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AMERICAN SOCIETY OF HEMATOLOGY 2014 HIGHLIGHTS* FEBRUARY 2015, VOL. 6, NO. 1, SUPPLEMENT

INTEGRATING COST, QUALITY, ACCESS INTO CLINICAL DECISION-MAKING IN ONCOLOGY www.ValueBasedCancerCare.com

Value and Cost-Effectiveness Immunotherapy with PD-1 Analyses Should Be Included Inhibitors the Newest Break­­ Reimbursement Decisions through in Hodgkin Lymphoma in By Kate Smith By Wayne Kuznar

© Lushpix www.fotosearch.com.

San Francisco, CA—Drug reimbursement decisions should incorporate value and cost-effectiveness, suggested Andreas Laupacis, MD, MSc, a palliative care specialist and Executive Director of the Li Ka Shing Knowledge Institute of St Michael’s Hospital, Toronto, Ontario, Canada, during the Special Symposium on Quality at ASH 2014. Dr Laupacis has chaired many drug reimbursement committees in Canada. He called cost-effectiveness “an ethical although admittedly imperfect tool

with which to make tough policy decisions.” Such calculations are “often messy,” because they usually lack validated surro- Andreas Laupacis, MD, MSc gate markers of long-term clinical outcomes, they are based on assumptions of a drug’s efficacy outside of clinical trials, and they involve modeling and sensitivity analyses. Continued on page 7

Computerized immune response: white blood cells attacking a cancer cell (blue).

San Francisco, CA—Two programmed-cell death receptor-1 (PD-1) inhibitors— the investigational drug nivo­lumab and the recently approved pem­bro­lizumab (Keytruda)—produced dramatic responses in patients with Hodg­kin lymphoma in phase 1 clinical trials. Complete or partial responses were reported by up to 87% of Continued on page 25

Psychological Distress and Financial Burden Impact Adherence to CML Treatment By Phoebe Starr San Francisco, CA—The era of tyrosine kinase inhibitors (TKIs) has transformed chronic myeloid leukemia

(CML) from an often fatal disease to a chronic disease with ongoing treatment. Joanne S. Buzaglo, PhD, Senior Continued on page 23

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

The Hematology Pipeline Is Abundant By Kate Smith and Wayne Kuznar San Francisco, CA—With new signaling pathways being explored, established drug classes expanding across the tumor spectrum, and immunotherapies investigated across tumor types, the hematology pipeline is abundant. Here are some of the most promising compounds in development presented at ASH 2014. Leukemia and Myelodysplastic Syndrome

ABT-199, an oral selective BCL-2

Continued on page 19

IN TH IS IS S U E HEALTH ECONOMICS. . . . . . . . . . . Cancer therapies targeting small populations dictate drug prices Financial toxicity impacts treatment adherence

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MULTIPLE MYELOMA. . . . . . . . . 12 Treatment advances in multiple myeloma Onyx 360 reduces patient distress Unprecedented remission rates with carfilzomib-based triplet Weekly carfilzomib safe and effective Oprozomib promising in myeloma © 2015 Engage Healthcare Communications, LLC

inhibitor, had considerable clinical activity in patients with poor-prognosis acute myeloid leukemia (AML). ABT199 is designed to selectively bind to and inhibit BCL-2, a critical regulator of apoptosis. AG-221, an oral selective inhibitor of the IDH2 gene, showed preliminary efficacy in patients with IDH2-positive AML or myelodysplastic syndrome (MDS). AG-221 was used in 45 patients with IDH2-mutated AML or MDS at

LEUKEMIA . . . . . . . . . . . . . . . . . . Sorafenib prolongs survival in ALL High remission rate with CAR-T in pediatric ALL Pediatric regimen new standard in young adults with ALL LYMPHOMA. . . . . . . . . . . . . . . . . Brentuximab cost-effective after transplant Stem-cell transplant safe in HIVrelated lymphoma

21

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PAYERS’ PERSPECTIVE. . . . . . . 26 Value of drugs and treatment adherence in hematologic cancers


THE POWER OF SECOND-GENERATION PROTEASOME INHIBITION:

SHAPING THE WAY FORWARD

Indication KyprolisÂŽ (carfilzomib) for Injection is indicated for the treatment of patients with multiple myeloma who have received at least 2 prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Important Safety Information CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS The safety of KYPROLIS was evaluated in clinical studies of 526 patients with relapsed and/or refractory multiple myeloma. Cardiac Arrest, Congestive Heart Failure, Myocardial Ischemia: Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset or worsening of pre-existing congestive heart failure with decreased left ventricular function or myocardial ischemia have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure congestive, pulmonary edema, ejection fraction decreased) were reported in 7% of patients. Monitor

Onyx, Onyx Pharmaceuticals, Onyx Pharmaceuticals logo, Kyprolis, and Kyprolis logo are all trademarks of Onyx Pharmaceuticals, Inc. Š2014 Onyx Pharmaceuticals, Inc., South San Francisco, CA TROPIC-KYPR-100826J November 2014 Printed in USA

for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 or 4 cardiac events until recovery and consider whether to restart KYPROLIS based on a benefit/risk assessment. Patients with New York Heart Association Class III and IV heart failure, myocardial infarction in the preceding 6 months, and conduction abnormalities uncontrolled by medications may be at greater risk for cardiac complications. Pulmonary Hypertension: Pulmonary arterial hypertension (PAH) was reported in 2% of patients treated with KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved or returned to baseline and consider whether to restart KYPROLIS based on a benefit/risk assessment. Pulmonary Complications: Dyspnea was reported in 35% of patients enrolled in clinical trials. Grade 3 dyspnea occurred in 5%; no Grade 4 events, and 1 death (Grade 5) was reported. Monitor and manage dyspnea immediately; interrupt KYPROLIS until symptoms have resolved or returned to baseline. Infusion Reactions: Infusion reactions were characterized by a spectrum of systemic symptoms including fever, chills, arthralgia, myalgia, facial flushing, facial edema, vomiting, weakness, shortness of breath, hypotension, syncope, chest tightness, or angina. These reactions can occur immediately following infusion or up to 24 hours after administration of KYPROLIS. Administer dexamethasone prior to KYPROLIS to reduce the incidence and severity of reactions. Inform patients of the risk and symptoms, and to contact physician if symptoms of an infusion reaction occur. Tumor Lysis Syndrome: Tumor lysis syndrome (TLS) occurred following KYPROLIS administration in < 1% of patients. Patients with multiple myeloma and a high tumor burden should be


Kyprolis® (carfilzomib) for Injection: 003-A1 Phase 2 Study Results* n

22.9% OVERALL RESPONSE RATE (ORR) (95% CI: 18.0, 28.5)1

n

7.8-MONTH MEDIAN DURATION OF RESPONSE (95% CI: 5.6, 9.2)1

n

Most patients across all phase 2 studies (85%) did not need to discontinue therapy due to an adverse event1,2 - Adverse reactions leading to discontinuation included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each)1

*Study PX-171-003 was a single-arm, multicenter clinical trial of KYPROLIS in 266 patients with relapsed multiple myeloma who had received at least two prior therapies (including bortezomib and thalidomide and/or lenalidomide) and whose disease had a ≤25% response to the most recent therapy or had disease progression during or within 60 days of the most recent therapy. At the time of study entry, patients had received a median of 5 prior lines of therapy. The primary endpoint was ORR. Response was determined by Independent Review Committee assessment using International Myeloma Working Group criteria.

considered to be at greater risk for TLS. Prior to receiving KYPROLIS, ensure that patients are well hydrated. Monitor for evidence of TLS during treatment, and manage promptly. Interrupt KYPROLIS until TLS is resolved. Thrombocytopenia: KYPROLIS causes thrombocytopenia with platelet nadirs occurring around Day 8 of each 28-day cycle and recovery to baseline by the start of the next 28-day cycle. In patients with multiple myeloma, 36% of patients experienced thrombocytopenia, including Grade 4 in 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation of treatment with KYPROLIS in < 1% of patients. Monitor platelet counts frequently during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated. Hepatic Toxicity and Hepatic Failure: Cases of hepatic failure, including fatal cases, have been reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver abnormalities until resolved or returned to baseline. After resolution, consider if restarting KYPROLIS is appropriate. Monitor liver enzymes frequently. Embryo-fetal Toxicity: KYPROLIS can cause fetal harm when administered to a pregnant woman based on its mechanism of action and findings in animals. There are no adequate and well-controlled studies in pregnant women using KYPROLIS. Carfilzomib caused embryo-fetal toxicity in pregnant rabbits at doses that were lower than in patients receiving the recommended dose. Females of reproductive potential should be advised to avoid becoming pregnant while being treated with KYPROLIS.

ADVERSE REACTIONS Serious adverse reactions were reported in 45% of patients. The most common serious adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and congestive heart failure (3%). Adverse reactions leading to discontinuation of KYPROLIS occurred in 15% of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acute renal failure (1% each). The most common adverse reactions (incidence ≥ 30%) were fatigue (56%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%).

USE IN SPECIFIC POPULATIONS Since dialysis clearance of KYPROLIS concentrations has not been studied, the drug should be administered after the dialysis procedure.

Please see Brief Summary of full Prescribing Information on adjacent pages. References: 1. KYPROLIS [prescribing information]. South San Francisco, CA: Onyx Pharmaceuticals, Inc.; 2012. 2. Siegel D, Martin T, Nooka A, et al. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica. 2013;98(11):1753-1761.


Brief Summary of Prescribing Information for IMBRUVICA® (ibrutinib) IMBRUVICA® (ibrutinib) capsules, for oral use See package insert for Full Prescribing Information

IMBRUVICA® (ibrutinib) capsules

INDICATIONS AND USAGE Mantle Cell Lymphoma: IMBRUVICA is indicated for the treatment of 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. Improvements in survival or disease-related symptoms have not been established. Continued approval for this indication may be contingentfor upon verification of clinical benefit in confirmatory trials [see Clinical KYPROLIS™ (carfilzomib) Injection Studies (14.1) in of fullPrescribing Prescribing Information]. Brief Summary Information. Please see the KYPROLIS package insert for full Chronic Lymphocytic Leukemia: IMBRUVICA is indicated for the treatment of patients with chronic prescribing information. lymphocytic leukemia (CLL) who have received at least onetreatment prior therapy [see Clinical Studiesmyeloma (14.2) INDICATIONS AND USAGE: KYPROLIS is indicated for the of patients with multiple in full Prescribing Information]. who have received at least two prior therapies including bortezomib and an immunomodulatory agent and have demonstrated disease progression within 60IMBRUVICA days of completion of the for lastthe therapy. Approval Chronic Lymphocytic Leukemia with on 17pordeletion: is indicated treatment of is based on response ratelymphocytic [see Clinicalleukemia Studies section of 17p full PI]. Clinical benefit, as improvement patients with chronic (CLL) with deletion [see Clinicalsuch Studies (14.2) in full in survival or symptoms, has not been verified. Prescribing Information].

DOSAGE AND ADMINISTRATION: Dosing Guidelines. KYPROLIS is administered intravenously over 2 to CONTRAINDICATIONS 10None minutes, on two consecutive days, each week for three weeks (Days 1, 2, 8, 9, 15, and 16), followed by a 12‑day rest period (Days 17 to 28). Each 28‑day period is considered one treatment cycle (Table 1). In WARNINGS AND PRECAUTIONS Cycle 1, KYPROLIS is administered at a dose of 20  mg/m2. If tolerated in Cycle  1, the dose should be Hemorrhage: Grade 23beginning or higherinbleeding events (subdural hematoma, gastrointestinal bleeding, escalated to 27 mg/m Cycle 2 and continued at 27 mg/m2 in subsequent cycles. Treatment hematuria and postuntil procedural occurred in up to 6% of patients. eventsand may be continued diseasehemorrhage) progression have or until unacceptable toxicity occursBleeding [see Dosage of any grade, including andusing petechiae, occurred in body approximately half patients treatedwith Administration]. The dose isbruising calculated the patient’s actual surface area at of baseline. Patients a with bodyIMBRUVICA. surface area greater than 2.2 m2 should receive a dose based upon a body surface area of 2.2 m2. The adjustments mechanism for the need bleeding well changes understood. Dose do not to beevents made isfornot weight of less than or equal to 20%. IMBRUVICA may increase the risk of hemorrhage in patients receiving antiplatelet or anticoagulant Table 1: KYPROLIS Dosage Regimen for Patients with Multiple Myeloma therapies. Cycle 1 Consider the benefit-risk of withholding IMBRUVICA for at least 3 to 7 days pre and post-surgery Week 1 Week 3 Studies Week depending upon the type of surgery and the risk of2 bleeding [see Week Clinical (14) in4 full Day Day Days Day Day Days Day Day Days Days Prescribing Information]. 2 3–7 8 9 10–14 15 16 17–21 22–28 1 Infections: and non-fatal infections have occurred with IMBRUVICA therapy. Twenty-five KYPROLIS Fatal20 No 20 20 20 No 20 20 No No 2 percent of patients with MCL and 26% of patients with CLL had infections Grade 3 Dosing or greater (20 mg/m ): Dosing Dosing Dosing NCI Common Terminology Criteria for Adverse Events (CTCAE) [See aAdverse Reactions]. Monitor Cycles 2 and Beyond patients for fever and infections and evaluate promptly. Week 1 Week 2 including neutropenia Week 3 (range,Week 4 Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias 23 to 29%), Day5 toDays Dayanemia Day (range, Days0 toDay Day Days Days Day(range, thrombocytopenia 17%), and 9%) occurred in patients treated 2 3–7 8 9 10–14 15 16 17–21 22–28 with IMBRUVICA.1 KYPROLIS 27 No 27 27 No 27 27 No No 27 Monitor complete blood counts monthly. Dosing Dosing Dosing Dosing (27 mg/m2):

Atrial Fibrillation: Atrial fibrillation and atrial flutter (range, 6 to 9%) have occurred in patients previouswith cycleIMBRUVICA, dosage is tolerated. treated particularly in patients with cardiac risk factors, acute infections, and Hydration FluidofMonitoring. Hydrate patients tomonitor reducepatients the risk of renal toxicity and fibrillation. of tumor lysis a previousand history atrial fibrillation. Periodically clinically for atrial syndrome KYPROLIS treatment [see Warnings and Precautions]. Maintain adequate fluidonset volume Patients (TLS) who with develop arrhythmic symptoms (e.g., palpitations, lightheadedness) or new status throughout treatment and monitor blood chemistries to each dyspnea should have an ECG performed. If atrial fibrillation closely. persists,Prior consider thedose risks in andCycle 1, benefitsgive 250 mL to 500 mLtreatment of intravenous normalmodification saline or other appropriate intravenous fluid. Give(2.3) an additional of IMBRUVICA and dose [see Dosage and Administration in full 250  mL  to 500  mL of intravenous  fluids as needed following KYPROLIS administration. Continue Prescribing Information]. intravenous hydration, as needed,Other in subsequent cycles. Also monitor during this period for fluid Second Primary Malignancies: malignancies (range, 5 to 10%)patients including carcinomas (range, overload [see Warnings and Precautions]. Dexamethasone Premedication. Pre‑medicate 1 to 3%) have occurred in patients treated with IMBRUVICA. The most frequent second primarywith dexamethasone 4 mg orally or intravenously prior to all4doses of KYPROLIS during Cycle 1 and prior to all malignancy was non-melanoma skin cancer (range, to 8%). KYPROLIS doses during the first cycle of dose escalation to 27 mg/m2 to reduce the incidence and severity Toxicity: Based on findings in animals, IMBRUVICA can cause fetal harm when ofEmbryo-Fetal infusion reactions [see Warnings and Precautions]. Reinstate dexamethasone premedication (4  mg administered to a pregnant woman. Ibrutinib caused malformations in rats at exposures 14 times orally or intravenously) if these symptoms develop or reappear during subsequent cycles. Dose those reported in patients with MCL and 20 times those reported in patients with CLL, receiving Modifications based on Toxicities. Recommended actions and dose modifications are presented the ibrutinib dose of 560 mg per day and 420 mg per day, respectively. Reduced fetal weights were in Table 2. observed at lower exposures. Advise women to avoid becoming pregnant while taking IMBRUVICA. a Table 2: Dose Modifications for Toxicity during KYPROLIS If this drug is used during pregnancy or if the patient becomesTreatment pregnant while taking this drug, the patientHematologic should be apprised of the potential hazard to a fetus [see Use in Specific Toxicity Recommended Action Populations]. a If

Table 1: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with MCL (N=111) (continued)

Table 2: Dose Modifications for Toxicitya during KYPROLIS Treatment (continued) All Grades Grade 3 or 4 System Organ Class Preferred Term until renal function • Withhold has recovered to(%) Grade 1 Renal Toxicity (%) or to baseline and monitor renal function. • Serum creatinine equal to or 5 41 General disorders at the next scheduled greater than 2 × baseline Fatigue• If attributable to KYPROLIS, restart Peripheraltreatment edema at a reduced dose35 and administrative site 2 3 (from 27 mg/m to [see Adverse Reactions] 182 Pyrexia conditions to 15 mg/m2). 1 20 mg/m2, OR from 20 mg/m 3 14 Asthenia • If not attributable to KYPROLIS, restart at the dose used Skin and subcutaneous Bruising prior to the event. 30 0 tissue disorders Rash 25 3 • If tolerated, the reduced dose may be escalated Petechiae 11 0 to the previous dose at the discretion of the physician. 1 37 Musculoskeletal and Musculoskeletal pain Withhold until resolved or returned to baseline.0 Peripheraltissue Neuropathy 14 connective disorders Muscle• spasms • Restart at the dose used prior • Grade 3 or 4 0 11 to the event or reduced Arthralgia 2 2 2 to 20 mg/m , OR from 20 mg/m [see Adversethoracic Reactions] 4 27 Respiratory, and Dyspnea dose (from 27 mg/m 2 0 19 of the physician. mediastinal disorders Cough to 15 mg/m ), at the discretion • If tolerated, the reduced dose 0 to the 11 may be escalated Epistaxis previous dose at the discretion of the physician. Metabolism and nutrition Decreased appetite 21 2 • Withhold until resolved or returned to baseline.4 Other disorders Dehydration 12 • Consider restarting at the next • Grade 3 or 4disorders non‑hematological Nervous system Dizziness 14 scheduled treatment 0 2 toxicities Headachewith one dose level reduction 13(from 27 mg/m 0to 2 2 2 20 mg/m , OR from 20 mg/m to 15 mg/m ). Table 2: Treatment-Emergent* of Hemoglobin, or • If Decrease tolerated, the reduced dosePlatelets, may be escalated to the Neutrophils in Patients previous with doseMCL at the(N=111) discretion of the physician. Percent of (NCI Patients National Cancer Institute Common Terminology Criteria for Adverse Events CTCAE)(N=111) Version 3.0.

a

Grade 3 or 4 vial (60 mg Administration Precautions. The quantity All of Grades KYPROLIS contained in one single‑use (%) (%) carfilzomib) may exceed the required dose. Caution should be used in calculating the quantity delivered to Platelets DecreasedDo not mix KYPROLIS with or administer 57 17 medicinal products. prevent overdosing. as an infusion with other The intravenous administration line should be flushed Injection, USP Neutrophils Decreased 47 with normal saline or 5% Dextrose 29 immediately before and after KYPROLIS administration. as a bolus. Hemoglobin Decreased 41 KYPROLIS should not be administered 9 KYPROLIS should be administered over 2 to 10 minutes. Reconstitution and Preparation for * Based on laboratory measurements and adverse reactions Intravenous Administration. KYPROLIS vials contain no antimicrobial preservatives and are intended onlypatients for single use.discontinued Unopened vials of KYPROLIS stablereactions until the date indicated on theThe package Ten (9%) treatment due to are adverse in the trial (N=111). most when frequent reaction leading was subdural hematoma stored inadverse the original package at 2°Ctototreatment 8°C (36°Fdiscontinuation to 46°F). The reconstituted solution contains(1.8%). carfilzomib Adverse reactions leading dose reduction 14% of patients. at a concentration of 2  to mg/mL. Read theoccurred completeinpreparation instructions prior to reconstitution. Reconstitution/Preparation Steps: 1. Remove vial from refrigerator just priorhave to use. 2. Aseptically Patients with MCL who develop lymphocytosis greater than 400,000/mcL developed intracranial lethargy, gait instability, and Water headache. However, of these cases onto reconstitutehemorrhage, each vial by slowly injecting 29 mL Sterile for Injection, USP,some directing the solution were in the setting of disease the INSIDE WALL OF THE VIALprogression. to minimize foaming. 3. Gently swirl and/or invert the vial slowly for about 1 minute, or of until complete of any or on powder NOT SHAKE avoid foam Forty percent patients haddissolution elevated uric acidcake levels studyoccurs.  includingDO 13% with valuesto above 10generation. mg/dL. Adverse reaction of hyperuricemia 15%2 to of patients. If foaming occurs, allow solution towas restreported in vial forfor about 5 minutes, until foaming subsides. 4. After reconstitution, KYPROLIS isThe ready fordescribed intravenousbelow administration. The reconstituted productinshould Chronic Lymphocytic Leukemia: data reflect exposure to IMBRUVICA beopen a clear, solution. If any discoloration particulate is observed, do not an labelcolorless clinical trial (Study 1) that included 48orpatients withmatter previously treated CLL anduse a the randomized trial5.(Study that included randomizedbag, patients with the previously treated reconstitutedclinical product. When 2) administering in 391 an intravenous withdraw calculated dose [see CLL or SLL. Dosage and Administration] from the vial and dilute into 50 mL 5% Dextrose Injection, USP intravenous bag.most 6. Immediately the adverse vial containing the inunused stabilities of reconstituted The commonly discard occurring reactions Studyportion. 1 and The Study 2 (≥ 20%) were thrombocytopenia, neutropenia, diarrhea, musculoskeletal upper respiratory KYPROLIS under various temperature and anemia, containerfatigue, conditions are shown inpain, Table 3. tract infection, rash,of nausea, and pyrexia. Table 3: Stability Reconstituted KYPROLIS Approximately five percent of patients receiving IMBRUVICA in Study 1 and 2 discontinued a Stabilityhematomas per Container treatment due to adverse events. These included infections, subdural and diarrhea. Conditions ofreduction Reconstituted Adverse Storage events leading to dose occurred in approximately 6% of patients. IV Bag KYPROLIS Study 1: Adverse reactions and laboratory abnormalities from the CLL trial (N=48) using single agent b Vial in Tables Syringe IMBRUVICA 420 mg daily occurring at a rate of ≥ 10% are presented 3 and 4. (D5W )

