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CLINICAL NEWS speakers

John P . Leonard , MD , New York-Presbyterian / Weill Cornell Medical Center , New York , NY

Mohamad Mohty , MD , PhD , Saint Antoine Hospital , Paris , France

Elaine Schattner , MD , Forbes contributor ; Weill Cornell Medical College , New York , NY

EDUCATION SPOTLIGHT SESSION Identification and Management of Toxicities Induced by Immunotherapies Monday , December 11 , 2017 , 2:45 – 4:15 p . m . Immune checkpoint inhibitors that can reverse tumorinduced T-cell suppression mediated by inhibitory ligands and T cells genetically modified with chimeric antigen receptors have produced impressive clinical responses in a broad spectrum of cancers . However , these promising immunomodulatory strategies have serious discuss grading and management of toxicities

CALQUENCE ® ( acalabrutinib ) capsules , for oral use and immune-related side effects of each of these approaches .

chair

Helen E . Heslop , MD , DSc , Baylor College of Medicine , Houston , TX

speakers

Daniel W . Lee III , MD , University of Virginia , Charlottesville , VA

2

Suzanne L . Topalian , MD , The Johns Hopkins University , Baltimore , MD

Table 3 : Hematologic Adverse Reactions Reported * in ≥ 20 % of Patients with MCL in Trial LY-004

Hematologic Adverse Reactions

CALQUENCE 100 mg twice daily N = 124

All Grades (%) Grade ≥ 3 (%)

Clinical Impact

Prevention or Management

Moderate CYP3A Inhibitors

Clinical Impact

Prevention or Management

Strong CYP3A Inducers

Clinical Impact

Prevention or Management

Gastric Acid Reducing Agents

Clinical Impact

Prevention or Management

• Co-administration of CALQUENCE with a strong CYP3A inhibitor ( itraconazole ) increased acalabrutinib plasma concentrations [ see Clinical Pharmacology ( 12.3 ) in the full Prescribing Information ].

• Increased acalabrutinib concentrations may result in increased toxicity .

• Avoid co-administration of strong CYP3A inhibitors with CALQUENCE .

• Alternatively , if the inhibitor will be used short-term , interrupt CALQUENCE [ see Dosage and Administration ( 2.2 ) in the full Prescribing Information ].

• Co-administration of CALQUENCE with a moderate CYP3A inhibitor may increase acalabrutinib plasma concentrations [ see Clinical Pharmacology ( 12.3 ) in the full Prescribing Information ].

• Increased acalabrutinib concentrations may result in increased toxicity .

• When CALQUENCE is co-administered with moderate CYP3A inhibitors , reduce acalabrutinib dose to 100 mg once daily .

• Co-administration of CALQUENCE with a strong CYP3A inducer ( rifampin ) decreased acalabrutinib plasma concentrations [ see Clinical Pharmacology ( 12.3 ) in the full Prescribing Information ].

• Decreased acalabrutinib concentrations may reduce CALQUENCE activity .

• Avoid co-administration of strong CYP3A inducers with CALQUENCE .

• If a strong CYP3A inducer cannot be avoided , increase the acalabrutinib dose to 200 mg twice daily .

• Co-administration of CALQUENCE with a proton pump inhibitor , H2-receptor antagonist , or antacid may decrease acalabrutinib plasma concentrations [ see Clinical Pharmacology ( 12.3 ) in the full Prescribing Information ].

• Decreased acalabrutinib concentrations may reduce CALQUENCE activity .

• If treatment with a gastric acid reducing agent is required , consider using a H2-receptor antagonist ( e . g ., ranitidine or famotidine ) or an antacid ( e . g ., calcium carbonate ).

Separate dosing by at least 2 hours [ see Dosage and Antacids

Administration ( 2.2 ) in the full Prescribing Information ].

H2-receptor antagonists

Proton pump inhibitors

Take CALQUENCE 2 hours before taking the H2-receptor antagonist [ see Dosage and Administration ( 2.2 ) in the full Prescribing Information ].

Avoid co-administration . Due to the long-lasting effect of proton pump inhibitors , separation of doses may not eliminate the interaction with CALQUENCE .

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary

Based on findings in animals , CALQUENCE may cause fetal harm when administered to a pregnant woman . There are no available data in pregnant women to inform the drugassociated risk . In animal reproduction studies , administration of acalabrutinib to pregnant rabbits during organogenesis resulted in reduced fetal growth at maternal exposures ( AUC ) approximately 4 times exposures in patients at the recommended dose of 100 mg twice daily ( see Data ). Advise pregnant women of the potential risk to a fetus .

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown . All pregnancies have a background risk of birth defect , loss , or other adverse outcomes . In the U . S . general population , the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4 % and 15-20 %, respectively .

