Importance With cure rates of childhood acute lymphoblastic leukemia (ALL) exceeding 85%, there is compelling need to mitigate treatment toxicities that can compromise quality of life. Peripheral neuropathy is the major dose-limiting toxicity of the microtubule inhibitor vincristine, an anticancer agent given to every child with ALL. Objective Identify genetic germline variants associated with the occurrence or severity of vincristine-induced peripheral neuropathy in children with ALL. Design, Setting and Participants All patients had been enrolled in one of two prospective clinical trials for childhood ALL that included treatment with 36–39 doses of vincristine. Genome-wide single nucleotide polymorphism (SNP) analysis and vincristine-induced peripheral neuropathy were assessed in all patients from whom DNA was available (n=321 patients); 222 patients (median age at 6.0 years, range 0.1–18.8 years) enrolled between 1994–1998 on the St. Jude Children’s Research Hospital protocol Total XIIIB (St. Jude cohort) with toxicity followed through January 2001, and 99 patients (median age 11.4 years, range 3.0–23.8 years) enrolled between 2007–2010 on the Children’s Oncology Group protocol AALL0433 (COG cohort) with toxicity followed through May 2011. Human leukemia cells and induced pluripotent stem cell neurons were used to assess the effects of lower CEP72 expression on vincristine sensitivity. Exposures Treatment with vincristine at a dosage of 1.5 or 2.0 mg/m2 as a component of protocol directed chemotherapy for childhood ALL. Main Outcomes and Measures Vincristine-induced peripheral neuropathy was assessed at each clinic visit using the National Cancer Institute Common Terminology Criteria for Adverse Events and prospectively graded as mild (grade 1), moderate (grade 2), serious/disabling (grade 3), or life-threatening (grade 4). Results Grade 2–4 vincristine-induced neuropathy during continuation therapy occurred in 28.8% of patients (n=64 of 222) in the St. Jude cohort and in 22.2% of patients (n=22 of 99) in the COG cohort. A SNP in the promoter region of the CEP72 gene, which encodes a centrosomal protein involved in microtubule formation, had a significant association with vincristine neuropathy (meta p =6.3 × 10−9). This SNP had a minor allele frequency of 37% (235/642), with 50 of 321 patients (16%, 95% CI 11.6%–19.5%) homozygous for the risk allele (TT at rs924607). Among patients with the high-risk CEP72 genotype (TT at rs924607), 28 of 50 patients (56%, 95% CI 41.2–70.0) developed at least one episode of grade 2–4 neuropathy, a higher rate than in patients with the CEP72 CC or CT genotype (58 of 271 patients; 21.4%, 95% CI 16.9–26.7); p=2.4×10−6. The severity (grade) of neuropathy was greater (2.4-fold by Poisson regression (p<0.0001), 2.7-fold based on mean grade of neuropathy (1.23 [95% CI 0.74 – 1.72] versus 0.45 [95% CI 0.3 – 0.6]; t test p=0.004)) in patients homozygous for the CEP72 risk allele (TT genotype), compared to patients with the CC or CT genotype. The CEP72 promoter SNP was show...

Importance Variability in prescribed 6-mercaptopurine and lack of adherence to 6-mercaptopurine could result in intra-individual variability in systemic exposure to 6-mercaptopurine (measured as erythrocyte thioguanine nucleotide levels) in children with acute lymphoblastic leukemia. The impact of intra-individual variability in systemic exposure to 6-mercaptopurine on relapse risk is unknown. Objective To determine impact of high intra-individual variability in 6-mercaptopurine systemic exposure on relapse risk in children with acute lymphoblastic leukemia. Design Prospective longitudinal design; daily adherence monitoring, 6-mercaptopurine dose-intensity and erythrocyte thioguanine nucleotide levels (pmol/8*10^8 erythrocytes) measured for 6 consecutive months per patient; cohort followed for a median of 6.7 years from diagnosis. Setting Children’s Oncology Group study (COG-AALL03N1); 94 participating institutions; ambulatory care setting. Participants Participants included 742 children meeting the following eligibility criteria: diagnosis of acute lymphoblastic leukemia at ≤21 years; in first continuous remission at study entry; receiving self/parent/caregiver-administered oral 6-mercaptopurine during maintenance. Median age at diagnosis: 5 years; 68% were male; 43% with NCI-based high-risk disease. Main Outcome Measures Adherence measured electronically using Medication Event Monitoring System that recorded date/time of each 6-mercaptopurine bottle opening; adherence rate defined as ratio of days of 6-mercaptopurine bottle opened to days when 6-mercaptopurine prescribed. 6-mercaptopurine doses actually prescribed were divided by planned protocol doses (75mg/m2/day) to compute average monthly dose-intensity. Electronically-monitored adherence (68,716 person-days), 6-mercaptopurine dose-intensity (120,439 person-days) and monthly erythrocyte thioguanine nucleotide levels (n=3,944 measurements) contributed to the analysis. Using intra-individual coefficients of variation (CV %), patients were classified as having stable (CV % <85th percentile) vs. varying (CV % ≥85th percentile) indices. Results Adjusting for clinical prognosticators, patients with 6-mercaptopurine non-adherence (mean adherence rate <95%) were at a 2.7 fold increased risk of relapse (95% confidence interval [CI], 1.3 to 5.6, p=0.01). Among adherers, high intra-individual variability in thioguanine nucleotide levels contributes to increased relapse risk (HR=4.4, 95% CI, 1.2 to 15.7, p=0.02). Furthermore, adherers with varying thioguanine nucleotide levels had varying 6-mercaptopurine dose-intensity (OR=4.5, p=0.006) and 6-mercaptopurine drug interruptions (OR=10.2, p=0.003). Conclusions and Relevance These findings emphasize the need to maximize 6-mercaptopurine adherence and maintain steady thiopurine exposure to minimize relapse in children with acute lymphoblastic leukemia.