• Withhold dose. or 4 Neutropenia •ADVERSE Grade 3REACTIONS following adverse reactions are discussed more detail in other sections ofdose, the labeling: • If fully in recovered before next scheduled continue •TheGrade 4 Thrombocytopenia • Hemorrhage [see Warnings and Precautions] at same dose level. [see Warnings and Precautions] • Infections [see Warnings and Precautions] • If recovered to Grade 2 neutropenia or Grade 3 thrombocytopenia, reduce dose by one dose level • Cytopenias [see Warnings and Precautions] (from 27 mg/m2 to 20 mg/m2, OR from 20 mg/m2 to • Atrial Fibrillation [see Warnings and Precautions] 15 mg/m2). • Second Primary Malignancies [see Warnings and Precautions] • If tolerated, the reduced dose may be escalated to the Because clinical trials are conducted previous under widely conditions, dose atvariable the discretion of theadverse physician.event rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of Non-Hematologic Toxicity Recommended Action another drug and may not reflect the rates observed in practice. • Withhold until resolved or returned to baseline.in a clinical Cardiac Toxicity Mantle Cell Lymphoma: The data described below reflect exposure to IMBRUVICA • After resolution, consider if restarting Grade 3 or 4, new onset or worsening of: trial that included 111 patients with previously treated MCL treated with 560 mgKYPROLIS daily withata median a reduced dose is appropriate (from 27 mg/m2 to •treatment congestive heart of failure; duration 8.3 months. 20 mg/m2, OR from 20 mg/m2 to 15 mg/m2). •Thedecreased left ventricular most commonly occurring adverse reactions (≥ 20%) were thrombocytopenia, diarrhea, • If tolerated, reduced dose mayupper be escalated to thetract function; anemia, fatigue, musculoskeletal neutropenia, pain,theperipheral edema, respiratory previous dose the discretion of vomiting the physician. nausea, bruising, dyspnea, constipation, rash,at abdominal pain, and decreased •infection, or myocardial ischemia appetite (see Tables 1 and 2). [see Warnings and Precautions] The most common Grade 3 or 4 non-hematological (≥ to 5%) were pneumonia, Pulmonary Hypertension • Withhold untiladverse resolvedreactions or returned baseline. abdominal pain, atrial fibrillation, diarrhea, fatigue, and skin infections. • Restart at the dose used prior to the event or reduced [see Warnings and Precautions] Fatal and serious cases of renal failuredose have(from occurred with2 to IMBRUVICA therapy. Increases2 in 20 mg/m2, OR from 20 mg/m 27 mg/m 2 creatinine 1.5 to 3 times the upper limit ofto normal occurred in 9% of patients. 15 mg/m ), at the discretion of the physician. Adverse reactions from the MCL trial (N=111) using single agent IMBRUVICA 560escalated mg daily to occurring • If tolerated, the reduced dose may be the previous dose at the discretion of the physician. at a rate of ≥ 10% are presented in Table 1. • Withhold untilinresolved returnedwith to baseline. Pulmonary Table Complications 1: Non-Hematologic Adverse Reactions ≥ 10% oforPatients MCL (N=111) • Consider restarting at the All nextGrades scheduled treatment • Grade 3 or 4 Grade 3 or 4 System and Organ Class Preferred Termlevel reduction (from 27 mg/m2 to with one dose [see Warnings Precautions] (%) (%) 2 2 2 20 mg/m , OR from 20 mg/m to 15 mg/m ). 5 51 Gastrointestinal disorders Diarrhea • If tolerated, the reduced dose may 0 the 31 be escalated to Nausea previous dose at the discretion of the physician. 0 25 Constipation • Withhold Hepatic Toxicity 24 to baseline. 5 Abdominal pain until resolved or returned 23 KYPROLIS is 0 Vomiting • After resolution, consider if restarting • Grade 3 or 4 elevation of 1 17a reduced dose (from appropriate; may be reinitiated at transaminases, bilirubin or otherStomatitis 2 0 11 20 mg/m2 to 15 mg/m Dyspepsia ) 27 mg/m2 to 20 mg/m2, OR from liver abnormalities Infections andand infestations tract with frequent monitoring of liver function. [see Warnings Precautions] Upper respiratory 0 the 34 be escalated to infection • If tolerated, the reduced dose may Urinaryprevious tract infection dose at the discretion14of the physician. 3 7 14 Pneumonia (continued) 5 14 Skin infections Sinusitis

13

1

Refrigerated (2°C to 8°C; 36°F to 46°F)

24 hours

24 hours

Room Temperature (15°C to 30°C; 59°F to 86°F)

4 hours

4 hours

24 hours

Table 3: Non-Hematologic Adverse Reactions in ≥ 10% of Patients with CLL (N=48) in Study 1

a

a

All Grades

4 hours

Grade 3 or 4

System Class to administrationPreferred Total time from Organ reconstitution should not Term exceed 24 hours. b 5% (%) Dextrose Injection, USP. (%)

WARNINGS ANDdisorders PRECAUTIONS: Cardiac Arrest, Congestive Heart63Failure, Myocardial Gastrointestinal Diarrhea 4 Ischemia. Constipation 23 2 or worsening Death due to cardiac arrest has occurred within a day of KYPROLIS administration. New onset Nauseawith decreased left ventricular21function or myocardial 2 of pre‑existing congestive heart failure ischemia Stomatitis 21 0 have occurred following administration of KYPROLIS. Cardiac failure events (e.g., cardiac failure Vomiting 19 2 congestive, pulmonary edema, ejection fraction decreased) Abdominal pain were reported in 7%15of patients. Monitor 0 for cardiac complications and manage promptly. Withhold KYPROLIS for Grade 3 13 or 4 cardiac events0 until recovery Dyspepsia and consider to restartUpper KYPROLIS basedtract on a benefit/risk assessment [see Dosage and Infections and whether infestations respiratory Administration]. Patients with Newinfection York Heart Association Class III and IV48 heart failure, myocardial infarction 2 in the preceding 6 months, and conduction Sinusitis abnormalities uncontrolled by 21medications were6 not eligible for Skinmay infection 17 6 Pulmonary the clinical trials. These patients be at greater risk for cardiac complications. Pneumonia 8 treated with Hypertension. Pulmonary arterial hypertension (PAH) was reported10in 2% of patients Urinary tract infection 10 0 KYPROLIS and was Grade 3 or greater in less than 1% of patients. Evaluate with cardiac imaging and/or General disorders and Fatigue 31 other tests as indicated. Withhold KYPROLIS for pulmonary hypertension until resolved4or returned to administrative site conditions 25 assessment [see 2 Dosage and baseline and consider whether to Pyrexia restart KYPROLIS based on a benefit/risk Peripheral edema 23 0 Administration]. Pulmonary Complications. 35% of patients enrolled in clinical Asthenia Dyspnea was reported in 13 4 trials. Grade 3 dyspnea occurred inChills 5%; no Grade 4 events, and 1 death Monitor 13(Grade 5) was reported. 0 and manage dyspnea immediately; interrupt KYPROLIS until symptoms Skin and subcutaneous Bruising 54 have resolved 2or returned to baseline [see Dosage and Administration reactions tissue disorders Rash and Adverse Reactions]. Infusion 27 Reactions. Infusion 0 were characterized by a spectrumPetechiae of systemic symptoms including fever, 17 chills, arthralgia,0 myalgia, facial flushing, facialthoracic edema,and vomiting, weakness, syncope, chest Respiratory, Cough shortness of breath, hypotension, 19 0 tightness, or angina. These reactions following mediastinal disorders can occur immediately Oropharyngeal pain or up to 24 hours 15after administration 0 of KYPROLIS. 10severity of reactions 0 [see Dosage Administer dexamethasone prior toDyspnea KYPROLIS to reduce the incidence and and Administration]. Inform patientsMusculoskeletal of the risk and symptoms and to contact physician if symptoms of an Musculoskeletal and pain 27 6 infusion reaction [see Patient Counseling Information]. Tumor23Lysis Syndrome. connective tissueoccur disorders Arthralgia 0 Tumor lysis spasms 2 with multiple syndrome (TLS) occurred followingMuscle KYPROLIS administration in < 1% 19 of patients. Patients myelomasystem and a high tumor burdenDizziness should be considered to be at greater Nervous disorders 21 risk for TLS. Prior 0 to receiving Headache 19 2 for evidence KYPROLIS, ensure that patients are well hydrated [see Dosage and Administration]. Monitor Peripheral neuropathy 0 Dosage and of TLS during treatment, and manage promptly. Interrupt KYPROLIS until10TLS is resolved [see Administration].Thrombocytopenia. KYPROLIS causes thrombocytopenia occurring Metabolism and nutrition Decreased appetite 17 with platelet nadirs 2 disorders around Day 8 of each 28‑day cycle and recovery to baseline by the start of the next 28‑day cycle. In patients withbenign, multiple myeloma, 36% of malignancies* patients experienced thrombocytopenia, including Neoplasms malignant, Second 10* 0 Grade 4 in unspecified 10%. Thrombocytopenia following KYPROLIS administration resulted in a dose reduction in 1% of patients and discontinuation KYPROLIS in < 1% of patients. 10 Monitor platelet counts frequently Injury, poisoning andof treatment with Laceration 2 during treatment with KYPROLIS. Reduce or interrupt dose as clinically indicated [see Dosage and procedural complications Administration]. Hepatic ToxicityAnxiety and Hepatic Failure. Cases of hepatic Psychiatric disorders 10 failure, including 0 fatal cases, Insomnia 10 0 Vascular disorders Hypertension 17 8 *One patient death due to histiocytic sarcoma.


IMBRUVICA® (ibrutinib) capsules

IMBRUVICA® (ibrutinib) capsules

Table 4: Treatment-Emergent* Decrease of Hemoglobin, Platelets, or Neutrophils in Patients with CLL (N=48) in Study 1

have been reported (< 1%). KYPROLIS can cause elevations of serum transaminases and bilirubin. Percent of Patients (N=48) Withhold KYPROLIS in patients experiencing Grade 3 or greater elevations of transaminases, bilirubin, or other liver abnormalities until resolved or returned to Allbaseline. Grades After resolution, consider Grade 3 iforrestarting 4 (%)and Adverse KYPROLIS is appropriate. Monitor liver enzymes frequently(%)[see Dosage and Administration Reactions]. Embryo-fetal Platelets DecreasedToxicity. KYPROLIS can cause71fetal harm when administered10to a pregnant woman Neutrophils based on its Decreased mechanism of action and findings in animals. There are no adequate and27 well‑controlled 54 studies in pregnant women using KYPROLIS. Carfilzomib caused embryo‑fetal toxicity in pregnant rabbits at Hemoglobin Decreased 44 0 doses that were lower than in patients receiving the recommended dose. Females of reproductive potential on to laboratory measurements IWCLL reactions should*beBased advised avoid becoming pregnantper while beingcriteria treatedand withadverse KYPROLIS. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the Study 2: Adverse reactions and laboratory abnormalities described below in Tables 5 and 6 reflect potential hazard to fetus [see with Use in Specific duration Populations]. exposure to the IMBRUVICA a median of 8.6 months and exposure to ofatumumab with a ADVERSE REACTIONS: The following adverse reactions are discussed in greater detail in other sections median of 5.3 months in Study 2. of the labeling: 5: Non-Hematologic Adverse Reactions ≥ 10% Reported Study 2 • Cardiac Arrest,Table Congestive Heart Failure, Myocardial Ischemia [see Warnings andinPrecautions] • Pulmonary Hypertension [seeWarnings and Precautions] IMBRUVICA Ofatumumab • Pulmonary Complications [seeWarnings and Precautions] (N=195) (N=191) • Infusion System Reactions [seeWarnings and Precautions] All Grades Grade 3 or 4 All Grades Grade 3 or 4 Organ Class • Tumor Lysis Syndrome (%) (%) (%) (%) ADR Term[seeWarnings and Precautions] • Thrombocytopenia [seeWarnings and Precautions] Gastrointestinal disorders • Hepatic Toxicity and Hepatic Failure [seeWarnings and Precautions] 4 to KYPROLIS 18 2 trials The mostDiarrhea common adverse reactions (incidence48of 30% or greater) observed in clinical Nausea 26 anemia, nausea, 2 thrombocytopenia, 18 dyspnea, diarrhea, 0 of patients with multiple myeloma were fatigue, and pyrexia. Clinical Trials Safety Experience. Because clinical trials are conducted under 1widely Stomatitis* 17 1 6 varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly Constipation 15 0 9 0 compared with rates in the clinical trials of another drug, and may not reflect the rates observed in medical Vomiting 14 0 6 1 as practice. A total of 526 patients with relapsed and/or refractory multiple myeloma received KYPROLIS General disorders and dexamethasone. Patients received a median of four treatment cycles with monotherapy or with pre‑dose site a medianadministration cumulative KYPROLIS dose of 993.4 mg. Deaths due to all causes within 30 days of the last dose conditions of KYPROLIS occurred in 37/526 (7%) of patients. Deaths not attributed to disease progression were 28 cardiac arrest,2cardiac disorder), 30 end‑organ failure 2 in 4 cardiac inFatigue 5 patients (acute coronary syndrome, patients (multi‑organ failure, hepatic failure, 24 renal failure), infection in 4 patients Pyrexia 2 15 (sepsis, pneumonia, 1 respiratory tract bacterial infection), dyspnea and intracranial hemorrhage in 1 patient each, and 1 patient Infections and infestations found dead of unknown causes. Serious adverse reactions were reported in 45% patients. The most tract common Upper seriousrespiratory adverse reactions were pneumonia (10%), acute renal failure (4%), pyrexia (3%), and infection 16leading to discontinuation 1 11 2 15% congestive heart failure (3%). Adverse reactions of KYPROLIS occurred in Pneumonia* 15 10 13 9 of patients and included congestive heart failure (2%), cardiac arrest, dyspnea, increased blood creatinine, and acuteSinusitis* renal failure (1% each). Adverse reactions occurring at 11 1 a rate of 10% or 6 greater are presented 0 in Table 4.Urinary tract infection 10 4 5 1 Table 4:Skin Incidence of Adverse Reactions Occurring in ≥ 10% of Multiple Myeloma and subcutaneous Patientstissue Treated with KYPROLIS disorders

Avoid concomitant use of strong CYP3A inducers (e.g., carbamazepine, rifampin, phenytoin and St. John’sof Wort). Consider alternative with less CYP3A induction [see Clinical Description Selected Adverse Drugagents Reactions. Renal Events: The most commonPharmacology renal adverse (12.3) in full increase Prescribing Information]. reactions were in blood creatinine (24%) and renal failure (9%), which were mostly Grade 1

USE IN SPECIFIC or Grade 2 in severity.POPULATIONS Grade 3 renal adverse reactions occurred in 6% of patients and Grade 4 events Pregnancy: Category Warningsblood and Precautions]. occurred in 1%.Pregnancy Discontinuations dueD [see to increased creatinine and acute renal failure were 1% Risk Based findings with in animals, IMBRUVICA canworsening cause fetalrenal harmfunction when administered each. In Summary: one patient, deathonoccurred concurrent sepsis and [see Dosage a pregnant woman. If IMBRUVICA is used during pregnancy if the patient becomes pregnant and toAdministration]. Peripheral Neuropathy: Peripheral neuropathyor(including all events of peripheral whileneuropathy taking IMBRUVICA, the patient be apprised of the hazard toenrolled the fetus. sensory and peripheral motorshould neuropathy) occurred in potential 14% of patients in clinical trials. GradeData: 3 peripheral occurred in 1% of patients. events Animal Ibrutinib neuropathy was administered orally to pregnant ratsSerious during peripheral the period neuropathy of organogenesis occurred < 1%ofof10, patients, resulted Ibrutinib in dose reduction and treatment discontinuation at oralindoses 40 andwhich 80 mg/kg/day. at a doseinof< 1% 80 mg/kg/day was associated with in < 1%. Withhold or discontinue recommended [see Dosage and Administration]. Herpes visceral malformations (hearttreatment and majorasvessels) and increased post-implantation loss. The dose of Infection: 80 mg/kg/day in animals is approximately 14 times theofexposure in antiviral patients prophylaxis with MCL Virus Herpes zoster reactivation was reported in 2% patients. (AUC) Consider and 20 times the exposure patientszoster with infection. CLL administered the dose of 560 mg daily and 420 mg for patients who have a history ofin herpes daily, respectively. Ibrutinib at doses of 40 mg/kg/day or greater was associated with decreased DRUG INTERACTIONS: Carfilzomib is primarily metabolized via peptidase and epoxide hydrolase fetal weights. dose of mg/kg/day in animals the exposure (AUC) in activities, and as The a result, the40 pharmacokinetic profileis approximately of carfilzomib 6istimes unlikely to be affected by patients with MCL administered the dose of 560 mg daily. concomitant administration of cytochrome P450 inhibitors and inducers. Carfilzomib is not expected to influence exposure of other [see Clinical Pharmacology of full PI]. milk. Because many Nursing Mothers: It is drugs not known whether ibrutinib is section excreted in human are excreted in human milk and because of the Category potential Dfor serious adverse reactions in USEdrugs IN SPECIFIC POPULATIONS: Pregnancy. Pregnancy [see Warnings and Precautions]. nursing infants from potential IMBRUVICA, a decision should be made whether to discontinue to Females of reproductive should be advised to avoid becoming pregnant while beingnursing treatedorwith discontinue taking into account the drugKYPROLIS to the mother. KYPROLIS. Basedtheondrug, its mechanism of actionthe andimportance findings inofanimals, can cause fetal harm whenPediatric administered to a safety pregnant Carfilzomib caused embryo‑fetal toxicity in pregnant Use: The andwoman. effectiveness of IMBRUVICA in pediatric patients has notrabbits been at doses that were lower than in patients receiving the recommended dose. If KYPROLIS is used during established. pregnancy, or Use: if theOfpatient becomes while taking drug, the patient be apprised of Geriatric the 111 patientspregnant treated for MCL, 63%this were 65 years of ageshould or older. No overall the potential hazard to the fetus.were Carfilzomib wasbetween administered pregnant rats andCardiac rabbits differences in effectiveness observed theseintravenously patients andtoyounger patients. during the period of organogenesis at doses 0.5, 1, and 2 mg/kg/day rats and 0.2, and 0.8 and mg/ adverse events (atrial fibrillation and ofhypertension), infections in (pneumonia and0.4, cellulitis) kg/day in rabbits. Carfilzomib was notand teratogenic at anyoccurred dose tested. rabbits, there was an increase in gastrointestinal events (diarrhea dehydration) moreInfrequently among elderly patients. pre‑implantation loss at randomized ≥ 0.4 mg/kg/day and 2,an increase resorptions post‑implantation Of the 391 patients in Study 61% werein≥ early 65 years of age. and No overall differencesloss in and effectiveness a decrease in fetal at the maternally dose of 0.8 mg/kg/day. The doses of 0.4 and 0.8more mg/ wereweight observed between age toxic groups. Grade 3 or higher adverse events occurred kg/day in rabbits are approximately 20% and 40%, respectively, (61% of theofrecommended dose in humans of frequently among elderly patients treated with IMBRUVICA patients age ≥ 65 versus 51% of 2 27 mg/m based on body Nursing It is not known whether KYPROLIS is excreted younger patients) [seesurface Clinicalarea. Studies (14.2) Mothers. in full Prescribing Information]. in human milk. Since many drugs are excreted in human milk and because of the potential for serious Renal Impairment: Less than 1% of ibrutinib is excreted renally. Ibrutinib exposure is not altered in adverse reactions in nursing infants from KYPROLIS, a decision should be made whether to discontinue patients with Creatinine clearance (CLcr) > 25 mL/min. There are no data in patients with severe nursing orimpairment to discontinue the<drug, taking into accounton thedialysis importance the drug to the mother. Pediatric renal (CLcr 25 mL/min) or patients [see of Clinical Pharmacology (12.3) in full Use.Prescribing The safety and effectiveness of KYPROLIS in pediatric patients have not been established. Geriatric Information]. Use. In studies of KYPROLIS there were no clinically significant differences observed in safety and efficacy Hepatic Impairment: Ibrutinib of is age metabolized in 65 years the liverofand increases in exposure between patients less than 65 years and patients agesignificant and older. Renal Impairment. The of ibrutinib are expected in patients with hepatic impairment. Patients with serum aspartate pharmacokinetics and safety of KYPROLIS were evaluated in a Phase 2 trial in patients with normal renal transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) ≥ 3.0 x upper limit of normal (ULN) function and those with mild, moderate, and severe renal impairment and patients on chronic dialysis. On were excluded from IMBRUVICA clinical trials. There is insufficient data to2recommend a dose of2 average, patients inwere treated forbaseline 5.5 cycles using impairment KYPROLIS doses of 15 mg/m on Cycle 1, 20 mg/m IMBRUVICA patients with hepatic [see Clinical Pharmacology (12.3) in full on Cycle 2, and Information]. 27 mg/m2 on Cycles 3 and beyond. The pharmacokinetics and safety of KYPROLIS were Prescribing not influenced by the degree of baseline renal impairment, including the patients on dialysis. Since dialysis Females and Malesconcentrations of Reproductive to avoid pregnant while clearance of KYPROLIS hasPotential: not been Advise studied,women the drug shouldbecoming be administered after the taking IMBRUVICA because IMBRUVICA can cause fetal harm [see Use in Specific Populations]. dialysis procedure [see Clinical Pharmacology section of full PI]. Hepatic Impairment. The safety, efficacy COUNSELING INFORMATION and PATIENT pharmacokinetics of KYPROLIS have not been evaluated in patients with baseline hepatic impairment. See FDA-approved patient labelingvalues (Patient Information) Patients with the following laboratory were excluded from the KYPROLIS clinical trials: ALT/AST ≥ 3 • × upper limit of normal (ULN) and bilirubin ≥ 2 × ULN [see Clinical Pharmacology section of full PI]. Hemorrhage: CardiacInform Impairment. with New ofYork Heart Association Class and IVorheart failure (blood were not patients Patients of the possibility bleeding, and to report anyIII signs symptoms in eligible for the or clinical Safety in populationbleeding). has not been evaluated. stools urine,trials. prolonged or this uncontrolled Inform the patient that IMBRUVICA may OVERDOSAGE: is no known specific antidote for KYPROLIS overdosage. In the event of an need to beThere interrupted for medical or dental procedures [see Warnings and Precautions]. overdosage, monitor the patient and provide appropriate supportive care. • Infections: NONCLINICAL TOXICOLOGY: Carcinogenesis, Mutagenesis, andanyImpairment of Fertility. Inform patients of the possibility of serious infection, and to report signs or symptoms (fever, Carcinogenicity studies have not been[see conducted Carfilzomib was clastogenic in the chills) suggestive of infection Warningswith andcarfilzomib. Precautions]. in vitro aberration test in peripheral blood lymphocytes. Carfilzomib was not mutagenic in • chromosomal Atrial Fibrillation: the in vitro bacterial reverse mutation (Ames) test and was not clastogenic in the in vivo mouse bone Counsel patients to report any signs of palpitations, lightheadedness, dizziness, fainting, marrow shortness micronucleus assay.and Fertility with [see carfilzomib have notPrecautions]. been conducted. No effects on of breath, cheststudies discomfort Warnings and reproductive tissues were noted during 28‑day repeat‑dose rat and monkey toxicity studies or in 6‑month • Second primary malignancies: rat and 9‑month monkey chronic toxicity studies. Animal Toxicology and/or Pharmacology. Monkeys Inform patients that other malignancies have occurred in patients who have beenrecommended treated with administered a single bolus intravenous dose of carfilzomib at 3 mg/kg (approximately 1.3 times IMBRUVICA, including skin cancers and other carcinomas [see Warnings and Precautions]. dose in humans of 27 mg/m2 based on body surface area) experienced hypotension, increased heart rate, and • Embryo-fetal increased serum levelstoxicity: of troponin‑T. The repeated bolus intravenous administration of carfilzomib at ≥ 2 mg/ of the potential hazard to using a fetusdosing and toschedules avoid becoming kg/dose Advise in rats women and 2  mg/kg/dose in monkeys similarpregnant to those[see usedWarnings clinically Precautions]. resultedand in mortalities that were due to toxicities occurring in the cardiovascular (cardiac failure, cardiac • Inform patients to take IMBRUVICA orally once daily according to their physician’s instructions fibrosis, pericardial fluid accumulation, cardiac hemorrhage/degeneration), gastrointestinal (necrosis/ and that the (glomerulonephropathy, capsules should be swallowed withdysfunction), a glass of water without being opened, hemorrhage), renal tubular whole necrosis, and pulmonary (hemorrhage/ broken, or chewed at approximately the in same each day [see and Administration inflammation) systems. The dose of 2 mg/kg/dose rats time is approximately halfDosage the recommended dose in full Prescribing 2 humans(2.1) of 27inmg/m based on Information]. body surface area. The dose of 2 mg/kg/dose in monkeys is approximately • Advise patients that in the event of a missed daily dose of IMBRUVICA, it should be taken as soon equivalent to the recommended dose in humans based on body surface area. as COUNSELING possible on theINFORMATION: same day with aDiscuss return to normal schedule the following day. Patients PATIENT thethefollowing with patients prior to treatment with should not take extra to capsules makephysician up the missed [see Dosage andfollowing Administration (2.5) KYPROLIS: Instruct patients contacttotheir if theydose develop any of the symptoms: in fullrigors, Prescribing Information]. fever, chills, chest pain, cough, or swelling of the feet or legs. Advise patients that KYPROLIS may • A dvise patients of the common side effects associated with IMBRUVICA [see cause fatigue, dizziness, fainting, and/or drop in blood pressure. Advise patients notAdverse to driveReactions]. or operate Direct theexperience patient to aany complete of adverseAdvise drug reactions in PATIENT machinery if they of theselistsymptoms. patients that they mayINFORMATION. experience shortness • Advise patients to inform their health care providers of all concomitant medications, including of breath (dyspnea) during treatment with KYPROLIS. This most commonly occurs within a day of dosing. prescription medicines, over-the-counter drugs, vitamins, andofherbal Drug Advise patients to contact their physicians if they experience shortness breath.products Counsel [see patients to Interactions]. avoid dehydration, since patients receiving KYPROLIS therapy may experience vomiting and/or diarrhea. • Apatients dvise patients they advice may experience loose stools or diarrhea, and should contact their Instruct to seekthat medical if they experience symptoms of dizziness, lightheadedness, or their diarrhea persists. Advise patients to maintain adequatecontraceptive hydration. measures to fainting doctor spells. ifCounsel females of reproductive potential to use effective prevent pregnancy during Active ingredient madetreatment in China. with KYPROLIS. Advise the patient that if she becomes pregnant during treatment, to contact her physician immediately. Advise patients not to take KYPROLIS treatment Marketed by: If a patient wishes to restart breastfeeding after treatment, advise her whileDistributed pregnant and or breastfeeding. Pharmacyclics, Inc. timing with her physician. Advise patients to discuss with their physician any to discuss the appropriate Sunnyvale, CA USA 94085 medication they are currently taking prior to starting treatment with KYPROLIS, or prior to starting any new and medication(s) Marketedduring by: treatment with KYPROLIS.

