intervals. Serious AEs were reported in 46% of patients, febrile neutropenia being the most common (32%). Among the 47 patients who received midostaurin therapy during induction, 35 patients (74%) achieved a CR or a CRi. Among the 85 patients who received midostaurin during consolidation therapy, 52 patients (61%) remained in CR/CRi. These results of the Radius-X ETP showed that the safety profile of midostaurin was consistent with that previously described in the pivotal phase 3 RATIFY trial. l Reference: Roboz G, et al. 2017 ASH. Abstract 1338.

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the median number of ivosidenib treatment cycles was 3 (range, 1-13). Two enasidenib-treated patients discontinued treatment due to progressive disease; 1 of these (200-mg arm) was fatal (lung infection). The most common treatment-emergent adverse events (TEAEs) with all regimens were grade 1 and 2 gastrointestinal events. In the enasidenib + AZA cohort, the most common TEAEs were nausea and hyperbilirubinemia (n = 4 each); the most common enasidenib-related TEAEs were nausea (n = 3), vomiting (n = 3), and hyperbilirubinemia (n = 2). In the ivosidenib + AZA cohort, TEAEs (any grade) included nausea (n = 8), constipation (n = 6), fatigue (n = 5), and diarrhea (n = 4); ivosidenib-related TEAEs of any grade occurring in >1 patient were fatigue (n = 4) and nausea (n = 6); there was 1 death due to pneumonia that was not considered treatment-related. Of note, IDH differentiation syndrome occurred in 1 patient each in the enasidenib 200mg and ivosidenib arms. In terms of response, ORR was 4/6 in the combined cohort receiving enasidenib + AZA; the best responses in the cohort receiving enasidenib 100 mg + AZA were 2 CRs, whereas that in the cohort receiving enasidenib 200 mg + AZA was 1 PR. The ORR was 8/11 patients in those receiving ivosidenib + AZA; 1 responder attained CR, 1 attained PR, 2 attained MLFS; 3 maintained stable disease. In conclusion, the preliminary results of the phase 1b portion of the ongoing phase 1b/2 study support the tolerability of the combination of ena sidenib or ivosidenib + AZA in patients with ND AML, with encouraging clinical activity. This combination is currently being evaluated in 2 randomized studies, including the phase 2 expansion portion of the current study and the phase 3 AGILE study of ivosidenib + AZA. l Reference: DiNardo CD, et al. 2017 ASH. Abstract 639.

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