Data

Animal Data In a combined fertility and embryo-fetal development study in female rats , acalabrutinib was administered orally at doses up to 200 mg / kg / day starting 14 days prior to mating through gestational day [ GD ] 17 . No effects on embryo-fetal development and survival were observed . The AUC at 200 mg / kg / day in pregnant rats was approximately 16-times the AUC in patients at the recommended dose of 100 mg twice daily . The presence of acalabrutinib and its active metabolite were confirmed in fetal rat plasma .

In an embryo-fetal development study in rabbits , pregnant animals were administered acalabrutinib orally at doses up to 200 mg / kg / day during the period of organogenesis ( from GD 6-18 ). Administration of acalabrutinib at doses ≥ 100 mg / kg / day produced maternal toxicity and 100 mg / kg / day resulted in decreased fetal body weights and delayed skeletal ossification . The AUC at 100 mg / kg / day in pregnant rabbits was approximately 4-times the AUC in patients at 100 mg twice daily .

Lactation Risk Summary

No data are available regarding the presence of acalabrutinib or its active metabolite in human milk , its effects on the breastfed child , or on milk production . Acalabrutinib and its active metabolite were present in the milk of lactating rats . Due to the potential for adverse reactions in a breastfed child from CALQUENCE , advise lactating women not to breastfeed while taking CALQUENCE and for at least 2 weeks after the final dose .

Pediatric Use The safety and efficacy of CALQUENCE in pediatric patients have not been established .

Geriatric Use Eighty ( 64.5 %) of the 124 MCL patients in clinical trials of CALQUENCE were 65 years of age or older , and 32 patients ( 25.8 %) were 75 years of age or older . No clinically relevant differences in safety or efficacy were observed between patients ≥ 65 years and younger .

PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling ( Patient Information ).

Hemorrhage

Inform patients to report signs or symptoms of severe bleeding . Inform patients that CALQUENCE may need to be interrupted for major surgeries [ see Warnings and Precautions ( 5.1 ) in the full Prescribing Information ].

Infections

Inform patients to report signs or symptoms suggestive of infection [ see Warnings and Precautions ( 5.2 ) in the full Prescribing Information ].

Cytopenias

Inform patients that they will need periodic blood tests to check blood counts during treatment with CALQUENCE [ see Warnings and Precautions ( 5.3 ) in the full Prescribing Information ].

Second Primary Malignancies

Inform patients that other malignancies have been reported in patients who have been treated with CALQUENCE , including skin cancer . Advise patients to use sun protection [ see Warnings and Precautions ( 5.4 ) in the full Prescribing Information ].

Atrial Fibrillation and Flutter

Counsel patients to report any signs of palpitations , lightheadedness , dizziness , fainting , shortness of breath , and chest discomfort [ see Warnings and Precautions ( 5.5 ) in the full Prescribing Information ].

Dosing Instructions

Instruct patients to take CALQUENCE orally twice daily , about 12 hours apart . CALQUENCE may be taken with or without food . Advise patients that CALQUENCE capsules should be swallowed whole with a glass of water , without being opened , broken , or chewed [ see Dosage and Administration ( 2.1 ) in the full Prescribing Information ].

Missed Dose

Advise patients that if they miss a dose of CALQUENCE , they may still take it up to 3 hours after the time they would normally take it . If more than 3 hours have elapsed , they should be instructed to skip that dose and take their next dose of CALQUENCE at the usual time . Warn patients they should not take extra capsules to make up for the dose that they missed [ see Dosage and Administration ( 2.1 ) in the full Prescribing Information ].

Drug Interactions

Advise patients to inform their healthcare providers of all concomitant medications , including over-the-counter medications , vitamins and herbal products [ see Drug Interactions ( 7 ) in the full Prescribing Information ].

Lactation

Advise women not to breastfeed during treatment with CALQUENCE and for at least 2 weeks after the final dose [ see Use in Specific Populations ( 8.2 ) in the full Prescribing Information ].

Distributed by : AstraZeneca Pharmaceuticals LP , Wilmington , DE 19850 Under license of Acerta Pharma B . V .

CALQUENCE is a registered trademark of the AstraZeneca group of companies . © AstraZeneca 2017

10 / 17 US-14202 11 / 17

SCIENTIFIC SPOTLIGHT SESSION Beyond Sequencing : Emerging Tools for Analysis of Multi-Omic Genomic Data in Acquired and Inherited Hematologic Disease Sunday , December 10 , 2017 , 4:30 – 6:00 p . m . Costs of next-generation sequencing ( NGS ) have plummeted , enhancing the scale and scope of genomic research . However , it has become clear that the NGS workhorse requires novel and creative analytic tools , integration of multi-omic data sets , and functional characterization of putative causal variants to better understand human disease and its optimal prevention and management . This session will feature presentations from investigators who have made major contributions to the functional genomics of acquired and inherited hematologic disease .

chair

Paul F . Bray , MD , University of Utah , Salt Lake City , UT

speakers

Jinghui Zhang , PhD , St . Jude Children ’ s Research Hospital , Memphis , TN

Ernest Turro , PhD , University of Cambridge , Cambridge , United

Kingdom ●

ASH Clinical News 91