Patients (N = 526) 13 3 0 0 [n (%)] 1 0 Grade 3 Grade 4 0 0 1 Gradesa Events Events 292 (55.5) 38 (7.2) 2 (0.4) 246 (46.8) 111 (21.1) 28 2 18 7 (1.3) 1 236 (44.9) 7 (1.3) 0 17 1 7 0 191 (36.3) 69 (13.1) 54 (10.3) 182 (34.6) 25 (4.8) 1 (0.2)b 14 1 6 0 172 (32.7) 4 (0.8) 1 (0.2) 11 0 5 0 160 (30.4) 7 (1.3) 2 (0.4) 149 (28.3) 17 (3.2) 0 145 (27.6) 7 (1.3) 0 11 0 3 0 137 (26.0) 1 (0.2) 0 127 1 (0.2) 10(24.1) 013 (2.5) 3 0 Lymphopenia 126 (24.0) 84 (16.0) 11 (2.1) Subjects with multiple events for a given ADR term are counted once only for each ADR term. Edema peripheral 126 (24.0) 3 (0.6) 0 The system organ class and individual ADR terms are sorted in descending frequency order in the IMBRUVICA arm. Vomiting 117 (22.2) 5 (1.0) 0 * Includes multiple ADR terms Constipation 110 (20.9) 1 (0.2) 0 Neutropenia 109 (20.7) (9.5) 4 (0.8) Table 6: Treatment-Emergent* Decrease of50 Hemoglobin, Platelets, or Neutrophils Back pain 106 (20.2) in Study 152 (2.9) 0 IMBRUVICA Ofatumumab Insomnia 94 (17.9) 0 0 (N=195) (N=191) Chills 84 (16.0) 1 (0.2) 0 All 83 Grades 4 All Grades 0 Grade 3 or 4 Arthralgia (15.8) Grade 3 7or(1.3) (%) (%) (%) (%) Muscle spasms 76 (14.4) 2 (0.4) 0 Neutrophils Decreased 51 23 57 26 Hypertension 75 (14.3) 15 (2.9) 2 (0.4) Platelets Decreased 52 5 45 10 Asthenia 73 (13.9) 12 (2.3) 1 (0.2) Hemoglobin Decreased 36 0 21 0 Hypokalemia 72 (13.7) 14 (2.7) 3 (0.6) * Based on laboratory measurements per IWCLL criteria Hypomagnesemia 71 (13.5) 2 (0.4) 0 DRUG INTERACTIONS Leukopenia 71 (13.5) 27 (5.1) 1 (0.2) Ibrutinib is primarily metabolized by cytochrome P450 enzyme 3A. Pain in extremity 70 (13.3) 7 (1.3) 0 CYP3A Inhibitors: In healthy volunteers, co-administration of ketoconazole, a strong CYP3A b Pneumonia 67 (12.7) 52 (9.9) 3 (0.6) inhibitor, increased Cmax and AUC of ibrutinib by 29- and 24-fold, respectively. The highest ibrutinib Aspartate aminotransferase increased 66 (12.5) 15 (2.9) 1 (0.2) dose evaluated in clinical trials was 12.5 mg/kg (actual doses of 840 – 1400 mg) given for 28 days • hr/mL which is5approximately Dizziness 66 ng (12.5) (1.0) (0.2) than steady with single dose AUC values of 1445 ± 869 50%1greater state exposures seen at the highest indicated Hypoesthesia 64 (12.2)dose (560 mg). 3 (0.6) 0 Avoid concomitant administration of IMBRUVICA or moderate inhibitors Janssen Biotech, Inc. Anorexia 63 (12.0) with strong 1 (0.2) 0 of CYP3A. For Horsham, PA USA 19044 (e.g., antifungals12and antibiotics for 7 days Pain strong CYP3A inhibitors used short-term 63 (12.0) (2.3) 0 or less, e.g., ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin) consider Patent http://www.imbruvica.com Hyperglycemia 62the (11.8) 16 (3.0)use. Avoid strong 3 (0.6) interrupting IMBRUVICA therapy during duration of inhibitor CYP3A inhibitors IMBRUVICA® is a registered trademark owned by Pharmacyclics, Inc. Chestthat wallare painneeded chronically. If a moderate 60 (11.4) 3 (0.6) 0 CYP3A inhibitor must be used, reduce the IMBRUVICA dose. Patients taking concomitant strong or moderate CYP3A4 inhibitors should8 be monitored more © Pharmacyclics, Inc. 2014 Hypercalcemia 58 (11.0) 13 (2.5) (1.5) © Janssen Biotech, 2014 closely for signs of IMBRUVICA toxicity [see Dosage and Administration (2.4) in full Prescribing Manufactured for: OnyxInc. Pharmaceuticals, Inc., 249 East Grand Avenue, Hypophosphatemia 55 (10.5) 24 (4.6) 3 (0.6) Information]. South San Francisco, PRC-00526 07/14 CA 94080 Hyponatremia 54 (10.3) 31 (5.9) 3 (0.6) 05‑1088‑00 Avoid grapefruit and Seville oranges during IMBRUVICA treatment, as these contain moderate U.S. Patent Numbers: 7,232,818; 7,417,042; 7,491,704; 7,737,112 a Nationalinhibitors Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 3.0. of CYP3A [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3) in full ©2014 Onyx Pharmaceuticals, Inc. TROPIC‑KYPR‑100826J November 2014 Rash* Petechiae Bruising* Event Musculoskeletal and Fatigueconnective tissue disorders Anemia Musculoskeletal Pain* Nausea Arthralgia Thrombocytopenia Nervous system disorders Dyspnea Headache Diarrhea Dizziness Pyrexia Injury, poisoning and Upper respiratory infection proceduraltract complications Headache Contusion Cough Eye disorders Blood creatinine increased Vision blurred

24 14 12All

One event was Grade 5 severity. Prescribing Information].

b

CYP3A Inducers: Administration of IMBRUVICA with rifampin, a strong CYP3A inducer, decreased ibrutinib Cmax and AUC by approximately 13- and 10-fold, respectively.


In This Issue INTEGRATING COST, QUALITY, ACCESS INTO CLINICAL DECISION-MAKING IN ONCOLOGY

PUBLISHING STAFF Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Vice President/Group Publisher Russell Hennessy rhennessy@the-lynx-group.com Vice President/Director of Sales & Marketing Joe Chanley jchanley@the-lynx-group.com Publisher Cristopher Pires cpires@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Senior Associate Editor Lilly Ostrovsky Associate Editor Lara J. Lorton Editorial Assistant Cara Guglielmon Production Manager Cara Nicolini THE LYNX GROUP President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Director, Strategy & Program Development John Welz Director, Quality Control Barbara Marino

HEALTH ECONOMICS

EMERGING THERAPIES

Value and cost-effectiveness analyses should factor in reimbursement Value of survival gains for MDS could exceed $100 billion US orphan drug spending expected to stabilize More…

The hematology pipeline is abundant

RECENT FDA APPROVALS Ibrutinib for Waldenström’s macroglobulinemia Blinatumomab first immunotherapy for B-cell ALL Ruxolitinib for polycythemia vera

MULTIPLE MYELOMA Treatment advances in multiple myeloma Onyx 360 reduces patient distress Unprecedented remission rates with carfilzomib-based triplet Weekly carfilzomib safe and effective Oprozomib promising in myeloma More…

Quality Control Assistant Theresa Salerno

Creative & Design Assistants Lora LaRocca Wayne Williams Director, Digital Media Anthony Romano Jr Digital Media Specialist Charles Easton IV Web Content Manager Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Mezzacappa Senior Project Managers Alyson Bruni Jini Gopalaswamy Project Manager Deanna Martinez Project Coordinator Mike Kodada IT Manager Kashif Javaid Administrative Team Leaders Rachael Baranoski Allison Ingram Administrative Assistant Amanda Hedman Office Coordinator Robert Sorensen Engage Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-992-1880 fax: 732-992-1881

Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 11 times a year by Engage Healthcare Communica­ tions, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2015 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.

Editor-in-Chief Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL

VALUE-BASED CANCER CARE

LYMPHOMA Immunotherapy with PD-1 inhibitors newest breakthrough in Hodgkin lymphoma Posttransplant brentuximab new standard in Hodgkin lymphoma Brentuximab cost-effective after transplant More…

PAYERS’ PERSPECTIVE Value of pharmaceuticals and treatment adherence in hematologic cancers

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 Linda D. Bosserman, MD, FACP Clinical Assistant Professor Medical Oncology and Hematology City of Hope Medical Group Rancho Cucamonga, CA Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, New York, NY Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers, Pittsburgh, PA Arlene A. Forastiere, MD Senior Vice President Medical Affairs, eviti, Inc, Philadelphia, PA Scott Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute, New York, NY Philip E. Johnson, MS, RPh, CPh H. Lee Moffitt Cancer Center Tampa, FL Kevin B. Knopf, MD, MPH Medical Oncology,
California Pacific Medical Center,
Sutter Health Care
 San Francisco, CA

Michael Kolodziej, MD National Medical Director, Oncology Solutions Aetna, Hartford, CT

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

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

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

FEBRUARY 2015

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

Jennifer Malin, MD, PhD Medical Director, Oncology and Care Management, WellPoint, Inc 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 Barbara L. McAneny, MD Chief Executive Officer New Mexico Oncology Hematology Consultants, Ltd. Albuquerque, NM Matthew Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth, Salt Lake City, UT Marcus Neubauer, MD Medical Director, Oncology Services, McKesson Specialty Health, The Woodlands, TX Lee Newcomer, MD, MHA UnitedHealthcare Group Minnetonka, MN Lynn Nishida, RPh Director, Clinical Services Catamaran Center of Excellence Northwest Region, Portland, OR

Mission Statement Value-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the cost-value 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.

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Denise K. Pierce DK Pierce & Associates Zionsville, IN

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

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6

Psychological distress and financial burden impact adherence to CML treatment Pediatric regimen new standard in young adults with ALL More…

VBCC Editorial Board

Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs

LEUKEMIA

Jayson Slotnik, JD, MPH Partner, Health Policy Strategies, LLC Washington, DC Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA John D. Sprandio, MD, FACP Chief Physician, Consultants in Medical Oncology and Hematology Chief of Oncology, Delaware County Memorial Hospital, Drexel Hill, PA Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA G. Rhys Williams, ScD, MS Amgen, Thousand Oaks, CA Winston Wong, PharmD President W-Squared Group Longboat Key, FL Burt Zweigenhaft, BS Chief Executive Officer, OncoMed Great Neck, NY

Permission requests to reprint all or part of any article published in this magazine should be addressed to editorial@valuebasedcancercare.com. Address all editorial queries to: editorial@valuebasedcancercare.com, Telephone: 732-992-1891, Fax: 732-992-1881. POSTMASTER: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 1249 South River Road, 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.

VOL. 6

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NO. 1

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SUPPLEMENT


Health Economics

Value and Cost-Effectiveness Analyses... Nevertheless, Dr Laupacis said that cost-effectiveness is an important component of reimbursement decisions. Using cost-effectiveness calculations, Canadian drug reimbursement committees decide whether to pay for a drug out of the public purse, to decline to pay because the drug is not cost-­ effective, or to pay for a restricted indication, such as a certain stage of cancer, Dr Laupacis indicated. Cost-effectiveness determinations help committees allocate resources fairly, he explained. “Resource allocation decisions must be made, ad hoc or in a planned manner. Doing so in a planned manner is better,” Dr Laupacis said. “If we pay for a very expensive drug or any intervention with very little value, we won’t be able to pay for something else with potentially more value,” he noted. “In the vast majority of circumstances, we have to ask how much value we are getting for the additional cost.” In the United States, payers can dic-

tate their reimbursement based on reliable cost-effective analyses.

Continued from page 1

price for consideration, with no opportunity for adjustment.

“If we pay for a very expensive drug or any intervention with very little value, we won’t be able to pay for something else with potentially more value…. We have to ask how much value we are getting for the additional cost.” —Andreas Laupacis, MD, MSc Negotiating Cost with Manufacturers

As of the past few years, Canadian drug reimbursement committees have been able to negotiate prices with manufacturers. This has been an improvement over the previous structure, in which the manufacturer submitted a

“This meant we often suggested that drugs not be funded, because at the price they charged, the drugs were not cost-effective,” Dr Laupacis said. “That changed recently, and if a drug is not felt to be cost-effective at the price submitted by the manufacturer, we have the ability to negotiate in an

attempt to find a price at which it becomes cost-effective,” he indicated. “Unfortunately, that price is not made public, and I find that unacceptable,” Dr Laupacis added. “People can find out what I charge for a consult, but we don’t know the price our government has negotiated with the manufacturer.” Regardless of a drug’s cost-effectiveness and perhaps a reasonable price, which is negotiated with the manufacturer, Dr Laupacis acknowledged that drug prices are still “massively higher” than they used to be, and are “generally not massively better” than the current best treatments. “For the way forward, there are no easy solutions,” Dr Laupacis concluded. His suggestions for payers are to: • Focus on getting high-quality information about effectiveness of drugs to accurately drive cost-effectiveness ratios • Negotiate prices aggressively based on­ cost-effectiveness • Use tools such as value-based discounts • I nvolve patients in the dialogue. n

American-Style Capitalism Drives Drug Development: Cancer Therapies Targeting Small Subpopulations Dictate Prices By Kate Smith San Francisco, CA—There is no way around the fact that American-style capitalism is at the root of drug development, and the costs associated with that endeavor, according to Alex W. Bastian, MBA, Vice President of Market Access, GfK Bridgehead, San Francisco, CA. GfK provides consulting services to pharmaceutical, biotechnology, medical device, and diagnostics industries. Speaking at the special session on drug pricing during ASH 2014, Mr Bastian asked the audience to “open its mind” to some concepts that are “realworld, practical, and deal with actual considerations that take place.” “Unfortunately, this is American-­ style capitalism,” he said. “Alternative pricing models are very difficult to implement.” Discussions about the cost of drugs have been a “constant theme” over the past century, and the problem is not unique to America, Mr Bastian said. “This is a global problem. The problems facing the United States in terms of cost are seen around the globe. It is not isolated to our cost of drugs alone.” Mr Bastian acknowledged, how­ ever, that in cancer drugs, “costs are increasing, especially as we are going VOL. 6

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after smaller niche populations.” The investment community must aim for a robust return on its money, and this gets trickier as tumors become more molecularly classified, he said. Potential markets for cancer drugs become smaller, as ever-more targeted treatments are required.

“This is American-style capitalism….We are frontloading cost, and the question is whether that is right. I can’t answer that. A healthy discussion is important.” —Alex W. Bastian, MBA

“For a population with very low prevalence rates, and high mortality, to justify investment by tumor types and subtumor types, we are talking fractions and subfractions,” Mr Bastian said. “Developing drugs is difficult for these populations.” Investors must justify their investments, he said, and they face “grave unintended consequences” if they advo-

cate for “hypertension-like drug prices” in the oncology arena. Mr Bastian acknowledged that patent protections are an important means of assuring the manufacturer a continuing profit for its efforts, but he pointed out that patents on a number of common agents will soon expire, and biosimilars will also begin appearing in the marketplace. “The days when Gleevec will cost cents on the dollar are close,” Mr Bastian said. Value-Based Pricing Is Needed

He suggests that the focus be on “value” rather than on cost. In hematology, value has clearly been proved by the doubling and even tripling of survival times in lymphoma, multiple myeloma, and some leukemia, as a result of novel agents. Nevertheless, Mr Bastian added that the treatment armamentarium is much weaker for hematologic cancers than for solid tumors, which highlights the difficulties in developing drugs in this setting. Since 1998, some 249 drugs in the hematology pipeline have failed to make it to market. “I don’t know at what price, but it is a lot,” Mr Bastian said. “The number of approvals is much less in comparison to other cancers.” FEBRUARY 2015

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KEY POINTS ➤ The costs of cancer drugs are increasing in large part because they target smaller and smaller subpopulations of patients ➤ High prices and healthy margins justify the continued investment in future therapies ➤ The United States bears the bulk of the high cost; whether this is right requires an open discussion

The need for new agents keeps the pipeline flowing, he said. The point is not that current treatments must be priced high to justify past investments, but that high prices and healthy margins justify the continued investment in future therapeutics, Mr Bastian said. Meanwhile, he acknowledged, “We are front-loading cost, and the question is whether that is right. I can’t answer that. A healthy discussion is important.” This discussion should examine total benefits, as well as costs, Mr Bastian emphasized, and must include “a rounded point of view.” n

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Stem-Cell Mobilization More Cost-Effective with Plerixafor By Kate Smith San Francisco, CA—The upfront use of plerixafor plus granulocyte colony-stimulating factor (G-CSF) for stem-cell mobilization is more cost-effective than the more widely used cyclophosphamide plus G-CSF regimen, according to a cost analysis from Memorial Sloan Kettering Cancer Center investigators that was presented at ASH 2014. “Phase 3 trials demonstrated higher stem-cell collection efficiency with plerixafor plus G-CSF, and plerixafor can rescue patients failing mobilization with G-CSF with or without cyclophosphamide. But despite the proven efficacy of plerixafor plus G-CSF, its upfront use has been limited, mostly due to concerns of the high cost of the drug,” said Salma Afifi, PharmD, of the Department of Pharmacy, Memorial Sloan Kettering Cancer Center, New York. “As a measure to contain cost, ‘on-demand’ plerixafor has been used in patients anticipated to be poor mobilizers with G-CSF with or without cyclophosphamide,” Dr Afifi said. The assumption is that using plerixafor plus G-CSF upfront will promote cost-effectiveness by limiting the use of plerixafor; however, a comprehensive comparison has not been done. This retrospective study is the first to compare the mobilization and cost-­ effectiveness of cyclophosphamide plus

G-CSF versus plerixafor plus G-CSF as upfront mobilization regimens. Dr Afifi and colleagues identified 223 patients with multiple myeloma undergoing upfront mobilization, with 111 patients receiving cyclophosphamide plus G-CSF and 112 patients receiving plerixafor plus G-CSF. Patients collecting <5 × 106 CD34+ cells/kg were considered mobilization failures and had a second attempt using an alternate approach. Mobilization costs included upfront mobilization, salvage mobilization, and complications directly related to the mobilization procedures. All costs were calculated using the institution’s ratio of cost to charges, and were normalized and adjusted based on institutional charges and costs for 2012. Differences in Outcomes Favor Plerixafor

Plerixafor was associated with re­­ duced use of G-CSF, fewer toxicities and related hospitalizations, and a lower rate of mobilization failure and its need for salvage mobilization associated with plerixafor plus G-CSF. The mean apheresis sessions were 2.3 with plerixafor and 2.6 with cyclophosphamide (P = .06). The median CD34+ cells/kg were 11.4 × 106 and 10.9 × 106, respectively (P = .29).

