Faculty Bibliography

The causes of individual relapses in children with acute lymphoblastic leukemia (ALL) remain incompletely understood. We evaluated the contribution of germline genetic factors to relapse in 2225 children treated on Children's Oncology Group trial AALL0232. We identified 302 germline single nucleotide polymorphisms (SNPs) associated with relapse after adjusting for treatment and ancestry and 715 additional SNPs associated with relapse in an ancestry-specific manner. We tested for replication of these relapse-associated SNPs in external data sets of antileukemic drug pharmacokinetics and pharmacodynamics and an independent clinical cohort. 224 SNPs were associated with rapid drug clearance or drug resistance, and 32 were replicated in the independent cohort. The adverse risk associated with black and Hispanic ancestries was attenuated by addition of the 4 SNPs most strongly associated with relapse in these populations [for blacks: model without SNPs hazard ratio (HR)=2.32, P=2.27 x 10-4, model with SNPs HR=1.07, P=0.79; for Hispanics: model without SNPs HR=1.7, P=8.23 x 10-5, model with SNPs HR=1.31, P=0.065]. Relapse SNPs associated with asparaginase resistance or allergy were overrepresented among SNPs associated with relapse in the more asparaginase intensive treatment arm (20/54 in Capizzi-methorexate arm vs 8/54 in high-dose methotrexate arm, P=0.015). Inherited genetic variation contributes to race-specific and treatment-specific relapse risk.Leukemia accepted article preview online, 18 January 2017. doi:10.1038/leu.2017.24.

Purpose Children with acute lymphoblastic leukemia (ALL) are generally instructed to take mercaptopurine (6-MP) in the evening and without food or dairy products. This study examines the association between 6-MP ingestion habits and 6-MP adherence, red cell thioguanine nucleotide (TGN) levels, and risk of relapse in children with TMPT wild-type genotype. Methods Participants included 441 children with ALL receiving oral 6-MP for maintenance. Adherence was monitored over 48,086 patient-days using the Medication Event Monitoring System; nonadherence was defined as adherence rate < 95%. 6-MP ingestion habits examined included: takes 6-MP with versus never with food, takes 6-MP with versus never with dairy, and takes 6-MP in the evening versus morning versus varying times. Results Median age at study was 6 years (range, 2 to 20 years); 43.8% were nonadherent. Certain 6-MP ingestion habits were associated with nonadherence (taking 6-MP with dairy [odds ratio (OR), 1.9; 95% CI, 1.3 to 2.9; P = .003] and at varying times [OR, 3.4; 95% CI, 1.8 to 6.3; P = .0001]). After adjusting for adherence and other prognosticators, there was no association between 6-MP ingestion habits and relapse risk (6-MP with food: hazard ratio [HR], 0.7; 95% CI, 0.3 to 1.9; P = .5; with dairy: HR, 0.3; 95% CI, 0.07 to 1.5; P = .2; taken in evening/night: HR, 1.1; 95% CI, 0.2 to 7.8; P = .9; at varying times: HR, 0.3; 95% CI, 0.04 to 2.7; P = .3). Among adherent patients, there was no association between red cell TGN levels and taking 6-MP with food versus without (206.1 +/- 107.1 v 220.6 +/- 121.6; P = .5), with dairy versus without (220.1 +/- 87.8 v 216.3 +/- 121.3; P =.7), or in the evening/night versus morning/midday versus varying times (218.8 +/- 119.7 v 195.5 +/- 82.3 v 174.8 +/- 93.4; P = .6). Conclusion Commonly practiced restrictions surrounding 6-MP ingestion might not influence outcome but may hinder adherence. Future recommendations regarding 6-MP intake during maintenance therapy for childhood ALL should aim to simplify administration.

Adequate exposure to oral 6-mercaptopurine (6MP) during maintenance therapy for childhood acute lymphoblastic leukemia (ALL) is critical for sustaining durable remissions; the accuracy of self-reported 6MP intake is unknown. We aimed to directly compare self-report to electronic monitoring (Medication Event Monitoring System [MEMS]), and identify predictors of over-reporting in a cohort of 416 children with ALL in first remission over 4 study months per patient (1,344 patient-months for the cohort) during maintenance therapy. Patients were classified as "perfect reporters" (self-report=MEMS), "over reporters" (self-report>MEMS by >/=5 days/month for >/=50% of study months), and "others" (all patients not meeting criteria for perfect- or over-reporter). Multivariable logistic regression examined sociodemographic and clinical characteristics, 6MP dose-intensity, TPMT genotype, TGN levels, and 6MP non-adherence (MEMs-based adherence rate <95%) associated with the over-reporter phenotype; generalized estimating equations (GEE) compared 6MP intake by self-report and MEMS over the study period. Self-reported 6MP intake exceeded MEMS at least some of the time in 84% of patients. Fifty (12%) patients were classified as perfect reporters, 98 (23.6%) as over-reporters, 2 (0.5%) as under-reporters, and 266 (63.9%) as others. Multivariable logistic regression technique identified the following variables associated with the over-reporter phenotype: i) non-white race: Hispanic, odds ratio (OR)=2.4, 95%CI, 1.1-5.1, p=0.02; Asian, OR=3.1, 95%CI, 1.2-8.3, p=0.02; African-American, OR=5.4, 95%CI, 2.3-12.8, p=0.0001; ii) paternal education

PMCID:5383868

PMID: 28153823

ISSN: 1528-0020

CID: 2437172