ASH Clinical News ACN_4.11_Full Issue_web | Page 39

CLINICAL NEWS

• uninsured : 3 % ( 6 % and < 1 %)

• Medicaid-insured : 4 % ( 6 % and < 1 %)

• Medicare-insured : 46 % ( 8 % and 86 %)

Patients with no insurance or Medicaid were more likely to be black or Hispanic , to live in an area with lower levels of educational achievement , on average , to have B-symptoms , and to be diagnosed

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

Hematologic Adverse Reactions at an advanced stage , compared with those with private insurance or Medicare ( p < 0.001 for all comparisons ).

Over a median follow-up of 57.9 months in the younger cohort and 42.8 months in the older cohort ( ranges not provided ), 11,547 patients died ( 26 %). For younger FL patients , median overall survival ( OS ) was 92 percent at 3 years , 88 percent at 5 years , and 84 percent at 7 years . In the older cohort ,

CALQUENCE ® ( acalabrutinib ) capsules , for oral use

CALQUENCE 100 mg twice daily N = 124

All Grades (%) Grade ≥ 3 (%)

Increases in creatinine 1.5 to 3 times the upper limit of normal occurred in 4.8 % of patients . DRUG INTERACTIONS Strong CYP3A Inhibitors

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

OS rates were 73 percent , 63 percent , and 52 percent , respectively .

Compared with patients < 65 years with private insurance , the prognosis was significantly worse for those with no insurance , Medicaid , or Medicare :

• no insurance : hazard ratio ( HR ) for OS = 1.96 ( 95 % CI 1.69-2.28 ; p < 0.0001 )

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

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

11 / 17 US-17859 2 / 18

2

• Medicaid : HR for OS = 1.82 ( 95 % CI 1.57-2.12 ; p < 0.0001 )

• Medicare : HR for OS = 1.96 ( 95 % CI 1.71-2.24 ; p < 0.0001 )

In the ≥65 years group , patients with Medicare also had a statistically significantly worse OS than privately insured patients ( HR = 1.28 ; 95 % CI 1.17-1.4 ; p < 0.0001 ).

These associations remained significant after adjusting for sociodemographic , prognostic , and treatment factors , the researchers noted . Disease stage , presence of B-symptoms , and comorbidities were significant predictors of FL survival in patients , “ contributing to the survival disparities seen with insurance status .” However , the authors contended , “ although stage is an important factor in how insurance status relates to FL survival , [ it ] does not fully explain the disparate outcomes and lead-time bias is unlikely to be the sole source for this difference .”

Based on their findings , the authors concluded that studies of outcomes in FL should include insurance status as a predictor . “ Further research on prognosis for FL should examine the impact of public policy … [ and ] other factors that influence access to care , such as individual-level socioeconomic status , regular primary-care visits , access to prescription medications , and care affordability [ related to FL outcomes ],” they added .

Because the analysis relied on the retrospective NCDB , the authors were not able to control for all possible confounders , which they noted as a limitation of the study . Potential confounders included individual-level socioeconomic status , health literacy , and adherence to follow-up – all of which were excluded from the registry . ●

The authors report financial relationships with AbbVie , Spectrum , Seattle Genetics , Gilead Sciences , and Bayer . The study was supported with funding from the National Institutes of Health .

REFERENCE

Goldstein JS , Nastoupil LJ , Han X , et al . Disparities in survival by insurance status in follicular lymphoma . Blood . 2018 July 14 . [ Epub ahead of print ]

ASH Clinical News 37