A successful total yield was achieved by 105 (94%) patients receiving pler­ ixafor plus G-CSF versus 92 (83%) pa­ tients receiving cyclophosphamide plus G-CSF (P = .01).

“This single institution study provides additional rationale for the standard use of plerixafor plus G-CSF as an upfront mobilization regimen in multiple myeloma patients.” —Salma Afifi, PharmD, and colleagues

Approximately 85% of each group went to transplant. Platelet engraftment and neutrophil engraftment were achieved by 100% of patients in each group. Overall, 13 (12%) patients were rehospitalized as a result of complications after receiving cyclophosphamide plus G-CSF, with an average hospital stay of 6.5 days. No patients in the plerixafor plus G-CSF arm were hospitalized. Of the patients in the cyclophosphamide plus G-CSF group, 19 (17%) failed first mobilization com-

pared with 7 (6.2%) patients receiving plerixafor plus G-CSF upfront. Plerixafor plus G-CSF More Cost-Effective

“Plerixafor plus G-CSF was more cost-effective than cyclophosphamide plus G-CSF,” Dr Afifi concluded. The average charges were $74,884 in the cyclophosphamide plus G-CSF cohort versus $59,127 in the plerixafor plus G-CSF cohort (P = .004). The average cost of stem-cell collection per patient was 22% higher in the cyclophosphamide group than in the plerixafor group (P = .017), Dr Afifi reported. “When the costs associated with salvage pheresis was discounted for the 19 patients in the cyclophosphamide plus G-CSF upfront group who failed first stem-cell mobilization, assuming that these patients could have been salvaged by plerixafor on demand, the cost per patient in the cyclophosphamide plus G-CSF group remains 1.26 times greater [P = .019] than that of the plerixafor plus G-CSF group,” Dr Afifi and her colleagues noted. “Overall, this single institution study provides additional rationale for the standard use of plerixafor plus G-CSF as an upfront mobilization regimen in multiple myeloma patients,” Dr Afifi concluded. n

High Cancer Drug Prices Hurt Patients San Francisco, CA—Hagop M. Kantarjian, MD, Professor and Chair of Leukemia, M.D. Anderson Cancer Center, Houston, TX, did not mince words during his talk at the ASH 2014 special session on drug pricing. “Drug prices are definitely too high, and this is harming our patients….We need a situation where cancer drugs are affordable and patients can take them without the anxiety associated with lack of affordability,” Dr Kantarjian said. Disputing the claim that rising prices is not a new concern, he pointed out that before 2000, the average cost of an oncology drug was less than $10,000 annually. Since then, prices have risen 10-fold, while the average household income has diminished by 8%. This disparity has compromised the financial and emotional security of many patients with cancer, whose outof-pocket expenses are simply unaffordable, Dr Kantarjian said. The end result, he suggested, is a “medical Darwinian system” in which

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“Drug prices are definitely too high, and this is harming our patients…. We need a situation where cancer drugs are affordable and patients can take them without the anxiety associated with lack of affordability.” —Hagop M. Kantarjian, MD

“if you can pay, you live, and if you cannot, you may die from your disease.” Although the concept of cost-sharing (ie, giving patients “skin in the game”) aims to facilitate value-based treatment choices, this holds true only for less expensive drugs and generics, and is not applicable to most cancer treatments, Dr Kantarjian said. “In cancer, new drugs are patented,

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and patients don’t have this choice. Having skin in the game is only harmful to them,” he said. Rebutting Common Arguments

Dr Kantarjian took exception to the arguments made to support high prices: that prices reflect the high cost of research and the cost–benefit ratio of the drug, that market forces will set pric-

es at reasonable levels, and that price control will stifle innovation. “None of these are true, morally justifiable, or defensible,” Dr Kantarjian maintains. He took exception to the argument that price reflects benefit, noting that some drugs prolong life by years and others by days, yet the near-universal annual cost of new agents is approximately $100,000. Market forces cannot correct price imbalances, he says, because drug companies do not compete on the basis of cost. In addition, drug companies set their own prices for the Medicare system. Although manufacturers indicate that they set prices by calculating cost–­ benefit ratio, examining the competitive marketplace, and estimating the potential market for the drug, Dr Kantarjian suggests that “companies look at the price of an existing drug and put a 20% higher price tag on the new one.” “Making progress in drug development in the long run is not a reason to increase prices to a profiteering level,” he concluded.—KS n

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Once Off Patent, Imatinib Will Be the Most CostEffective Treatment for Newly Diagnosed CML By Wayne Kuznar San Francisco, CA—Once Gleevec loses patent exclusivity in 2016, imatinib will become the most cost-effective initial treatment strategy for patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, said Richard A. Larson, MD, Director, Hematologic Malignancies Clinical Research Program, University of Chicago, IL, at ASH 2014. Dr Larson’s analysis showed an incremental cost-effectiveness ratio of $291,000 per quality-adjusted life-year (QALY) when generic imatinib was used as the initial therapy in a step therapy regimen. Lifelong treatment with a tyrosine

KEY POINTS ➤ Once it loses patent exclusivity in 2016, imatinib will be the most cost-effective treatment for newly diagnosed chronicphase CML ➤ Generic imatinib had an incremental cost-effectiveness ratio of $291,000 per QALY when used as the initial therapy in a step therapy regimen ➤ In a 12-month CCyR model, step therapy was shown to cost less and offer clinically equivalent use compared with physician’s choice over the first 5 years of therapy

kinase inhibitor (TKI) is recommended for patients with chronic-phase CML, and although out-of-pocket costs vary within and between health systems, they may be considerable, and costs influence daily adherence and outcomes, Dr Larson said. Currently, imatinib, dasatinib, and nilotinib are approved by the FDA as frontline therapies for chronic-phase CML. “When imatinib loses patent exclusivity in early 2016, 6 to 8 manufacturers are expected to enter the generic imatinib market,” said Dr Larson. In evaluating the clinical outcomes and economic costs of imatinib versus second-generation TKIs as initial treatment for patients with newly diagnosed CML, Dr Larson’s group applied “value of information” as an outgrowth of comparative effectiveness methods to prospectively assess step therapy and physician’s choice. In step therapy, all patients begin with imatinib but are switched for intolerance or failure of efficacy. In the physician’s choice model, imatinib, dasatinib, and nilotinib were prescribed equally for initial therapy. “I believe this currently reflects the situation in the United States,” said Dr Larson. The results were evaluated from a commercial payer perspective, with comparison of treatment costs and outcomes over the first 5 years of therapy. The end points used for this analysis were complete cytogenetic response (CCyR) at 12 months and

“When imatinib loses patent exclusivity in early 2016, 6 to 8 manufacturers are expected to enter the generic imatinib market.” —Richard A. Larson, MD

overall survival. In the step therapy model, if imatinib failed or was not tolerated as the initial choice, patients were switched to dasatinib or to nilotinib in equal proportions. In the physician’s choice model, if the initial second-generation TKI failed, patients were switched to an alternate second-generation TKI (with a small percentage switched to imatinib). Patients with CCyR by 12 months continued to receive initial TKI ther-

apy up to complete remission and were assumed to survive for 5 years. It was assumed that patients without CCyR by 12 months were switched to an alternate TKI and also survived for 5 years. Patients who progressed to accelerated-phase CML or blast crisis CML (an estimated 5% of patients) received allogeneic transplantation, assuming a 1-year survival of 50%. The model assumed an annual cost of $60,390 for imatinib, $95,338 for dasatinib, and $91,644 for nilotinib. The cost of imatinib was assumed to decrease with its availability as a generic, remaining at 100% of the branded-­ drug price for the first 6 months, 60% to 80% of the branded-drug price in the second 6 months, and 10% to 30% thereafter. The 12-month CCyR model showed that step therapy costs less and offers clinically equivalent utility compared with physician’s choice over the first 5 years (with step therapy at approximately $184,000 vs physician’s choice at $216,000). The QALYs remained similar between step therapy and physician’s choice (3.25 vs 3.36, respectively). Step therapy was estimated to have an incremental cost-effectiveness ratio of $291,000 per QALY. Multivariate probabilistic sensitivity analyses found step therapy to be cost-effective in 73.3% of 10,000 Monte Carlo simulations, with the currently accepted willingness-to-pay threshold of $100,000 per QALY. n

Orphan Drug Expenditures in the United States Expected to Stabilize San Francisco, CA—The increase in orphan drug expenditures is expected to slow, said Victoria Divino, Senior Consultant at IMS Health, at ASH 2014. Ms Divino and colleagues evaluated the trends in orphan drug expenditures over time in the United States, calculating the total expenditures for branded orphan drugs from 2007 to 2013 and projected drug expenditures for 2­014 to 2018. “Future trend analysis suggests that while orphan drug expenditures in 2014 to 2018 will increase, there will be a slowing down in growth, and growth will remain fairly stable as a

“Concerns that growth in orphan drug expenditures may lead to unsustainable drug expenditures do not appear to be justified.” —Victoria Divino

proportion of total drug expenditures,” said ­Ms Divino. “Concerns that growth in orphan drug expenditures may lead to unsustainable drug expenditures do not appear to be justified,” she emphasized. Orphan drug development is increasing in hematologic malignancies. “Despite the clinical value of orphan drugs, payer sensitivity to orphan drugs is increasing, due to the perceived potential impact on payers’ drug budgets,” Ms Divino said. “Little evidence and data have been generated as to the actual burden of orphan drug expenditures in the United States.” Continued on page 10

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Financial Toxicity Impacts Treatment Adherence Oncologists must address costs with their patients By Kate Smith San Francisco, CA—The cost of paying for cancer impacts the efficacy of treatment, according to S. Yousuf Zafar, MD, MHS, Associate Professor of Medicine, Duke Cancer Institute, Durham, NC. High patient cost burden is associated with a 70% higher likelihood of a patient’s nonadherence to treatment, Dr Zafar said at the ASH 2014 special session on drug pricing. Dr Zafar coined the now-familiar concept of “financial toxicity,” which, he says, is as important as drug toxicity when it comes to patients with cancer. A patient’s inability to afford the cost of cancer therapy is as important to the patient’s health as potential drug toxicity. Therefore, Dr Zafar urges oncologists to discuss costs with their patients to improve outcomes. Patient–physician communication about the cost reduces out-of-pocket (OOP) costs to patients, even in oncology, where treatment options are often limited, he says. “It’s important for physicians to recognize that some patients are at risk for financial toxicity,” he said. His position is supported by the following

“It’s important for physicians to recognize that some patients are at risk for financial toxicity.… We have to involve patients. I do this in the clinic every day.” —S. Yousuf Zafar, MD, MHS

statistics related to cancer care: • 50% of Medicare beneficiaries pay

10% of the cost OOP •  28% of Medicare beneficiaries spend >20% OOP • Nearly 50% of patients take money from their savings and cut back on basics to pay for care • The average patient spends approximately $5000 OOP • The average insurance deductible has risen from $584 in 2006 to $1217 in 2014 • Since 2006, the cost of insurance premiums has risen by 182%, and employees’ contributions have gone up 128% • A cancer diagnosis raises the risk for bankruptcy nearly 3-fold. Contributing to the rising cost for patients are 4-tiered formularies, which have become increasingly common. There were no fourth-tier drugs in 2003, but by 2013, approximately 23% of drugs were in the fourth tier. This usually includes all oral chemotherapy agents. The cumulative cost of treatment to the patients not only impacts their emotional and financial health, but it can also compromise clinical outcomes, according to Dr Zafar.

Patient–Physician Discussions About Cost

In prospective, longitudinal studies of patients with cancer, Dr Zafar and colleagues have found that 52% of patients want to discuss treatment-related OOP costs with their oncologist, and 51% want their oncologist to take cost into account when making treatment decisions, but only 19% of patients have actually discussed these things with their doctors. Among patients who did discuss costs, 57% report having lower OOP costs as a result, mainly because they were referred to a financial assistance organization (53%). Other reasons for lower costs include physicians negotiating with insurance companies on the patient’s behalf (25%), patients switching to less expensive medications (19%), tests altered (13%), and office visits scaled back (6%), Dr Zafar said. He emphasizes that cost issues do not get resolved in the absence of price transparency and discussions with patients. “We have to involve patients” in their care, Dr Zafar said. “I do this in the clinic every day.” n

Orphan Drug Expenditures in the United States Expected to... Continued from page 9

Of the 356 branded orphan drugs analyzed, 291 (82%) “orphan-only” drugs were included in a primary analysis. In a secondary analysis, expenditures were adjusted for 65 (18.3%) of the 356 orphan drugs, which were identified as “partial orphans,” because they are approved for orphan and for nonorphan indications. Study Details

In the primary analysis of orphan-­ only drugs, the expenditures represented 4.3% to 7.7% of the total US drug expenditures from 2007 to 2013. Overall, the orphan drug expenditures totaled $15 billion to $30 billion, representing 4.8% to 8.9% of the total US drug expenditures from 2007 to 2013. “While we observe a trend for increasing costs, it’s also important to note that the number of drug approvals has increased over time,” said Ms Divino. There was a total of 210 unique orphan drugs in 2007, which increased to 286 drugs in 2013.

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In addition, oncology was the most common therapeutic class of orphan drug approved, with 101 (32.0%) of the total 356 orphan drugs with an orphan indication for oncology. In 2007, $15.08 billion was spent on orphan drugs, with 29.3% representing cancer-related orphan drugs compared with $30.08 billion in 2013, of which 40.7% was for cancer-related orphan drugs. Using sales data from 2007 to 2013, the investigators estimated the orphan drug expenditures to be $33.5 billion to $44.2 billion for 2014 to 2018, representing 8.8% to 9.5% of the total US drug expenditures. The future costs were estimated as the number of new approvals times the average cost per drug annually added to the previous year’s total orphan drug sales. Orphan drug expenditures of $34.9 billion to $54.9 billion were estimated for 2014 to 2018, representing 9.2% to 11.8% of the total US drug costs. Although select orphan drugs may be costly, the population using these

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orphan drugs is small. The adjusted drug expenditures for 64 partial orphan drugs represented 0.5% to 1.2% of the total US drug sales from 2007 to 2013. A disease-factoring analysis suggested that most unadjusted partial orphan drug sales were for nonorphan indications. “Following adjustment, orphan indication costs were minimal and represented only 7.2% to 10.5% of total unadjusted partial orphan drug expenditures in 2007 to 2013, respectively,” Ms Divino said. “While associated orphan drug expenditures have increased, these drugs benefit many patients with previously underserved rare conditions. While this study examined drug expenditures, it’s important to consider the value of orphan drugs to both patients and society, such as health and quality-of-life improvements, reductions in costly hospitalizations, increased productivity, and the ability to go back to work,” said Ms Divino. “The annual expenditures

KEY POINTS ➤ Based on a new analysis, the concern that growth in orphan drugs will cause unsustainable spending is unjustified ➤ The total US drug expenditures for orphan drugs increased by 0.5% to 1.2% from 2007-2013 to 2014-2018, but the growth in orphan drugs is expected to slow ➤ Orphan drugs are often costly, in part because they serve a small patient population ➤ The total spending on orphan drugs is low compared with spending on all drugs ➤ Orphan drugs often benefit patients with previously underserved rare conditions

on orphan drugs are small relative to the total pharma drug expenditures,” she ­concluded.—WK n

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Economic Value of Survival Gains for MDS Could Exceed $100 Billion By Chase Doyle San Francisco, CA—The introduction of the 3 targeted therapies—lenalidomide, decitabine, and azacitidine—for myelodysplastic syndrome (MDS) has resulted in a 74% increase in median survival and generates more than $100 billion in value resulting from survival gains for current and future patients, reported Joanna P. MacEwan, PhD, Associate Research Economist, Precision Health Economics, San Francisco, CA, at ASH 2014. Despite improvement in cancer survival since the 1970s, critics have argued that newer cancer treatments offer minimal survival gains, at high costs. Noting the lack of economic analyses, Dr MacEwan and colleagues studied the value of MDS treatments relative to their cost. Building on an existing analytic framework using data on survival and prescription drug claims, the researchers conducted 3 subanalyses, including survival analysis, the value of survival gains, and value appropriation.

Cox proportional hazards models were applied to estimate the increase in survival associated with the introduction of new therapies for MDS in 38,085 patients with MDS diagnosed between 2001 and 2011. The results showed that patients diagnosed with MDS since 2006 (when all 3 therapies

mately 25%) increased from 33 months to 57.5 months, representing a ­ 74% improvement. “The annual value of survival gains associated with these innovative treatments—roughly $208,000 per year—equaled the estimated amount a patient would be willing

“The annual value of survival gains associated with these innovative treatments—roughly $208,000 per year—equaled the estimated amount a patient would be willing to pay for the higher survival profile associated with new therapies.” —Joanna P. MacEwan, PhD

were available) had an approximate 10% lower mortality risk than patients diagnosed between 2001 and 2003 (hazard ratio, 0.901; P <.10). The median survival in patients with MDS who received lenalidomide, decitabine, or azacitidine (approxi-

to pay for ­­ the higher survival profile associated with new therapies,” Dr MacEwan suggested. This value was estimated to exceed the cost of therapy, with an annual net benefit of $68,200 to patients with MDS and a lifetime benefit of

KEY POINTS ➤ Treatment with lenalidomide, decitabine, or azacitidine showed an increase in median survival from 33 months to 57.5 months, representing a 74% improvement ➤ The annual survival gain associated with these treatments was roughly $208,000

$238,700. The present value of survival gains for all current and future cohorts was determined to be $101.5 billion. Based on estimates of patent expiration and price decreases after the patent expirations, the investigators concluded that 85% of the value of survival gains created by novel therapies ($86.5 billion) will accrue to patients with MDS, with the remaining 15% accruing to the drugs’ manufacturers. n

RECENT FDA APPROVALS Ibrutinib Gets New Indication for Waldenström’s Macroglobulinemia

On January 29, 2015, the US Food and Drug Administration (FDA) ap­­ proved a new indication for ibrutinib (Imbruvica; Pharmacyclics) under its priority review process for the treatment of patients with Waldenström’s macroglobulinemia (WM), a rare type of non-Hodgkin lymphoma. Ibrutinib had previously received a breakthrough therapy designation by the FDA for this use. WM progresses gradually over time, resulting from the overproduction of B-cells within the bone marrow, lymph nodes, liver, and spleen. These B-cells also overproduce immunoglobulin M, which may lead to bleeding and vision and nervous system problems. Ibrutinib inhibits the abnormal activity of these B-cells to fight WM. The approval was based on a clinical study of 63 previously treated patients with WM. The patients received 420 mg of oral ibrutinib daily until disease progression or until side effects became intolerable. The overall response rate to the drug was 62%, with a response duration ranging from 2.8 months to approximately 18.8 months. The most common adverse events with ibrutinib are thrombocyto­­penia,

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neutropenia, diarrhea, anemia, fatigue, musculoskeletal pain, bruising, nausea, upper respiratory tract infection, ­and rash. Ibrutinib was initially approved by the FDA in November 2013 for the treatment of patients with mantle-cell lymphoma; in February 2014, it was approved for patients with previously treated chronic lymphocytic leukemia (CLL), and in July 2014, for patients with CLL and a deletion in chromosome 17. Ruxolitinib Gets New Indication for Polycythemia Vera

On December 14, 2014, the FDA approved ruxolitinib (Jakafi; Incyte) for the treatment of patients with polycythemia vera (PV) who have had an inadequate response to or are intolerant of hydroxyurea. The approval was based on a randomized, multicenter, open-label, active-control trial of 222 patients with PV. The composite end point was durable hematocrit control and spleen volume reduction, and a durable hematocrit control that obviated the need for regular phlebotomy. Ruxolitinib was significantly better than best-available therapy in durable hematocrit control and in spleen volume reduction by week 32 (21% vs

1%; P <.001) and week 48 (19% vs 1%; ­­­P <.001), and had a 55% rate of durable hematocrit control by week 48. The most common (incidence >20%) hematologic adverse reactions through week 32 were thrombocytopenia and anemia. The most common (incidence >10%) nonhematologic adverse events were headache, abdominal pain, diarrhea, dizziness, fatigue, pruritus, dyspnea, and muscle spasms. Overall, 4% of patients discontinued therapy because of adverse events. The recommended starting dose of ruxolitinib is 10 mg twice daily, with modifications in some patient populations. Blinatumomab First Immunotherapy Approved by the FDA for B-Cell ALL

On December 3, 2014, the FDA approved blinatumomab (Blincyto; Amgen) for the treatment of patients with relapsed or refractory Philadelphia chromosome (Ph)-negative precursor B-cell acute lymphoblastic leukemia (ALL), a rare and rapidly growing form of ALL. Blinatumomab is intended for use in patients with B-cell ALL. Blinatumomab is the first immunotherapy approved by the FDA for patients with leukemia. The drug acts as a connector between the CD19 protein (which is found on the surface of most B-cell lymFEBRUARY 2015

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phoblasts) and the CD3 protein found on T-cell lymphocytes, using the body’s T-cells to destroy the leukemia cells. The FDA had initially granted this drug a breakthrough therapy designation, and applied its priority review and accelerated programs for this approval. The FDA is now requiring the manufacturer to conduct a new clinical trial to show a survival benefit with blinatumomab in patients with relapsed or refractory Ph-negative precursor B-cell ALL. The approval was based on a clinical trial of 185 adults with Ph-negative relapsed or refractory precursor B-cell ALL. All patients received an infusion of blinatumomab for at least 4 weeks. Overall, 32% of patients had complete remission lasting approximately 6.7 months. The trial was not designed to show improvement in survival. Blinatumomab is associated with significant risks, including cytokine release syndrome, encephalopathy, and nervous system events. It was approved with a Risk Evaluation and Mitigation Strategy program and has a boxed warning regarding these risks. The most common side effects reported were pyrexia, headache, peripheral edema, febrile neutropenia, nausea, hypokalemia, fatigue, constipation, diarrhea, and tremor. n

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Multiple Myeloma MYELOMA OVERVIEW

Treatment Advances in Multiple Myeloma: Implications for Patients, Providers, and Payers

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eoplasms of the blood and lymphoid tissue are often classified into the 4 broad categories of leukemia, Hodgkin lymphoma, non-Hodgkin lymphoma, and myeloma, and account for approximately 9% of all cancers. As a group, hematologic malignancies are the fourth most frequently diagnosed cancer in men and in women in the economically developed world.1 Clinical Burden

Multiple myeloma accounts for approximately 13% of all hematologic malignancies.2 Myeloma is characterized by the neoplastic growth of plasma cells in the bone marrow, which crowds out and inhibits the production of normal blood cells and antibodies, resulting in marrow failure. Myeloma also results in bone destruction in most patients. As myeloma cells proliferate, enhanced bone resorption and suppressed bone formation cause destructive osteolytic lesions.2-4 Myeloma typically occurs in bone marrow with the most activity, which includes the spine, ribs, shoulders, and pelvic girdle.4 With an incidence of 4.5 to 6 cancers per 100,000 people annually, myeloma is relatively rare compared with other cancers2; however, its incidence rate has risen by 36% between 1975 and 2011.5 The National Cancer Institute estimated that there would be 24,050 new cases of myeloma in 2014 and 11,090 people would die of the disease.6 In comparison, more than 200,000 new cases of prostate, breast, and lung cancers are diagnosed annually.6 The median age at myeloma diagnosis ranges from 63 to 70 years.2 Despite the introduction of several new therapeutic agents in the past decade, myeloma remains incurable. The 5-year survival rate, which varies by International Staging System stage,7 was estimated to be approximately 45% overall between 2004 and 2010 compared with 26.3% in 1975.6 The goals of treatment for people with myeloma are to reduce symptoms, to slow disease progression, and to achieve disease remission for the longest possible period, while maintaining the best possible quality of life. Treatment is tailored for each patient and is based on the extent of the disease and the rate of disease progression. Many patients require myeloma-specific treatment that may include combination drug therapy, high-dose chemotherapy with stem-cell transplantation, radiation therapy for local disease, and/or new and emerging

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drug therapies that are under investigation in clinical trials.5 The Myeloma Treatment Landscape

The evolution of the management of myeloma, including the use of high-dose therapy, advancements in stem-cell transplantation, and more recently, novel therapeutic agents, has resulted in improved patient survival.8 In particular, the introduction of therapies such as the immunomodulatory agents thalidomide and lenalidomide and the proteasome inhibitor bortezomib has led to dramatically improved response rates in patients with newly diagnosed myeloma.9

A robust line of therapies is in development for the treatment of myeloma. Monoclonal antibody therapies, such as elotuzumab and daratumu­ mab, the oral proteasome inhibitor ixazomib, and the deacetylase inhibitor panobinostat, are currently being evaluated in clinical trials.

omib and the immunomodulatory agent pomalidomide. Single-agent carfilzomib is recommended as a therapeutic option for patients who have received bortezomib and an immunomodulatory agent, whereas pomalidomide (in combination with dexamethasone) is recommended for patients who have received at least 2 previous therapies, including lenalidomide and bortezomib.10 A robust line of therapies is in development for the treatment of myeloma. Monoclonal antibody therapies, such as elotuzumab and daratumumab, the oral proteasome inhibitor ixazomib, and the deacetylase inhibitor panobinostat, are currently being evaluated in clinical trials. In addition, novel agents acting on the cell cycle, signaling pathway inhibitors, kinase inhibitors, and drugs acting on the unfolded protein response pathway are in the preclinical or clinical stages of development.13 The Burden of MyelomaRelated Complications

The management of cancer remains an important issue for US payers. Driven by the development of new drugs, diagnostics, and surgical techniques, along with the aging and expansion of the population with cancer, the cost of cancer care continues to increase and is expected to reach $174 billion by 2020.14 Of note, end-of-life treatment accounts for a substantial proportion of this cost.15 The cost of myeloma accounts for approximately 9% to 10% Based on current evidence, the of the total cancer care costs, a disproNational Comprehensive Cancer Net­­ portionately high proportion compared work recommends bortezomib and lena- with the incidence and prevalence of lidomide as induction therapy (in combi- myeloma versus other tumor types.8 Skeletal-related complications, such nation with dexamethasone) in patients with newly diagnosed myeloma. In addi- as pathologic fractures (particularly vertion, lenalidomide and bortezomib are tebral), intractable bone pain, hypercallisted as preferred maintenance regimens cemia, and spinal cord compression, are after stem-cell transplant or nontrans- common in patients with myeloma.16 Bone pain, which is often worsened by plant active primary treatment.10 Despite therapeutic advances, the movement, is present in approximately disease will eventually relapse or be­­ 60% of patients at the time of a myelocome refractory to treatment in most ma diagnosis.17 Despite the availability patients with myeloma. In addition, the of supportive therapies, as many as 90% myeloma growth rate, as measured by of patients with myeloma will develop the monoclonal protein doubling time, osteolytic lesions, and approximately increases progressively with each relapse 60% will have a fracture at some point for patients whose disease responds to during the course of their disease.18,19 the initial therapy, and remission dura- Furthermore, the presence of a pathotions become increasingly shorter.11 As logic fracture in patients with myeloa result, patients with myeloma typical- ma is associated with at least a 20% ly require ≥1 additional cycles of treat- increased mortality risk.20 Not only are skeletal-related compliment or new regimens.12 Newer agents approved for later-line­­ cations responsible for significant mortreatment of myeloma include the­ bidity and mortality in patients with epoxyketone proteasome inhibitor carfilz­­ myeloma,16 but they are also an impor­

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tant contributor to myeloma-related healthcare costs, which significantly add to the economic burden of patients with myeloma in the United States.21 In fact, metastatic bone disease in patients with myeloma has been estimated to account for excess direct annual costs of $57,720 per patient.22 Several additional comorbidities are relatively common in patients with relapsed myeloma and add to the cost burden associated with the disease. In one study, the prevalence of anemia at any time during the study was 85%.23 Renal impairment is also relatively common, manifesting in 20% to 40% of patients.24 In self-reported patient data and clinical trials, peripheral neuropathy has been identified as a relatively common and potentially debilitating disease-related complication of relapsed and/or refractory myeloma.25,26 Supportive treatment with bone health agents, growth factors, and other therapies is therefore an important consideration in the treatment of symptomatic myeloma. Accordingly, the International Myeloma Working Group (IMWG) consensus guidelines include the following recommendations for the management of bone disease27: ➤ Consideration of bisphosphonates in all patients with myeloma receiving first-line antimyeloma therapy, regardless of the presence of osteolytic bone lesions on conventional radiography ➤ Intravenous zoledronic acid or pami­ dronate for the prevention of skeletal-­ related events; zoledronic acid is ­­preferred in pa­­tients with newly diagnosed myeloma ➤ Bisphosphonates should be administered intravenously every 3 to 4 weeks during initial therapy, but preventive strategies must be instituted to avoid renal toxicity or osteonecrosis of the jaw ➤ Zoledronic acid or pamidronate should be continued in patients with active disease and should be resumed after disease relapse. Additional nonpharmacotherapeutic options include kyphoplasty for symptomatic vertebral compression fractures, and low-dose radiation therapy for the palliation of uncontrolled pain, impending pathologic fracture, or spinal cord compression.27 Given the prevalence of myeloma-related complications requiring treatment, it is reasonable to infer that these associated conditions are responsible for a substantial proportion of the overall healthcare costs associated with myeloma. One

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Multiple Myeloma retrospective cohort study evaluating healthcare costs for patients receiving the novel agents bortezomib, thalidomide, and lenalidomide supports this hypothesis.28 Teitelbaum and colleagues found that the mean total healthcare costs during 1 year after treatment initiation was $118,353. Of this total, index medications accounted for $42,279 (35.7%) of the mean total cost, whereas ambulatory visits accounted for $35,863 (30.3%) and inpatient hospitalizations accounted for $30,480 (25.8%), with other medical costs, emergency department visits, and retail pharmacy costs accounting for the remainder.28 Of course, not all myeloma-related complications will require incremental healthcare utilization. However, they may affect patient well-being and health-related quality of life (HRQOL). In a Danish study, fatigue, reduced role function, insomnia, and nonspecific pain were all identified as factors that are detrimental to HRQOL.29 Other common symptoms of myeloma that may negatively affect the quality of life of patients include nausea and vomiting, loss of appetite and weight loss, increased vulnerability to infections, increased or decreased urination, increased thirst, and confusion.30 The Case for Combination Therapy in Myeloma

Despite the clinical advances of the past decade, there remains an unmet need for the improved treatment of myeloma, especially in the relapsed or refractory setting. Although patients may achieve remission after treatment with second- or third-line therapy, tumors typically recur more aggressively after each relapse, leading to a decreased duration of response. Over time, some patients will experience treatment-­ refractory disease, which is associated with poorer median survival.26 Evidence of this trend was seen when the IMWG conducted a study to determine the outcome of patients with disease refractory to bortezomib and at least 1 of the immunomodulatory agents. Despite the initial responses of >30% in these patients with relapsed and refractory disease, a median eventfree survival of 5 months and an overall survival (OS) of 9 months highlight the limited durability of these responses and the poor outcomes among patients whose disease no longer responds to existing newer therapies.31 The data show that disease progression and myeloma-related complications impact patient outcomes as well as healthcare spending.26,28,31 Therefore, minimizing the incidence of disease re­­ lapse and maximizing relapse-free in­tervals would be in the best interest of all stakeholders. Patients benefit from longer event-free intervals and longer OS, VOL. 6

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and payers may benefit from averted or delayed myeloma-related complications. Until recently, sequential therapy has been the standard treatment for patients with myeloma. However, evidence from clinical trials provides a compelling case for the use of combined therapies in patients with relapsed myeloma and in those with newly diagnosed myeloma. The use of combination therapies for myeloma, as in many other cancers, is more effective at inducing durable responses than sequential treatment with a single agent. Furthermore, combination therapies can lead to synergistic mechanisms of tumor apoptosis, allowing for improved overall response as well as depth of response compared with single-agent therapy.32 Combination therapies with proteasome inhibitors and immunomodulators have been tested in clinical trials and are currently being used in clinical practice. A triplet regimen consisting of bortezomib, the immunomodulatory agent thalidomide, and high-dose dexamethasone

Evidence from clinical trials provides a compelling case for the use of combined therapies in patients with relapsed myeloma and in those with newly diagnosed myeloma. The use of combination therapies for myeloma...is more effective at inducing durable responses than sequential treatment. was investigated in a phase 3 study.33 Although the regimen showed improved efficacy compared with the doublet of thalidomide and dexamethasone in patients whose disease had relapsed after autologous stem-cell transplantation, the patients who received the 3-drug regimen had a discontinuation rate of 28% as a result of adverse events.33 A triplet combination of bortezomib, lenalidomide, and dexamethasone was investigated in patients with relapsed (including drug-refractory) myeloma, showing an overall response rate of 64% and a median progression-free survival (PFS) of 9.5 months.34 In this study, only 5 (7.8%) of the 64 treated patients had adverse events requiring therapy discontinuation.34 Similarly, carfilzomib has been recently studied in the ASPIRE trial.35 In this study, the addition of carfilzomib to lenalidomide and dexamethasone led to significantly improved outcomes in

patients with relapsed myeloma, with a clinically relevant 31% decrease in the risk for disease progression or death and an increase of 8.7 months (26.3 months in the carfilzomib group vs 17.6 months in the control group; P = .001) in median PFS. Thus far, no other regimens have been associated with an equivalent duration of median PFS in the absence of transplantation.35 These findings reinforce the evidence in support of a triplet regimen composed of a proteasome inhibitor, an immunomodulatory agent, and dexamethasone in patients with relapsed myeloma.34,35 Conclusion

With advances in treatment, the OS of patients with myeloma has improved, and myeloma is evolving into a chronic disease; however, the total costs of myeloma are high in relation to its incidence and prevalence. A substantial proportion of the total costs result from myeloma-related complications. One analysis of inpatient treatment of myeloma-related complications estimated that payer costs were $31,016 for surgery to the bone, $23,347 for pathologic fracture, and $43,691 for spinal cord compression.36 These data underscore the need for an evidence-based approach to the management of patients with myeloma that supports therapeutic options yielding the best possible outcomes and HRQOL while reducing the overall cost to the healthcare system. Although further research is required to close the evidence gaps, there is currently no reason to believe that these objectives are mutually exclusive. n

References

1. Smith A, Howell D, Patmore R, et al. Incidence of haematological malignancy by sub-type: a report from the Haematological Malignancy Research Network. Br J Cancer. 2011;105:1684-1692. 2. Bauer K, Rancea M, Schmidtke B, et al. Thirteenth biannual report of the Cochrane Haematological Malignancies Group—focus on multiple myeloma. J Natl Cancer Inst. 2011;103:E1-E19. 3. Matsumoto T, Abe M. Bone destruction in multiple myeloma. Ann N Y Acad Sci. 2006;1068:319-326. 4. Multiple Myeloma Research Foundation. Definition of multiple myeloma. www.themmrf.org/multiple-­ myeloma/what-is-multiple-myeloma/multiple-myeloma-­ definition/. Accessed January 8, 2015. 5. Leukemia & Lymphoma Society. Facts 2014-2015. www.lls.org/content/nationalcontent/resourcecenter/­ freeeducationmaterials/generalcancer/pdf/facts.pdf. Accessed January 12, 2015. 6. National Cancer Institute. SEER stat fact sheets: myeloma. http://seer.cancer.gov/statfacts/html/mulmy.­ html. Accessed January 12, 2015. 7. American Cancer Society. Survival rates by stage for multiple myeloma. Revised January 23, 2015. www. cancer.org/cancer/multiplemyeloma/detailedguide/ multiple-myeloma-survival-rates. Accessed January 23, 2015. 8. Klein IM, Boccia RV, Cannon E, et al. Evolving strategies for the management of multiple myeloma: a managed care perspective. Am J Manag Care. 2014;20 (2 suppl):S45-S60. 9. Anderson KC, Kyle RA, Rajkumar SV, et al; for the ASH/FDA Panel on Clinical Endpoints in Multiple Myeloma. Clinically relevant end points and new drug approvals for myeloma. Leukemia. 2008;22:231-239. 10. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): multiple myeloma. Version 2.2015. September 30, 2014. www.nccn.org/professionals/physi cian_gls/pdf/myeloma.pdf. Accessed January 18, 2015. 11. National Cancer Institute. Plasma cell neoplasms

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(including multiple myeloma) treatment (PDQ®): refractory multiple myeloma. www.cancer.gov/cancer topics/pdq/treatment/myeloma/healthprofessional/ page10. Accessed January 18, 2015. 12. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med. 2011;364:1046-1060. 13. Ocio EM, Richardson PG, Rajkumar SV, et al. New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG). Leukemia. 2014; 28:525-542. 14. National Cancer Institute. Cancer prevalence and cost of care projections. http://costprojections.cancer. gov. Accessed January 17, 2015. 15. Sullivan R, Peppercorn J, Sikora K, et al. Delivering affordable cancer care in high-income countries. Lancet Oncol. 2011;12:933-980. 16. Berenson JR. Myeloma bone disease. Best Pract Res Clin Haematol. 2005;18:653-672. 17. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78:21-33. 18. Melton LJ III, Kyle RA, Achenbach SJ, et al. Fracture risk with multiple myeloma: a population-based study. J Bone Miner Res. 2005;20:487-493. 19. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-1664. 20. Saad F, Lipton A, Cook R, et al. Pathologic fractures correlate with reduced survival in patients with malignant bone disease. Cancer. 2007;110:1860-1867. 21. Smyth EN, Conti I, Wooldridge J, et al. Frequency, health care resource use (HCRU), and costs associated with skeletal related events (SREs) in US patients with multiple myeloma (MM). Blood. 2013;122. Abstract 2968. 22. Schulman KL, Kohles J. Economic burden of metastatic bone disease in the U.S. Cancer. 2007;109:23342342. 23. Birgegård G, Gascón P, Ludwig H. Evaluation of anaemia in patients with multiple myeloma and lymphoma: findings of the European Cancer Anaemia Survey. Eur J Haematol. 2006;77:378-386. 24. Kleber M, Ihorst G, Terhorst M, et al. Comorbidity as a prognostic variable in multiple myeloma: comparative evaluation of common comorbidity scores and use of a novel MM-comorbidity score. Blood Cancer J. 2011;1:e35. 25. Burnette BL, Dispenzieri A, Kumar S, et al. Treatment trade-offs in myeloma: a survey of consecutive patients about contemporary maintenance strategies. Cancer. 2013;119:4308-4315. 26. Dimopoulos MA, Richardson PG, Moreau P, Anderson KC. Current treatment landscape for relapsed and/or refractory multiple myeloma. Nat Rev Clin Oncol. 2015;12:42-54. 27. Terpos E, Morgan G, Dimopoulos MA, et al. International Myeloma Working Group recommendations for the treatment of multiple myeloma–related bone disease. J Clin Oncol. 2013;31:2347-2357. 28. Teitelbaum A, Ba-Mancini A, Huang H, Henk HJ. Health care costs and resource utilization, including patient burden, associated with novel-agent-based treatment versus other therapies for multiple myeloma: findings using real-world claims data. Oncologist. 2013;18:37-45. 29. Johnsen AT, Tholstrup D, Petersen MA, et al. Health related quality of life in a nationally representative sample of haematological patients. Eur J Haematol. 2009;83:139-148. 30. Multiple Myeloma Research Foundation. Multiple myeloma symptoms. www.themmrf.org/multiple-­ myeloma/symptoms/. Accessed January 8, 2015. 31. Kumar SK, Lee JH, Lahuerta JJ, et al; for the International Myeloma Working Group. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26:149-157. Erratum in: Leukemia. 2012;26:1153. 32. Anderson KC. New insights into therapeutic targets in myeloma. Hematology Am Soc Hematol Educ Program. 2011;2011:184-190. 33. Garderet L, Iacobelli S, Moreau P, et al. Superiority of the triple combination of bortezomib-thalidomide-­ dexamethasone over the dual combination of thalidomide-dexamethasone in patients with multiple my­ eloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005-04 Randomized Phase III Trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2012;30:2475-2482. Errata in: J Clin Oncol. 2012;30:3429; J Clin Oncol. 2014;32:1285. 34. Richardson PG, Xie W, Jagannath S, et al. A phase 2 trial of lenalidomide, bortezomib, and dexamethasone in patients with relapsed and relapsed/refractory myeloma. Blood. 2014;123:1461-1469. 35. Stewart AK, Rajkumar SV, Dimopoulos MA, et al; for the ASPIRE Investigators. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372:142-152. 36. Barlev A, Song X, Ivanov B, et al. Payer costs for inpatient treatment of pathologic fracture, surgery to bone, and spinal cord compression among patients with multiple myeloma or bone metastasis secondary to prostate or breast cancer. J Manag Care Pharm. 2010;16:693-702.

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Multiple Myeloma

Onyx 360 Program Shown to Reduce Patient Distress By Kate Smith San Francisco, CA—Patients with multiple myeloma express a high level of “distress,” which providers and counselors can evaluate and manage, according to a report from the Cancer Support Community (CSC), Washington, DC. At ASH 2014, Victoria Kennedy, LCSW, and colleagues described the Onyx 360 program, which uses a very brief distress screening measure, ad­ministered by telephone, to identify patients with psychosocial distress. The program then provides patient access to psychosocial care and results in a meaningful reduction in distress, Ms Kennedy said. An analysis of distress before and after access to Onyx 360 showed high uptake of support services offered through the program and a significant reduction in patients’ and their caregivers’ level of distress. Distress screening at pivotal points along the disease continuum can identify problems before a crisis event occurs, can allow patients to voice concerns and gain information, and can improve the use of healthcare resources, the investigators noted. “We know that up to 40% of patients experience significant levels of distress, but fewer than 10% actually use psycho-

social supportive services, often because they lack awareness of or access to them,” Ms Kennedy noted. Although distress screening has been promoted by many cancer organizations, surveys show that only 50% of

Unlike standard patient assistance (reimbursement) programs, the goal of Onyx 360 is to deliver integrated biopsycho­ social care with reimburse­­­ ment assistance. patients treated at academic centers, and substantially fewer in nonacademic centers, report being asked about distress, she added. Onyx 360 Program

CSC provides evidence-based support programs for patients and their families. CSC collaborated with Onyx Pharmaceuticals to be part of its integrated patient assistance program, which screens and refers patients and caregivers for psychosocial services. Unlike

standard patient assistance (reimbursement) programs, the goal of Onyx 360 ­­is to deliver integrated biopsychosocial care with reimbursement assistance. Patients who contacted Onyx 360 were asked distress-screening questions by an oncology nurse during an initial phone call, and their answers translated into a distress level rating. Patients were given the opportunity to request support services, including reimbursement and clinical support, transportation assistance, and real-time referrals to key resources. Consenting patients and caregivers were transferred to CSC, whose mental health professionals further assessed them and offered free counseling and resource referral, group support, and treatment decision-making counseling. Patients were then rescreened 30 days after their initial call. Success of the Program

A total of 151 patients were evaluated for changes in their levels of distress between the initial and follow-up calls. Distress levels significantly diminished for the 90% of patients who engaged with the resources and services within Onyx 360, Ms Kennedy reported. “This decrease was greatest in patients

who initially had the highest levels of distress,” she said. During the follow-up call, 82% of patients reported lower levels of distress for at least 1 screening question. For at least 1 question, 56% of patients reported a subsequent level of distress that ­­was at least 3 levels below their initial ­­distress on a scale of 0 to 10. Among patients who had initially reported a high level of distress, the mean stress level was reduced by ­2.6 levels. The study showed that the percentage of patients reporting a high level of distress decreased over time, from 47% to 29% at follow-up. Setting a New Industry Standard

The researchers noted that integrated distress screening, referral, and follow-up represent a new industry standard for patient access programs. It improves psychosocial outcomes and overall satisfaction in patients with advanced myeloma. The researchers hope to learn whether patients who are able to reduce their distress level will be more adherent to treatment, and whether this will increase value to the patient and to the healthcare system. n

Interim ASPIRE Results: Carfilzomib-Based Triplet Yields “Unprecedented” Remission Rates San Francisco, CA—An “unprecedented” duration of remission for patients with relapsed multiple myeloma was achieved with a carfilzomib-based triplet, according to the lead investigator of the ASPIRE trial. At ASH 2014, A. Keith Stewart, MD, of the Mayo Clinic in Scottsdale, AZ, announced that, “By adding carfilz­ omib to the gold standard in multiple myeloma therapy, we are observing an unprecedented duration of remission, without additional toxicity, in relapsed and heavily pretreated patients.” The ASPIRE trial enrolled 792 patients with relapsed or refractory myeloma from 20 countries. Patients had received 1 to 3 previous regimens (average, 2), and were randomized to receive carfilzomib plus lenalidomide and lowdose dexamethasone, or the lenalidomide and dexamethasone doublet alone. Significant Differences Observed

The carfilzomib triplet led to a median progression-free survival (PFS) of 26.3 months compared with 17.6 months in the control arm, a highly significant

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3­ 1% reduction in the risk for PFS events ­­(P <.001), Dr Stewart reported. The objective response rate was also significantly higher for the triplet—87% versus 67% in the control arm, respectively; complete responses were achieved

“Dr Stewart’s study will establish a new standard of care in this patient population.” —Brad Kahl, MD

in 32% versus 9% of patients, respectively, a difference that Dr Stewart considered particularly important. At the time of this interim analysis, the median overall survival (OS) was not reached in either group, but a trend toward longer survival in the carfilzomib arm was observed. At 24 months, the event-free OS rate was 73.3% versus 65.0%, respectively; the median durations of response were 28.6 and 21.2 months, respectively.

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“Despite adding a third drug and being on treatment significantly longer,” Dr Stewart noted, patients tolerated the triplet well and continued to receive treatment. Toxicity was no higher with 3 drugs than with 2, and the quality-of-life scores were better in the carfilzomib arm, ­he reported. Treatment discontinuations resulting from the study drug were similar between the arms, at approximately 16%. The rates of peripheral neuropathy were also the same (17%), “confirming the lack of this toxicity with carfilzomib,” said Dr Stewart. However, hypertension was more common with the addition of carfilzomib—14% versus 7%, respectively. Reassuringly, Dr Stewart added, cardiac and renal events, which have been reported in some previous studies of heavily pretreated patients with myeloma, were only “marginally higher” with 3 drugs and were overall consistent with or were lower than previously reported events. “To some degree, this puts to rest the concerns that have been raised anec-

KEY POINTS ➤ The addition of carfilzomib to lenalidomide plus dexamethasone led to 8.7 months longer progression-free survival ➤ Adding carfilzomib also led to significantly higher objective response and complete response rates ➤ Carfilzomib plus lenalidomide and dexamethasone could become the new standard of care for patients with relapsed myeloma

dotally about carfilzomib,” he said. Based on the findings from the ASPIRE trial, Dr Stewart suggested, “It’s fair to say that carfilzomib/lenalidomide/ dexamethasone could represent a new standard of care in relapsed myeloma.” Press briefing moderator Brad Kahl, MD, of the University of Wisconsin School of Medicine and Public Health, Madison, agreed, stating, “Dr Stewart’s study will establish a new standard of care in this patient population.”—KS n

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REGISTER TODAY JULY 22-25, 2015 THE WESTIN SEATTLE • SEATTLE, WASHINGTON

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Multiple Myeloma

By Kate Smith San Francisco, CA—Monoclonal antibodies may be to multiple myeloma what rituximab has been to lymphoma, according to myeloma experts who expressed enthusiasm over these emerging agents at an education session at ASH 2014. “Monoclonal antibodies present an attractive therapeutic strategy,” said Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston. “Monoclonal antibodies have activity in high-risk disease and represent truly novel mechanisms of action.” “Elotuzumab is the most advanced in development, and is currently in phase 3 testing in both the upfront and relapsed/refractory settings and primarily in combination. Daratumumab and SAR650984 show promise. Numerous other potential targets in the myeloma plasma cells have been identified, and a number of other monoclonal antibodies are in development as well,” Dr Richardson said.

Elotuzumab is the most advanced in development.” —Paul G. Richardson, MD

aging efficacy in a phase 1b/2 study of patients with relapsed or refractory disease. “What was particularly exciting was that we saw a remarkable response rate in this relapsed/refractory population, recognizing that they were lenalidomide-naïve,” said Dr Richardson, who presented the final results from a randomized phase 2 cohort of 73 patients. The overall response rate was 84%. A complete response (CR) or stringent CR was achieved by 14% of patients. The median duration of response was 20.8 months, which is reflected by the long progression-free survival (PFS)— 29 months, and 32.5 months with the highest dose of elotuzumab. Approximately 66% of patients had diarrhea and muscle spasms, and nearly 50% reported constipation, nausea, and upper respiratory tract infection. The

Elotuzumab

Elotuzumab is a humanized immunoglobulin G1 monoclonal antibody that targets the signaling lymphocytic activation molecule F7. The regimen of elotuzumab plus lenalidomide and dexamethasone demonstrated encour-

© American Society of Hematology. All rights reserved.

Monoclonal Antibodies Poised to Be “Blockbusters” in Myeloma

“Anti-CD38 monoclonal antibodies…will be.” —Thomas G. Martin, III, MD

most common grade 3 or 4 adverse events were neutropenia, thrombocytopenia, lymphopenia, and anemia. Infusion reactions occurred in 11% of patients. “It’s important to judge safety in the context of the duration of treatment; patients were on therapy for a number of years,” said Dr Richardson. Anti-CD38 Monoclonal Antibodies

The data were slightly less mature but at least as impressive for the antiCD38 antibodies SAR650984 and daratumumab. “These anti-CD38 monoclonal antibodies, I believe, will be blockbuster drugs and will be an important component to multiple myeloma treatment,” predicted Thomas G. Martin, III, MD, Associate Director, Myeloma Program, University of California, ­San Francisco.

Dr Martin led a study of SAR650984 given in combination with lenalidomide and dexamethasone in 31 heavily pretreated patients with relapsed or refractory disease. The combination produced responses in 58% of patients overall, rising to 63% in the highest-dose cohort. The median PFS was 6.2 months, but it had not been reached in the least pretreated patients. “SAR650984 in combination with lenalidomide and dexamethasone showed encouraging activity in this heavily pretreated population,” without increasing toxicity, Dr Martin said. The other anti-CD38 antibody, daratumumab, was evaluated in combination with standard regimens in the MMY1001 study of 18 patients with newly diagnosed disease and 7 patients with relapsed or refractory disease. Backbone regimens included bortezomib/dexamethasone (VD), bortezomib/ thalidomide/dexamethasone (VTD), bortezomib/melphalan/prednisone (VMP), and pomalidomide/dexamethasone (POM-DEX). For daratumumab combined with VD, VMP, and VTD in the upfront setting in patients with newly diagnosed myeloma, 100% of the patients responded. With POM-DEX, in patients with relapsed or refractory disease, 50% responded and 1 of these patients had a stringent CR, reported Philippe Moreau, MD, of Nantes University Hospital, France. n

Pomalidomide plus Low-Dose Dexamethasone Combination Likely to Be Cost-Effective San Francisco, CA—Pomalidomide plus low-dose dexamethasone is “likely to be a cost-effective use of healthcare resources,” according to researchers from the United Kingdom, who presented a pharmacoeconomic analysis at ASH 2014. Although the incremental cost-effectiveness ratio (ICER) for quality-adjusted life-years (QALYs) gained slightly exceeded $100,000, which is the often-cited willingness-to-pay threshold, Steve Schey, MD, of King’s College London, and colleagues suggested in their poster that “end-of-life drugs that significantly improve survival and health-related quality of life and address unmet needs can be considered to be cost-effective at a higher willingness-to-pay threshold.” The pomalidomide plus low-dose dexamethasone regimen demonstrated a significant overall survival ben-

16

efit versus high-dose dexamethasone in the pivotal phase 3 MM-003 study, when adjusted for crossover (12.7 vs 5.7 months, respectively; P <.001). The investigators explored the cost-­ effectiveness of the pomalidomide/ dexamethasone regimen versus current care from UK and Irish healthcare payer perspectives. Current care included in the economic model consisted of retreatment with bortezomib (intravenous or subcutaneous), bortezomib in combination with lenalidomide, and bendamustine regimens. The costs and outcomes were modeled to estimate the cost per lifeyear and cost per QALY gained over a lifetime horizon (25 years). The efficacy data were obtained from a systemic review of the regimen in patients who had previously been treated with bortezomib and lenalidomide. Three studies relevant to ques-

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tion of pomalidomide/dexamethasone versus current practice were included in the analysis. The economic evaluation included the cost of treatment, administration, monitoring, tests, the management of adverse events, blood

“End-of-life drugs that significantly improve survival and healthrelated quality of life and address unmet needs can be considered to be cost-effective at a higher willingness-to-pay threshold.” —Steve Schey, MD, and colleagues

transfusions, concomitant medication, and terminal care. The medical costs were presented in US dollars. Survival and Quality of Life

The model predicted that patients who receive pomalidomide/dexamethasone live for a mean of 2.2 years compared with 1.2 years with current care; the QALYs were 1.3 versus 0.7, respectively, representing an additional 0.6 QALYs. In the base-case analysis, pomalidomide/dexamethasone was associated with a total incremental cost of $59,250 per patient over a lifetime horizon compared with current care. The model predicted an ICER of $100,920 per QALY compared with current care. The probabilistic ICER obtained through 1000 probabilistic model runs was consistent, at $101,947 per QALY, Dr Schey reported. —KS n

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Weekly Carfilzomib Safe and Effective By Kate Smith San Francisco, CA—The weekly administration of carfilzomib may be equivalent to the current practice of twice-weekly injections, according to an abstract presented at ASH 2014 by Antonio Palumbo, MD, of the University of Turin, Italy, and colleagues. “With weekly injections, treatment becomes more feasible, and we can keep patients on treatment longer. That translates into efficacy,” Dr Palumbo said in an interview. The phase 1/2 study evaluated the safety and efficacy of weekly carfilzomib in elderly patients newly diagnosed with myeloma (median age, 74 years) and determined the maximum tolerated dose for weekly administration of the drug. The rationale for studying weekly carfilzomib came from the observation that the weekly administration of bortezomib has proved safe and efficacious. “We have previously seen that with once-weekly administration of bortezomib, the risk of adverse events, especially peripheral neuropathy, was diminished significantly,” Dr Palumbo said. To evaluate once-weekly carfilzomib, Dr Palumbo and colleagues enrolled 12 patients in a dose-finding phase of the trial and then added 18

patients for phase 2 of the study. The escalating doses started at 45 mg/m2; the maximal planned dose was 70 mg/m2. Carfilzomib was given on days 1, 8, and 15, along with oral cyclophosphamide

“With weekly injections, treatment becomes more feasible, and we can keep patients on treatment longer. That translates into efficacy.” —Antonio Palumbo, MD

and oral dexamethasone. Of the 30 patients in the trial, 21 received the maximum tolerated dose (70 mg/m2) ­of carfilzomib. After the completion of 9 cycles, patients received 28-day maintenance cycles with carfilzomib at the maximum tolerated dose until disease progression or intolerance. The median relative dose intensity was 100% for carfilzomib, 100% for cyclophosphamide, and 96% for dexamethasone. At the time of the analysis, 77% of patients had received at least 4 cycles.

No Increase in Toxicity, High Response Rates

Deep Responses Achieved

Dr Palumbo reported that the “grade 3/4 adverse events were very rare and very low” with once-weekly higher-dose carfilzomib, and they were not increased over what has been observed with twice-weekly dosing. Dose reductions also appeared to be required less frequently (10%) with once-weekly dosing than with twice-weekly dosing (21%). Grade 3/4 hematologic events were observed in 23% of patients in this study compared with 27% in studies of twice-weekly dosing; grade 3/4 nonhematologic events were seen in 30% and 29% of patients, respectively. With once-weekly dosing, grade 3/4 adverse events were primarily grade 3 neutropenia (10%), anemia (10%), and cardiac toxicity (7%), and grade 4 cardiac toxicity (7%) and pulmonary embolism (3%). Grade ≥3 thrombocytopenia, fatigue/fever, gastrointestinal toxicity, infection, and venous thromboembolism occurred in fewer than 5% of patients each. Showing data from a study of twice-weekly carfilzomib (36 mg/m2), he noted that toxicity numbers were “superimposed with ours,” a finding that Dr Palumbo called “reassuring.”

The preliminary response data showed an overall response rate of 86%, with 64% of patients having at least a very good partial response, 41% achieving at least a near-complete response (CR), and 25% achieving a CR, stringent CR, or near-CR. By cycle 9, a very good partial response or better was achieved by 91% of patients receiving weekly carfilzomib compared with 77% of patients receiving the drug twice weekly at 36 mg/m2 in previous studies. A nearCR was reached by cycle 9 in 41% of patients with once-weekly dosing and by 47% of patients on the twice-weekly schedule. The median time to first response (at least a partial response) was 1 month, and the median duration of response was not reached in the study. Dr Palumbo indicated that the response rates will improve over time. “We need at least 6 cycles to maximize response,” he pointed out. “We start seeing stringent CRs at 8 cycles. Some patients improved their response beyond induction, into maintenance. With prolonged treatment, we will increase the percentage of patients with more profound CRs.” n

Novel Oral Proteasome Inhibitor Oprozomib Shows Promise in Myeloma San Francisco, CA—The oral anti­ myeloma proteasome inhibitor oprozomib, given as a single agent in a dose-escalation study, “showed promising antitumor activity,” which included responses even in patients with carfilzomib-refractory multiple myeloma, according to Ravi Vij, MD, of Washington University in St Louis, MO. Oprozomib binds selectively and irreversibly to its target, resulting in sustained cancer-cell inhibition. At ASH 2014, Dr Vij presented data from an ongoing multicenter open-­label phase 1b/2 study of 129 patients with hematologic malignancies, including 87 patients with relapsed and/or refractory multiple myeloma. “The majority of patients had seen bortezomib and carfilzomib, and quite a few were refractory to both these drugs,” he noted. Patients received oprozomib in various schedules and dose levels in 2-week cycles. During the phase 1b of the study, the formulation of oprozomib was changed from powder in a capsule to an extended-­ release tablet; in phase 2, step-up dosing was VOL. 6

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introduced. These amendments appeared to improve the drug’s tolerability. Clinical Benefit of 50%

In the phase 1b cohort of patients receiving 150 to 330 mg daily for 2 of every 7 days (2/7 schedule), the objective response rate was 31.3% and the clinical benefit rate was 50%. In the patients in the phase 1b/2 of the trial who received 150- to 270-mg daily for 5 of 14 days (5/14 schedule), the response rate was 23.3% and the clinical benefit rate was 32.6%. Of note, these response rates were observed before the step-up dosing schedule was initiated. The response data were not presented for the step-up cohorts, because of limited treatment exposure (approximately 7 weeks). Responses were achieved by 18.2% of patients with carfilzomib-­refractory disease, Dr Vij added. The recommended phase 2 dose and schedules were the 2/7 step-up schedule at 240 to 300 mg daily and the 5/14 step-up schedule at 150 to 180 mg daily.

Improved Tolerability

In the cohorts that did not benefit from step-up dosing, the most common grade ≥3 nonhematologic adverse events were diarrhea, nausea, and vomiting. With step-up dosing, these events were uncommon.

“Our preliminary data suggest that step-up dosing is associated with improved tolerability.” —Ravi Vij, MD

In the 240- to 300-mg daily step-up cohorts in phase 2, grade ≥3 nausea and diarrhea were observed in only 10% of patients each. Hematologic toxicities grade ≥3 were limited to anemia (11%) in the 240- to 300-mg daily cohort and neutropenia (10%) in the 150- to ­180-mg daily cohort. Treatment-emergent peripheral neuropathy was rare, occurring in only 6% of patients, with only 1 case of grade 3. FEBRUARY 2015

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Rash was reported in 7% of patients, with no grade ≥3. A total of 3 deaths were reported in the 5/14 dosing cohort before step-up dosing was instituted; 2 from upper gastrointestinal bleeding and 1 from disease progression. “Our preliminary data suggest that step-up dosing is associated with im­­ proved tolerability, with fewer gastrointestinal adverse events observed, and less hematologic toxicity, although the numbers are small,” Dr Vij reported. “With the phase 2 step-up dose of 150-180 mg daily, we have seen no grade 3 gastrointestinal toxicity. There’s also a hint that dose reductions and discontinuations for adverse events are less.” Enrollment in the 2/7 and 5/14 schedules is continuing. The target enrollment for the phase 2 portion of the myeloma cohort is 94 patients. All current and newly enrolled patients are receiving extended-release tablets of oprozomib. Most patients receive premedication with antidiarrheal and antiemetic agents.—KS n

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New Data on Ixazomib Maintenance Support LongTerm Oral Therapy in Patients with Myeloma By Kate Smith Dr Kumar reported. The rate of CRs plus near-CRs increased from 24% after induction to 62%, with 71% being very

ing maintenance therapy at the time of the report. The estimated percentage of patients surviving without progression

“Oral weekly ixazomib may be an ideal maintenance drug in terms of tolerability, safety, and convenience…. Single-agent ixazomib maintenance for up to 1.9 years was feasible, with a generally manageable safety profile, in patients not undergoing autologous stem-cell transplant.”

© American Society of Hematology. All rights reserved.

San Francisco, CA—Data from a phase 1/2 clinical trial support further evaluation of the investigational oral proteasome inhibitor ixazomib in combination with lenalidomide and dexamethasone for the treatment of patients with newly diagnosed multiple myeloma. Approval of this drug would introduce an all-oral treatment regimen for this disease. In a study reported at ASH 2014 by Shaji K. Kumar, MD, of the Mayo Clinic, Rochester, MN, long-term maintenance with ixazomib improved the depth of response after induction in patients with treatment-naïve myeloma. The overall response rate was 90%; complete response (CR) rate was 22% in patients after induction, which increased to 52% by the end of maintenance. Of the 65 patients enrolled, 25 entered the maintenance phase and received a median of 31 total cycles (induction and maintenance) and 19 maintenance cycles. “With maintenance, we saw a deepening of response in 48% of patients,”

—Shaji K. Kumar, MD

good partial responses or better. Ixa­ zomib maintenance contributed to the durable responses, he said. Half of the patients were still receiv-

at 2 years was 57%. Serious adverse events were observed in 4 (19%) patients during maintenance with ixazomib, none of which were considered

to be related to treatment. Ixazomib is the first oral proteasome inhibitor and has physiochemical properties distinct from bortezomib. The triplet of bortezomib, lenalidomide, and dexamethasone has been shown to produce high response rates, and increasing evidence suggests that extended treatment may add benefit to conventional induction strategies. “Agents for continuous therapy, however, need to be convenient and well-tolerated,” Dr Kumar suggested. “Oral weekly ixazomib may be an ideal maintenance drug in terms of tolerability, safety, and convenience.” “Single-agent ixazomib maintenance for up to 1.9 years was feasible, with a generally manageable safety profile, in patients not undergoing autologous stem-cell transplant,” he said. “New-onset toxicity during single-agent ixazomib maintenance was limited.” Phase 3 trials that include patients who are newly diagnosed with myeloma and patients with relapsed myeloma are under way. n

Dissecting the Treatment Costs of Newly Diagnosed Myeloma in First 2 Years San Francisco, CA—In the treatment of patients newly diagnosed with multiple myeloma, medical, nondrug costs, particularly outpatient costs, account for approximately 75% of the total expenditures for the first 2 years after diagnosis, according to a new analysis of a large US claims database presented at ASH 2014. Recent studies have suggested that medical costs, such as hospital admissions, are the main contributors to overall cost during first-line treatment of patients with relapsed or refractory myeloma using novel agents, said X. Henry Hu of Global Health and Patient Outcomes Research, a division of Celgene Corporation. “We need to understand the full range of costs associated with the management of myeloma patients,” said Mr Hu. Mr Hu and colleagues examined the MarketScan database of 6238 patients with newly diagnosed myeloma to analyze the healthcare expenditures for inpatient care, outpatient services, and prescription drugs. Overall, the total healthcare expenditures were $65,607

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per patient annually for the first 2 years after diagnosis. The smallest proportion of costs was attributed to drugs compared with outpatient and inpatient costs during that period. When analyzed by transplantation status, the total annual costs were $182,061 per patient undergoing stemcell transplant versus $50,840 for other patients (Table). “Outpatient costs accounted for the greatest proportion of overall costs for both patient groups,” he said. The distribution of total costs during the first 2 years after diagnosis was fairly

similar for the transplant and nontransplant groups.

“We need to understand the full range of costs associated with the management of myeloma patients….Changes were most marked in the stemcell transplant patients.” —X. Henry Hu

Table Overall Costs in the First 2 Years After Diagnosis Nontransplant, $ (N = 5536)

Received transplant, $ (N = 702)

Inpatient

11,719

61,802

Outpatient

27,438

83,320

Drug

11,683

36,939

Overall

50,840

182,061

Annual cost per patient

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Overall, the healthcare costs de­­ creased for both patient groups during the second year. The decreases were seen in inpatient and outpatient costs; however, drug costs increased in both groups. “Changes were most marked in the stem-cell transplant patients,” Mr Hu noted. “Transplant costs were considerably higher during the first year following diagnosis than in the subsequent year.” In year 2, the transplant group had 63% lower inpatient costs and 50% lower outpatient costs, but the drug costs increased by 28%. For the nontransplant group, the inpatient costs were 46% lower, the outpatient costs were 29% lower, and the drug costs were increased by only 4% in year 2 versus in year 1 after the diagnosis. The investigators concluded that outpatient costs account for most expenditures, and that stem-cell transplant is associated with markedly higher healthcare expenditures, particularly with respect to inpatient costs, particularly in year 1.—KS n

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Emerging Therapies

The Hematology Pipeline Is... escalating doses. Responses were seen in 56% of patients, including 15 complete responses (CRs) and 10 partial responses. Responses were durable, with CRs lasting up to 8 cycles; many patients continue to receive AG-221, reported Eytan M. Stein, MD, of Memorial

Continued from page 1

Olaptesed pegol, a novel L-stereoisomer RNA aptamer that binds and neutralizes CXCL 12/SDF-1, produced an 82% overall response rate (ORR) when combined with bendamustine and rituximab in an open-label study of 28 patients with relapsed or refractory

Sloan Kettering Cancer Center, New York. Dr Stein called the 56% response rate “a very big deal” in this hard-totreat population. The targeting of a specific genotype will increase efficacy, he said, and potentially “extend life spans and minimize toxicity.”

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Over the past decade, significant progress has been made in the management of multiple myeloma, including new standards of care and the development and approval of several novel, effective agents. Despite this progress, more work needs to be done and numerous questions remain regarding the application and interpretation of recent clinical advances. In this sixth annual “Considerations in Multiple Myeloma” newsletter series, we continue to explore unresolved issues related to the management of the disease and new directions in treatment. To ensure an interprofessional perspective, our faculty is comprised of physicians, nurses, and pharmacists from leading cancer institutions, who provide their insight, knowledge, and clinical experience related to the topic at hand. In this second issue, experts from Dana-Farber Cancer Institute answer questions related to the management of patients in the maintenance setting.

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chronic lymphocytic leukemia (CLL). The ORR of bendamustine plus rituximab without olaptesed has historically been 59%. Olaptesed in combination with bendamustine and rituximab was safe and well-tolerated. XmAb5574, a novel humanized immunoglobulin G1 CD19 monoclonal antibody with an engineered Fc region to enhance Fc gamma receptor binding affinity, showed promising preliminary efficacy in high-risk patients with heavily pretreated CLL. Responses were reported in 67% of 16 patients who received XmAb5574. The results with this drug compare favorably with single-agent CD20 antibodies in relapsed CLL. Current studies are investigating XmAb5574 in combination with other agents. Another anti-CD19 antibody agent, MEDI-551, was evaluated in combination with bendamustine versus rituximab and bendamustine in 147 patients with relapsed or refractory CLL in a phase 2 trial that was presented by Douglas E. Gladstone, MD, of the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. The preliminary results showed clinical activity, with comparable safety observed between the MEDI-551 and rituximab arms. The investigators may also have identified a biomarker of response—low baseline levels of a microRNA signature. Pracinostat, an investigational oral histone deacetylase (HDAC) inhibitor, resulted in a rate of 45% for the composite end point of CR and CR with incomplete blood count recovery and morphologic leukemia-free status when combined with azacitadine in a phase 2 trial of 33 patients with AML and intermediate- or unfavorable-risk cytogenetics (see article, page 21). Vosaroxin, a first-in-class anticancer quinolone derivative, in combination with cytarabine improved the median overall survival compared with placebo plus cytarabine (7.5 months vs 6.1 months, respectively) in a phase 3 study of patients with relapsed or refractory AML. CTL019, a chimeric antigen receptor targeting CD19, achieved durable remission in children with relapsed or refractory acute lymphocytic leukemia who were given T-cells engineered with CTL019 (see article, page 22). In patients with MDS, rigosertib did not meet the primary end point in the phase 3 ONTIME trial; however, it did improve survival in several subgroups, including patients whose disease progressed with or failed to respond to previous treatment with hypomethylating agents, patients at very high risk, and patients with certain karyotypic abnorContinued on page 20

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The Hematology Pipeline Is... malities. “Patients in these subgroups have a very poor prognosis, and currently there is no approved drug available to treat their disease, once they have failed hypomethylating agents,” said Guiller­­mo Garcia-Manero, MD, of M.D. Anderson Cancer Center, Houston. Dr Garcia-Manero also presented findings for SGI-110, a novel subcutaneous hypomethylating agent, in 102 patients with MDS and chronic myelo­ monocytic leukemia (CMML). CRs plus minor CRs were reported in 19% to 22% of patients, depending on the dose used. Transfusion independence for ≥8 weeks was reported in approximately 33% of patients in total, and in 50% of the treatment-naïve patients. The investigators noted that SGI-110 was well-tolerated and showed biological and clinical activity in intermediate- and high-risk patients with MDS and CMML. SGI-110 has “particularly promising activity” in patients who previously received azacitidine or decitabine, the researchers noted. Sotatercept (ACE-011), a first-inclass activin type-2A receptor fusion protein, may have a role in patients with MDS and anemia, especially when their disease does not respond to erythropoiesis-stimulating agents. In a phase 2 study from the Moffitt Cancer Center, 45% of 54 patients receiving intravenous sotatercept demonstrated a reduced need for transfusion or an increase in hemoglobin level. Non-Hodgkin Lymphoma

Polatuzumab vedotin and pinatuzumab vedotin, 2 antibody-drug conjugates, showed activity and tolerability in a phase 2 randomized trial of patients with relapsed or refractory non-Hodg­kin lymphoma (NHL). In the ROMULUS trial, patients received polatuzumab or pinatuzumab, plus rituximab. Both regimens were generally well-tolerated, with similar toxicity profiles. Neutropenia, peripheral neuropathy, and diarrhea were the principal toxicities. In patients with diffuse large B-cell lymphoma (DLBCL), the ORRs were 56% with polatuzumab and 57% with pinatuzumab (plus rituximab), and the CRs were 15% and 24%, respectively. In follicular lymphoma, the ORRs were 70% and 62%, and the CRs were 40% and 10%, respectively. The higher CR rate with polatuzumab plus rituximab compared with pinatuzumab plus rituximab suggests that polatuzumab may have greater clinical activity in this patient population. Combination studies of polatuzumab plus rituximab with chemotherapy and with antibody-­ drug conjugate schedules to reduce peripheral neuropathy are ongoing or in planning.

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MOR00208, an Fc-engineered hu­­­ manized anti-CD19 antibody, was evaluated as a single agent in a phase 2a study of patients with relapsed or refractory B-cell NHL. Among the first 51 patients in the trial, the response rate was 24%. The drug was well-tolerated, without significant toxicity from the infusion. Accrual to the study i­s continuing. Alisertib (MLN8237), an oral Aurora A kinase inhibitor, was investigated alone and in combination with rituximab in a phase 2 study of 11 patients with high-risk relapsed or refractory B-cell NHL. Alisertib was well-tolerated, wi th 1 patient responding and able to proceed to transplant. Enrollment ­­is continuing.

Nivolumab and pembrolizumab, the 2 most recently approved programmed-cell death receptor (PD)-1 inhibitors approved for patients with melanoma, showed exciting findings in patients with classic Hodgkin lymphoma. Copanlisib, a novel PI3K inhibitor, was explored in 33 patients with indolent NHL or with CLL. The ORR in both patient populations was 44%; when divided by disease state, the ORR was 48% in patients with NHL and 38% in patients with CLL. The combined median duration of response was 390 days, and the median progression-free survival was 288 days. Grade ≥3 events included hypertension (48%), neutropenia (33%), hyperglycemia (30%), anemia (15%), and thrombocytopenia (15%). The investigators noted that copanlisib is active as a single agent in heavily pretreated patients with advanced refractory or relapsed follicular NHL, marginal zone lymphoma, small lymphocytic lymphoma, and CLL, and its toxicity level is acceptable. Based on these results, a phase 2b study in patients with relapsed or refractory indolent NHL has been initiated. DLBCL is a particularly aggressive subtype of NHL, and novel treatments are clearly needed. A number of novel agents were presented at ASH 2014, but their efficacy was modest. Buparli­ sib (BKM120), an oral pan-class I PI3K inhibitor, was active among 64 patients with relapsed or refractory DLBCL NHL in a phase 2 study presented by Anas Younes, MD, of Memorial Sloan Ket-

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FEBRUARY 2015

Continued from page 19

tering Cancer Center. Tumor reduction was observed in 67% of heavily pretreated patients; durable CRs were seen in 31% and 88% of the DLBCL and follicular lymphoma subsets, respectively; however, the primary objective of ORR was not met in either cohort. The investigators indicated that “targeting all 4 PI3K isoforms in DLBCL is a viable strategy and worthy of further exploration in patients with NHL.” Barasertib, a potent Aurora B kinase inhibitor, showed promising results in a phase 2 trial of patients with relapsed or refractory DLBCL. In 15 patients, the response rate was 20%, and 33% attained stable disease. The median PFS was 60 days. The study provided proof of concept that Aurora B kinase is a valid target in DLBCL. Mogamulizumab, a humanized mono­­ clonal antibody targeting the CC chemokine receptor 4 (CCR4), achieved stable disease or better in 46% of patients (11% responses) with peripheral T-cell lymphoma, with an acceptable safety profile, in a multicenter phase 2 study of heavily pretreated relapsed or refractory patients. The CCR4 is expressed on 30% to 65% of tumor cells in patients with peripheral T-cell lymphoma, whose prognosis is generally poor. Mogamulizumab binds to CCR4. The drug is already approved outside of the United States for this patient population.

tumor reduction. The median response duration was approximately 6 months. MK2206 was well-tolerated; rash was the main toxicity. Multiple Myeloma

Monoclonal antibodies may be poised to be the “rituximab of myeloma,” experts predicted at ASH 2014. Elotuzumab (which received breakthrough therapy designation for myeloma in May 2014), in combination with lenalidomide and dexamethasone, induced an 84% ORR in a phase 1b/2 study of patients with relapsed or refractory myeloma (see article, page 16). The data were less mature but were at least as impressive for the 2 antiCD38 antibodies, SAR650984 and daratumumab. SAR650984 yielded a 63% response rate in optimally treated patients with myeloma. Daratumumab (which received a breakthrough therapy designation for myeloma in 2013) showed impressive results in combination with standard regimens, yielding a 100% response rate in some cohorts (see article, page 16). Ricolinostat (ACY-1215), a selective oral HDAC6 inhibitor, is in early-stage studies but is of particular interest to myeloma specialists. In a phase 1b study of 42 patients with relapsed or refractory myeloma, ricolinostat, in combination with bortezomib and dexamethasone, was well-tolerated, with diarrhea Hodgkin Lymphoma as the only dose-related side effect. Nivolumab and pembrolizumab, the The response rate was 44%, and only 2 most recently approved programmed-­ 3 patients showed progressive disease. cell death receptor (PD)-1 inhibitors Responses were seen even in bortezoapproved for patients with melanoma, mib-refractory patients. showed exciting findings in patients with Panobinostat, another HDAC inhibclassic Hodgkin lymphoma. Although itor, is in phase 3 development. Jatin the results for these 2 PD-1 inhibitors Shah, MD, of M.D. Anderson Cancer came from small, phase 1 studies in Center, presented data for panobinospatients with Hodgkin lymphoma, they tat in combination with bortezomib, earned spots at press conferences at the lenalidomide, and dexamethasone in 31 meeting and drew large attendance at newly diagnosed patients with myeloASH 2014 sessions. In this patient popu- ma. He reported an ORR of 95%, lation, the ORR was 87% for nivolumab including 50% CRs or near-CRs. Dr and 66% for pembrolizumab in patients Shah pronounced the regimen “very with disease progression with standard well-tolerated,” with limited grade 3 therapies (see article, page 25). or 4 toxicity. Panobin­ ostat was also MK2206, an oral AKT inhibitor, combined with carfilz­omib in a phase 1 induced response in patients with classic study of 28 heavily pretreated patients Hodgkin lymphoma and indolent lym- with relapsed or refractory myeloma. phoma; however, its single-agent activ- Jonathan L. Kaufman, MD, of Emory ity was low in patients with DLBCL, University, reported an ORR of 46% T-cell lymphoma, or mantle-cell lym- (44% in patients refractory to bortezophoma in a phase 2 study of 50 patients mib) and no unexpected toxicities. The with refractory disease. MK2206 is median PFS was 11.4 months. the first oral non-ATP competitive Ixazomib and oprozomib, 2 novel allosteric inhibitor of the AKT path- oral proteasome inhibitors, have way 1, 2, and 3 that is currently in clin- shown promising results in myeloma. ical development. Objective responses Long-term data were presented for were observed in 14% of patients (20% ixazomib; oprozomib is in earlier-stage among patients with Hodgkin lympho- development (see articles, page 17 and ma), and 40% of patients showed some page 18). n

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Pracinostat-Azacitidine Combination Generates Responses in Older Adults with Acute Myeloid Leukemia By Wayne Kuznar San Francisco, CA—Nearly 50% of elderly patients with newly diagnosed acute myeloid leukemia (AML) who received pracinostat, an investigational HDAC (histone deacetylase) inhibitor, in combination with azacitidine had responses in an ongoing phase 2 clinical trial. Furthermore, “no patient who achieved a clinical response has progressed,” according to lead investigator Guillermo Garcia-Manero, MD, Chief, Section of Myelodysplastic Syndromes, Department of Leukemia, M.D. Anderson Cancer Center, Houston, and colleagues. Previously, pracinostat demonstrated clinical evidence of single-agent activity in patients with AML and myelofibrosis. In a phase 1 dose-escalation study of 14 evaluable patients with AML, 2 patients achieved a complete response (CR)—1 lasting more than 206 days and 1 lasting more than 362 days.

Study Details

The interim phase 2 data presented at ASH 2014 come from the ongoing MEI-004 trial investigating the effectiveness and safety of the pracinostat and azacitidine combination in treatment-naïve older patients with AML.

“No patient who achieved a clinical response has progressed….Most clinical responses occur within the first 2 cycles and continue to improve with ongoing therapy.” —Guillermo Garcia-Manero, MD, and colleagues

The study is enrolling patients aged ≥65 years with newly diagnosed de novo (N = 29), secondary disease (N = 12) or

treatment-related AML with intermediate- or unfavorable-risk cytogenetics and ≥20% bone marrow blasts. Overall, 80% of the patients had an ECOG performance status of 0 to 1; the remaining 20% had an ECOG status of 2. Patients received pracinostat 60 mg orally 3 days weekly for 21 days of a 28-day cycle. Azacitidine was given subcutaneously or intravenously on days 1 to 7, or days 1 to 5 and 8 and 9 (based on site determinations) of each 28-day cycle. The main end point is CR and full response with incomplete blood count recovery, along with morphologic leukemia-free state. At study evaluation, 41 patients were registered at 15 centers; enrollment has been continuing since the end of 2013, and 25 patients are still active in the study. Reasons for study discontinuation included progressive disease (N = 6), adverse events (N = 6), or other (N = 4). Interim efficacy data in 33 patients

show that 45% achieved the primary end point. “Most clinical responses occur within the first 2 cycles and continue to improve with ongoing therapy,” according to the researchers. “The observed response rate may increase with longer follow-up of patients achieving partial response or stable disease.” In addition, 3 patients had a partial response or a partial response with incomplete blood count recovery, and 4 had stable disease; 4 patients had no clinical benefit. The most common treatment-emergent adverse events were neutropenia, febrile neutropenia, thrombocytopenia, nausea, anemia, and fatigue. Adverse events resulting in dose reductions were uncommon. Six patients have received pracinostat beyond 230 days, which attests to its long-term tolerability. These data support definitive development of pracinostat in combination with azacitidine as treatment for older patients with AML. n

Sorafenib Prolongs Event- and Relapse-Free Survival in Acute Myeloid Leukemia

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Sorafenib is a multikinase inhibitor with activity against several oncogenic kinases that may play a role in AML. The drug is approved for the treatment of several types of solid tumors, including thyroid, liver, and kidney cancer. In this study, patients aged 18 to 60 years with newly diagnosed AML

© American Society of Hematology. All rights reserved.

San Francisco, CA—Sorafenib added to standard therapy significantly im­­ proves event-free survival (EFS) and relapse-free survival compared with standard chemotherapy alone in younger patients with newly diagnosed acute myeloid leukemia (AML). In a phase 2 clinical trial of 267 patients with AML aged ≤60 years, sorafenib extended median EFS by 20.5 months versus 9.2 months with placebo, but it did not improve overall survival (OS), reported Christoph Röllig, MD, MSc, Universitätsklinikum Dresden, Germany, at ASH 2014. “These data constitute the first randomized evidence that kinase inhibitors work in AML,” Dr Röllig said. “Based on these results, we cannot call sorafenib a standard treatment for AML yet. It would be nice to have a second confirmatory trial, and we would like to see what happens to overall survival after a longer period of follow-up.” Nevertheless, the improvement in EFS is clinically meaningful, he said.

received daunorubicin 60 mg/m2 on days 3 to 5 plus cytarabine 100 mg/ m2 continuous intravenous infusion on days 1 to 7 for 2 cycles, followed by cytarabine 3 g/m2 twice daily on days 1, 3, and 5 for 3 cycles. Nonresponders

received second induction with cytarabine plus mitoxantrone. Allogeneic stem-cell transplant was scheduled for intermediate- or high-risk patients. Patients were randomized to sorafenib 800 mg daily or to placebo in addition to standard chemotherapy on days 10 to 19 of induction, from day 8 of each

“These data constitute the first randomized evidence that kinase inhibitors work in AML.” —Christoph Röllig, MD, MSc

consolidation until 3 days before the start of the next consolidation, and as maintenance for 12 months after consolidation. Complete response was 59% in the placebo arm versus 60% in the sorafenib FEBRUARY 2015

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arm (P = .764). With a median follow-up of 3 years, the median EFS was 20.5 months with sorafenib and 9.2 months with placebo; the 3-year EFS rate was 40% versus 22%, respectively (P = .013). The median relapse-free survival was 23 months in the placebo arm but has not yet been reached in the sorafenib arm, corresponding to a 3-year relapsefree survival of 38% with placebo versus 56% for sorafenib (P = .017). The median OS had not yet been reached for either arm, but the 3-year OS rates are 56% and 63% for placebo and sorafenib, respectively. Toxicity was much more likely with sorafenib compared with placebo. Hazard ratios with sorafenib were 3.61 for bleeding, 3.84 for rash, 3.36 for liver toxicity, and 3.53 for fever. Hand-foot syndrome occurred only in the sorafenib arm. The most common reported grade ≥3 adverse events were fever (40%), infections (22%), and bleeding events (2%).—WK n

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Leukemia

CAR-T Achieves High Rate of Remission in Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia By Wayne Kuznar It also allows activation of the T-cell, which causes significant proliferation. More than 130 patients at the University of Pennsylvania and the Children’s Hospital of Philadelphia, encompassing ALL, chronic lymphocytic

CR was achieved in 36 (92%) patients 28 days after T-cell infusion. There have been 10 relapses, 50% related to disappearance of the engineered T-cells (ie, CD19-positive relapse) and 50% related to antigen escape

“About two thirds of the patients retain their T-cells for 6 months or longer. It’s a key point in terms of maintaining remission in these patients.”

© American Society of Hematology. All rights reserved.

San Francisco, CA—Administration of T-cells engineered with a chimeric antigen receptor (CAR) targeting CD19 (CTL019) persist over the long-term and induce durable remissions in children with relapsed or refractory acute lymphoblastic leukemia (ALL). In this phase 1/2 study, 92% of patients achieved complete responses (CRs) with CTL019, reported Stephan A. Grupp, MD, PhD, Director of Translational Research, Center for Childhood Cancer Research, the Children’s Hospital of Philadelphia, at ASH 2014. In July 2014, CTL019 received breakthrough therapy designation from the US Food and Drug Administration as a treatment for pediatric and adult patients with relapsed or refractory ALL. The CAR process uses genetically modified T-cells to target cancer, explained Dr Grupp. This genetic modification allows the expression of a CAR protein on the surface of the T-cell. The T-cell receptor gains this new recognition capability through the CAR protein, which allows interaction with the cancer cell, with the intent of killing it.

—Stephan A. Grupp, MD, PhD

leukemia, and non-Hodgkin lymphoma, have been treated with CTL019. Dr Grupp’s report focused on 39 pediatric patients with relapsed, treatment-resistant ALL, who received CTL019 at a median of 3.6 × 106 cells/kg during 1 to 3 days. One week before CTL019 treatment, 87% of patients received lymphodepleting chemotherapy.

(ie, CD19-negative relapse). Of the patients who relapsed with CD19-positive disease after achieving CR, 40% had disease refractory to previous treatment with blinatumomab. The median follow-up has been 6 months, but 15 patients have been followed for ≥1 year, with the longest being 31 months. Only 3 patients

have subsequently undergone stemcell transplant. Response seems to be independent of the disease burden. In patients with >50% bone marrow blasts by minimal residual disease, the overall response rate was 82%, similar to the response rate of 88% in patients with >5% blasts. The significant risk of treatment is a cytokine-release syndrome, which is higher in patients with high disease burden, although all patients have some degree of cytokine-release syndrome at peak T-cell expansion. “Patients who have <50% bone marrow blasts essentially do not have significant degrees of cytokine-release syndrome,” Dr Grupp noted. “About two thirds of the patients retain their T-cells for 6 months or longer,” Dr Grupp said. “It’s a key point in terms of maintaining remission in these patients.” The duration of response has been favorable: 76% of the patients remain in remission if they reach 6-months remission. The event-free survival rate at 6 months is 70%, and the overall survival rate is 75%. n

Pediatric Regimen a New Standard for Adolescents and Young Adults with Acute Lymphoblastic Leukemia By Alice Goodman San Francisco, CA—Early results of the large, prospective Intergroup C10403 trial demonstrate that a high-intensity pediatric-inspired regimen improves event-free survival (EFS) and overall survival (OS) in adolescent and young adults with acute lymphoblastic leukemia (ALL). Many smaller studies have shown that adolescent and young adults have improved outcomes on pediatric regimens, but this is the first large data set to validate this practice. The 2-year EFS was 66% and the 2-year OS was 79%. “These results are a major improvement compared with 34% and 39%, respectively, in historical controls. This is a clear opportunity to improve care in adolescent and young adults with ALL,” said lead investigator Wendy Stock, MD, University of Chicago Medical Center, Chicago, IL. The study showed that the presence of a BCR-Abl1–like signature and aberrant CRLF2 expression were associated

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with worse EFS and OS rates and are considered factors for increased risk in this patient population. Patients without these clinical features had excellent EFS and OS, Dr Stock told listeners at ASH 2014.

“These results are a major improvement compared with 34% and 39%, respectively, in historical controls. This is a clear opportunity to improve care in adolescent and young adults with ALL.” —Wendy Stock, MD

The Intergroup C10403 trial was undertaken by cooperative groups in North America to evaluate treatment with a pediatric intensive regimen

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delivered by hematologists/oncologists treating adult patients. Dr Stock presented the main results of the trial. Additional analysis of adherence and outcomes based on psychosocial factors will be presented in the future. A total of 296 adolescent and young adults (median age, 25 years) with ALL were treated between 2007 and 2013. Overall, 75% of the patients had B-precursor ALL and 24% had T-precursor ALL. In addition, 31% of the patients were obese, with body mass index >30 kg/m2, and 7% were morbidly obese. The backbone of the pediatric-­ inspired regimen included intensified glucocorticoid, vincristine, and asparaginase and more maintenance therapy. The regimen included induction, consolidation, interim maintenance, delayed intensification, and prolonged maintenance (2 years for girls and 3 years for boys). The EFS rate was similar among

the treatment groups, regardless of the age-group or a precursor B- or T-­ lineage. The OS was significantly worse in the obese patients, and significantly improved in patients with undetectable minimal residual disease. Dr Stock and colleagues will propose a successor US Intergroup trial that should begin in 2015. The plans include the use of the molecular signature of the disease to stratify patients and to add a novel antibody or a targeted kinase inhibitor to eradicate any minimal residual disease and improve outcomes. “This is a phenomenal achievement,” said Yoav Messinger, MD, Pediatric Oncologist at Children’s Hospital and Clinics of Minnesota, Minneapolis, chair of the session where these data were presented. “We have been waiting for a long time for these data, which put what we already know into a formalized protocol on a large-scale basis.” n

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Psychological Distress and Financial Burden Impact Adherence to CML... Continued from page 1

Vice President of Research and Training at the Cancer Support Community, presented results from a patient survey of patients with CML at ASH 2014, indicating that the treatment of CML imposes a significant economic burden on patients and increases psychosocial distress, which together lead to reduced adherence to treatment. The survey data “suggest that psychosocial distress and financial burden may have a greater impact on treatment adherence than financial burden alone,” said Dr Buzaglo. Several other studies have reported that the financial burden associated with CML treatment is negatively affecting treatment adherence. Studies have reported significant decreases in 5-year event-free survival with poor adherence to TKIs, and poor adherence occurs more frequently than physicians recognize. Patient-Reported Outcomes

The Cancer Support Community, in partnership with the Leukemia & Lymphoma Society, registered 484 patients living with CML to the Cancer Experience Registry. Of the registrants, 81% (N = 393) responded to this survey that included questions about the financial burden of CML and cancer-related distress.

Stress and anxiety over managing the financial impact of CML was measured with the Impact of Event Scale, and 15 items from a validated distress

• 10% skipped dosages of their CML medication. In total, 31% of the patients were defined as having poor drug adherence.

The survey data “suggest that psychosocial distress and financial burden may have a greater impact on treatment adherence than financial burden alone.” —Joanne S. Buzaglo, PhD, and colleagues

screener were calculated to create a score for overall distress; of this, 4 items were summed to indicate risk for depression. The analysis included 327 US-based patients with a median age of 59 years. The annual income of patients surveyed was <$40,000 in 32% of patients; $40,000 to $79,000 in 31% of patients; and ≥$80,000 in 37% of patients. Impact of Cost of Care on Medication Adherence

• 19% of patients reported missing a dose of oral medication for their CML at least once monthly • 14% reported postponing prescription

Nearly 50% of the patients reported out-of-pocket (OOP) costs of ≥$100 related to CML monthly, 27% spent ≥$250, 15% spent ≥$500, and 5% spent ≥$1000. Moreover, 38% said they had to use copay assistance because of the medical costs of CML treatment, 35% had to cut grocery expenses, 33% depleted their savings, 30% used pharmaceutical assistance programs, 18% sold personal property, 17% asked their healthcare provider for a less expensive treatment, 13% had liquidated their assets, 6% went into bankruptcy, and 4% foreclosed on their homes.

Psychological Distress

To reduce the costs associated with CML, 23% of patients postponed seeking psychological support, 17% delayed follow-up on recommendations for complementary treatment (ie, physical therapy), 16% postponed doctors’ appointments, and 12% postponed follow-up screening and/or blood work. Approximately 45% of patients were at risk for depression and 37% reported clinically high levels of stress-related intrusive ideation about the financial cost of cancer. Greater OOP costs were associated with higher overall distress (P <.001) and increased risk for depression (P <.001), adjusting for income. Among those at risk for depression, financial burden increased the odds of poorer drug adherence by more than 7-fold. Among those not at risk for depression, financial burden had a modest impact on drug adherence (odds ratio, 1.3; P = .60). “Implications for future research and practice so that patients fully benefit from CML therapy include the development and evaluation of interventions that enhance patient–clinician communications, psychosocial distress screening and referral, and financial counseling and assistance,” concluded Dr Buzaglo. n

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Lymphoma

Posttransplant Brentuximab: New Standard in Hodgkin Lymphoma? By Phoebe Starr San Francisco, CA—Early posttransplant consolidation with brentuximab vedotin (Adcetris) significantly improved progression-free survival (PFS) compared with placebo in patients with Hodgkin lymphoma who are at risk for disease progression in the placebo-controlled phase 3 AETHERA trial. AETHERA is the first placebo-­ controlled trial to compare brentuximab and placebo in patients with Hodgkin lymphoma after transplant. The results of the study were presented at the 2014 American Society of Hematology annual meeting. The median PFS was 43 months for the group receiving brentuximab versus 24 months for the group receiving placebo (P = .001), representing a 43% reduction in the risk for disease progression. The 2-year PFS rates were 65% and 45%, respectively, for the cohorts. “In my opinion, once this study is published, brentuximab should be the standard of care for patients with risk factors for disease progression,” namely, with remission duration <1 year, extranodal

disease, B symptoms, 2 or more previous salvage therapies, and primary refractory disease, stated lead investigator Craig H. Moskowitz, MD, Clinical Director, Division of Hematologic Oncology, Memorial Sloan Kettering Cancer Center, New York. Dr Moskowitz called the 20% difference in 2-year PFS “unprecedented” in any lymphoma. Autologous stem-cell transplant (ASCT) cures approximately 50% of patients with relapsed or refractory Hodgkin lymphoma. The other 50% will relapse after transplant. Before this study, no investigational regimen had improved posttransplant outcomes. Brentuximab is an antibody-drug conjugate directed to CD30, which is typically expressed in classic Hodg­kin lymphoma cells. Although brentuximab has been approved by the FDA for the treatment of relapsed or refractory Hodgkin lymphoma and for systemic anaplastic large-cell lymphoma, it is not approved for posttransplant consolidation.

“Once this study is published, brentuximab should be the standard of care for patients with risk factors for disease progression.” The 20% difference in 2-year PFS is “unprecedented” in any lymphoma. —Craig H. Moskowitz, MD Study Details

The international multicenter trial enrolled 329 patients with Hodgkin lymphoma who had at least 1 risk factor for relapse. Approximately 50% of the patients had ≥3 risk factors for disease progression at baseline. After ASCT, patients were randomized to 16 cycles of treatment with brentuximab or placebo. Of patients in the place-

bo group who progressed, 85% were crossed over to brentuximab. Brentuximab achieved superior PFS in all prespecified subgroups, including primary refractory patients who relapsed within 12 months of frontline therapy and patients who relapsed after 12 months with extranodal disease. The overall survival (OS) was no different between the 2 treatment arms in the interim analysis at 2 years, which could be attributed to the high percentage of patients receiving placebo who crossed over to the active treatment arm. The final OS analysis will be presented in 2016. The most common adverse events in the brentuximab arm included peripheral sensory neuropathy (56%), neutropenia (35%), upper respiratory tract infection (26%), fatigue (24%), and peripheral motor neuropathy (23%). Dose reductions of brentuximab effectively alleviated peripheral neuropathy in the majority of patients. n

Stem-Cell Transplant Safe in HIV-Related Lymphoma

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Alvarnas, MD, Director of Medical Quality at City of Hope, Duarte, CA. © American Society of Hematology. All rights reserved.

San Francisco, CA—Patients with HIV-­related lymphoma should not be excluded from clinical trials of autol­ ogous hematopoietic-cell transplant (AHCT). Moreover, they should be offered AHCT as a standard treatment option, according to the results of a phase 2 trial reported at the 2014 American Society of Hematology meeting. The concern has been that immunocompromised patients, such as those with HIV infection, are at greater risk for serious infections. Thus, they are typically not considered candidates for AHCT, which is a curative therapy for lymphoma. Despite effective antiretroviral therapy, HIV infection (AIDS) persists as a risk factor for lymphoma. “Chemotherapy-sensitive patients with relapsed/refractory HIV-related lymphoma may successfully undergo AHCT with favorable outcomes. Our study shows that exclusion from clinical trials on the basis of HIV infection alone is no longer justified. In fact, in clinical practice, patients with controlled HIV infection—with emphasis on the word ‘controlled’—should be receiving transplants as standard of care,” said lead study investigator Joseph

Single-Arm Clinical Trial

“Exclusion from clinical trials on the basis of HIV infection alone is no longer justified….Payers should also recognize that this treatment [AHCT] should now be the standard of care for these patients.” —Joseph Alvarnas, MD

“These results are an important advancement for patients and their

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physicians seeking access to effective treatments. Payers should also recognize that this treatment should now be the standard of care for these patients,” Dr Alvarnas stated.

FEBRUARY 2015

The single-arm, multi-institutional trial was conducted jointly by the Blood and Marrow Transplant Clinical Trials Network and the AIDS Malignancy Clinical Trials Consortium. The results should be generalizable to a broader spectrum of centers, because the 16 transplant centers included in the study do not specialize in the treatment of HIV and AIDS. The single-arm study showed that AHCT achieved an estimated 1-year overall survival rate of 86.6% and a progression-free survival rate of 82.3% in patients with HIV-related lymphoma. The estimated rate of disease progression at 1 year was 12.5% and the estimated mortality rate was 5%. The study included 40 HIV-infected patients with lymphoma who had at least 1 risk factor for disease progression; approximately 50% had ≥3 risk factors for disease progression. Patients underwent AHCT with a modified

KEY POINTS ➤ For chemotherapy-sensitive patients with relapsed/ refractory HIV-related lymphoma, AHCT should now be the standard of care ➤ Excluding patients from clinical trials on the basis of HIV infection is no longer justified ➤ AHCT resulted in an estimated 1-year OS rate of 86.6% and PFS of 82.3% in these patients

BEAM (carmustine, etoposide [Toposar], cytarabine [Depocyt], melphalan [Alkeran]) regimen. Patients did not receive antiretro­ viral therapy during the preparative regimen; that therapy was resumed after the resolution of gastrointestinal toxicities. All patients received standard institutional supportive care after transplant. At a press conference, Dr Alvarnas noted that a case-control study of 151 matched patients with lymphoma who did not have HIV infection showed similar mortality outcomes to the patients in the present study.—PS n

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patients who had exhausted other treatment options, providing solid evidence that targeting the immune system can be effective in hematologic malignancies, similar to solid tumors. The data were presented at the 2014 American Society of Hematology meeting. “Strategies that target tumor cells using the immune system are extremely exciting,” said Catherine M. Bollard, MBChB, MD, Blood and Marrow Transplant Specialist, Children’s National Health System, and Professor of Microbiology, Immunology, and Tropical Medicine, George Washington University, Washington, DC. “I see this as a way forward in how we will revolutionize treatments in hematology.” Nivolumab

Nivolumab was tested in 23 patients with Hodgkin lymphoma, 87% of whom had received previous treatment with at least 3 regimens, including stem-cell transplant and brentuximab vedotin (Adcetris). In all, 35% of the patients had received at least 6 previous regimens. All tumors had genetic abnormalities involving 9p24.1, leading to overexpression of the PD-1 ligands. Nivolumab 3 mg/kg was administered every 2 weeks until disease progression or severe toxicity. “Treatment resulted in a response rate of 87%, which is quite high for patients who were heavily pretreated,” said lead investigator Philippe Armand, MD, PhD, Senior Physician,

© American Society of Hematology. All rights reserved.

Immunotherapy with PD-1 Inhibitors the Newest...

“Treatment [with nivolumab] resulted in a response rate of 87%, which is quite high for patients who were heavily pretreated.” —Philippe Armand, MD, PhD

data assessment, 48% of the responses were ongoing, and 43% of patients were still receiving treatment. Some patients have been in remission for >1 year, said Dr Armand. The safety profile of nivolumab mirrored that in solid tumors. Overall, 22% of patients had grade 3 drug-related adverse events (AEs); no deaths or drug-related grade 4 AEs were reported. Two patients discontinued treatment as a result of AEs. “There was no apparent increase in lung toxicity, which we worry about, because many patients had other treatments that can cause lung injury,” Dr Armand said. In May of this year, the FDA granted nivo­lumab a breakthrough therapy designation for relapsed Hodgkin lymphoma. Pembrolizumab

Pembrolizumab was evaluated in 29 heavily pretreated patients with Hematologic Malignancies, Dana-­ classic Hodgkin lymphoma who had progressed after treatment with brenFarber Cancer Institute, Boston. Responses were seen in 100% of tuximab vedotin. Craig H. Mosko­ patients who had not undergone a witz, MD, Clinical Director, Division stem-cell transplant and in 80% who of Hematologic Oncology, Memorial had a transplant but did not receive Sloan Kettering Cancer Center, New brentuximab. At an average of 40 York, presented the results of the trial weeks, the complete response rate was at the meeting. The response rate was 66%, reported 17% overall, and 60% in brentuximab-naïve patients. Another 13% of Dr Moskowitz, with complete responses in 21% of the patients and partial patients had stable disease. The progression-free survival rate responses in 45%. Responses occurred was 86% at 24 weeks. At the time of in 75% of the patients with previous

Continued from page 1

stem-cell transplant and in 44% of those who were transplant-ineligible or who had refused transplant. The median time to response was 12 weeks, and the median duration of response was not reached. “Almost all patients had some evidence of tumor shrinkage,” Dr Moskowitz said. The clinical benefit rate, which includes stable disease, was 86%. “Many patients had stable disease on pembro­ lizumab. In fact, some who have been on treatment the longest had stable disease,” he said. Pembrolizumab 10 mg/kg was administered every 2 weeks until progressive disease, excessive toxicity, or the completion of 24 months of therapy. Overall, 52% of the patients had received at least 5 previous lines of treatment. All patients had previously failed therapy with brentuximab, and 69% had stemcell transplant failure. There were 4 treatment-related grade ≥3 AEs—1 patient each with axillary pain, hypoxia, joint swelling, and pneumonitis. There were no grade 4 AEs or treatment-related deaths. Pembrolizumab and nivolumab have individually demonstrated single-­ agent activity in patients with Hodgkin lymphoma, said Dr Moskowitz, commenting on these results. He noted that future evaluations in combination with standard therapies, or even as maintenance treatment to enhance the posttransplant immune response will be important. n

Brentuximab Cost-Effective After Transplant By Chase Doyle San Francisco, CA—The use of brentuximab vedotin (Adcetris) to prevent progression after autologous stem-cell transplantation (ASCT) in patients with Hodgkin lymphoma is expected to increase survival and be cost-effective, according to a cost-effectiveness analysis presented at ASH 2014. Relapsed or refractory Hodgkin lymphoma after ASCT carries an unfavorable prognosis, with a median overall survival of less than 2 years. It is also very costly to treat. Novel agents that reduce the risk for disease progression and the need for further treatment, including ASCT, offer the potential to be not only clinically effective but also cost-effective, noted Joshua A. Roth, PhD, MHA, of the Hutchinson Institute for Cancer Outcomes Research, Seattle, WA. Brentuximab vedotin, a CD30-directed antibody-drug conjugate, significantly improved progression-free survival when given after ASCT in the AETHERA trial (see article, page 24). VOL. 6

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Cost-Effective

The objective of the current analysis was to evaluate the cost-effectiveness of brentuximab treatment strategy after ASCT to prevent or delay disease progression in patients with Hodgkin lymphoma compared with best supportive care. The investigators constructed a decision model evaluating the potential cost-effectiveness of brentuximab vedotin versus best supportive care. Adults with relapsed or refractory Hodgkin lymphoma “enter” the model immediately after receiving ASCT, and then receive brentuximab vedotin plus best supportive care or best supportive care alone. After treatment, patients are tracked in monthly cycles through the 5 health states of remission, relapse/salvage therapy, relapse/palliative care, second remission, and death, with transition probabilities derived from peer-reviewed literature, bone marrow transplant registry data, and US life tables.

When used after ASCT to prevent progression, brentuximab vedotin has the potential to be cost-effective compared with best supportive care only in adults with relapsed or refractory Hodgkin lymphoma. —Joshua A. Roth, PhD, MHA

In the base case, a brentuximab vedotin strategy yields 2.01 quality-­ adjusted life-years (QALYs) at a total cost of $147,790. With an incremental cost-effectiveness ratio of $74,000 per QALY, treatment with brentuximab vedotin is cost-effective by contemporary standards of willingness to pay in the United States ($100,000-$150,000 per QALY). Probabilistic sensitivity analysis results demonstrated that brentuximab vedotin is expected to be cost-effective in 24%, 81%, and 95% of simulations at willingness-to-pay levels FEBRUARY 2015

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of $50,000, $100,000, and $150,000 per QALY, respectively. The investigators concluded that when used after ASCT to prevent progression, brentuximab has the potential to be cost-effective compared with best supportive care only in adults with relapsed or refractory Hodgkin lymphoma. Dr Roth also noted that the results of the forthcoming phase 3 AETHERA trial would provide definitive evidence of the efficacy of brentuximab in this setting and, consequently, more precise evidence of the cost-effectiveness of this strategy. n

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Payers’ Perspective

The Value of Pharmaceuticals and Adherence to Therapy in the Management of Hematologic Cancers Atheer A. Kaddis, PharmD Senior Vice President, Sales and Industry Relations Diplomat Specialty Pharmacy

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onsistent with past meetings, the 2014 annual meeting of the American Society of Hematology (ASH) included very insightful and educational presentations on the value of pharmaceuticals, cost implications, and the importance of adherence to therapy that can help guide policy decisions for pharmacy and medical directors. This is especially impor­ tant considering the impact of the new treatments for hematologic cancers that have been introduced to the market over the past 12 months. Novel therapies for hematologic cancers are a major area of focus for payers. In 2014, the US Food and Drug Administration approved 4 new molecular entities for the treatment of hematologic cancers, impacting the medical and pharmacy budgets for payers. These 4 drugs include belinostat for relapsed or refractory peripheral T-cell lymphoma; blinatumomab for Philadelphia chromosome–negative relapsed or refractory precursor acute lymphoblastic leukemia; ibrutinib for several indications, including mantle-cell lymphoma and chronic lymphocytic leukemia (CLL); and idel­ alisib for several indications, including CLL, follicular B-cell non-Hodgkin lymphoma, and small lymphocytic lymphoma.1 Of these novel therapies, 2 are administered intravenously (belinostat and blinatumomab) and 2 are administered orally (ibrutinib and idelalisib), with direct implications for payers. Cancer care, including hematologic cancers, is a major area of focus in the current drug development arena, and is one of the leading contributors to the overall growth in spending for payers. This highlights the importance of evaluating the information presented at the recent ASH meeting as well as other developments in hematologic cancers. Reimbursement, Value, and Cost-Effectiveness

At a special symposium on quality care and discussed in this special issue (see article on page 1), Andreas Laupacis, MD, MSc, suggested that drug reimbursement decisions should incorporate value and cost-effectiveness. Dr Laupacis is actively involved in drug reimbursement committee decisions in Canada. Focusing on cost-effectiveness, Canadian drug reimbursement committees decide whether to pay for particular drugs, decline to pay because of a lack

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of cost-effectiveness, or to pay for a restricted indication using public funds. Even though we do not have nationalized healthcare in the United States, Dr Laupacis suggests that private payers in the United States can still dictate their reimbursement policies based on reliable cost-effective analyses. His suggestions for payers include: • Focusing on getting high-quality information about the effectiveness of drugs to accurately drive cost-effectiveness ratios • Negotiating drug prices aggressively based on cost-effectiveness • Using tools such as value-based discounts • Involving patients in the care dialogue. Given these suggestions, and considering that more than $1 billion in additional funding was appropriated to comparative effectiveness research in the Affordable Care Act,2 we are likely to see more focus on value in healthcare, cost-effectiveness, and comparative effectiveness research in the near future. Economic Burden and Adherence to Therapy

Several presentations at ASH 2014 focused on the cost of care for hematologic cancers and the impact of these costs on patient medication adherence. Decreased adherence to therapy can have a detrimental effect on patient morbidity and mortality, especially for cancer diagnoses. Joanne S. Buzaglo, PhD, studied the economic burden on patients diagnosed with chronic myeloid leukemia (CML). The availability of new breakthrough therapies for the treatment of CML has transformed this condition from an often fatal disease to a chronic disease that requires ongoing treatment. The Cancer Support Community, in partnership with the Leukemia & Lymphoma Society, registered 484 patients living with CML to the Cancer Experience Registry. Overall, 81% of patients responded to a survey about the financial burden of CML and cancer-related psychological distress. Among these patients with CML, 19% reported missing a dose of their oral CML medication at least once monthly, 14% reported postponing prescriptions, and 10% said they skipped dosages of their prescribed CML medication. By these measures, 31% of the patients with CML were

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FEBRUARY 2015

Cancer care, including hematologic cancers, is a major area of focus in the current drug development arena, and is one of the leading contributors to the overall growth in spending for payers. defined as having poor medication adherence (see article on page 1). In addition, nearly 50% of the patients reported out-of-pocket (OOP) costs of ≥$100 related to CML, 27% spent ≥$250 monthly, 15% spent ≥$500, and 5% of patients spent ≥$1000. To be able to pay for their CML medication, 38% of patients said that they had to use copay assistance, 35% had to cut grocery expenses, 33% depleted their savings, 30% used pharmaceutical assistance programs, 18% sold personal property, 17% asked their healthcare provider for a less expensive treatment, 13% had liquidated their assets, 6% went into bankruptcy, and 4% of patients foreclosed on their homes. Other studies have also shown that cancer treatments can lead to rates of bankruptcy that are more than double the rate among people without cancer.3 These statistics are very concerning, and Dr Buzaglo concluded that “implications for future research and practice so that patients fully benefit from CML therapy include the development and evaluation of interventions that enhance patient–clinician communications, psychosocial distress screening and referral, and financial counseling and assistance.” S. Yousuf Zafar, MD, MHS, who had coined the term “financial toxicity,” has been pointing at different occasions how

the cost of paying for cancer impacts the efficacy of treatment. At ASH 2014, Dr Zafar said that a high patient cost burden is associated with a 70% higher likelihood of nonadherence to treatment. He stated that financial toxicity is as important as drug toxicity when it comes to the management of patients with cancer (see article on page 10). Some of the statistics supporting the concept of “financial toxicity” in regard to the treatment of cancer include that 50% of Medicare beneficiaries pay 10% of the cost of OOP therapy, 28% of Medicare beneficiaries spend >20% of the cost of OOP treatment, and nearly 50% of patients take money from their savings and cut back on basics to pay for care. In prospective, longitudinal studies of patients with cancer, Dr Zafar and colleagues found that 52% of patients want to discuss treatment-related OOP costs with their oncologist, and 51% want their oncologist to take cost into account when making treatment decisions, but only 19% of patients have actually discussed this with their oncologist, leaving a gap in treatment that can result in patient nonadherence. By contrast, among patients who did discuss costs with their oncologist, 57% reported having lower OOP costs, primarily a result of being referred to a financial assistance organization. This is very interesting, considering that financial assistance programs and organizations contribute millions of dollars in aid annually to patients who cannot afford their medications. Specialty pharmacies are particularly adept at helping patients obtain this financial support when needed. In addition to presenting data on the value of pharmaceuticals and adherence to therapy in the treatment of hematologic cancers, many studies were presented at ASH 2014 related to new advances in the treatment of hematologic cancers, advances in treatment regimens, and updates on the cost of treatment. ASH should be commended for another insightful and educational meeting. n References

1. CenterWatch. FDA approved drugs. www.center watch.com/drug-information/fda-approved-drugs/ year/2014. Accessed February 6, 2015. 2. Donnelly J. Health policy briefs: Comparative effectiveness research. Health Affairs. Updated October 8, 2010. www.healthaffairs.org/healthpolicybriefs/brief. php?brief_id=27. Accessed February 6, 2015. 3. Ramsey S, Blough R, Kirchoff A, et al. Washington State cancer patients found to be at greater risk for bankruptcy than people without a cancer diagnosis. Health Aff (Millwood). 2013;32:1143-1152.

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