Novel and replicated clinical and genetic risk factors for toxicity from high-dose methotrexate in pediatric acute lymphoblastic leukemia.

Methotrexate (MTX) is a key component of treatment for high-risk pediatric acute lymphoblastic leukemia (ALL) but may cause acute kidney injury and prolonged hospitalization due to delayed clearance. We conducted a retrospective cohort study of pediatric patients with ALL who received 4000-5000 mg/m 2 of MTX to identify clinical and genetic factors that may predict which children are at risk for creatinine increase and prolonged MTX clearance. We performed germline genotyping to determine genetic ancestry and allele status for 49 single nucleotide polymorphisms (SNPs) identified from the literature as related to MTX disposition. Bayesian hierarchical ordinal regression models for creatinine increase and for prolonged MTX clearance were developed. Hispanic ethnicity, body mass index (BMI) < 3%, BMI between 85-95%, and Native American genetic ancestry were found to be associated with an increased risk for creatinine elevation. Older age, Black race, and use of the intensive monitoring protocol were associated with a decreased risk for creatinine elevation. Older age, B- compared to T-ALL, and the minor alleles of rs2838958/SLC19A1 and rs7317112/ABCC4 were associated with an increased risk for delayed clearance. Black race, MTX dose reduction, and the minor allele of rs2306283/SLCO1B1 were found to be associated with a decreased risk for delayed clearance. These predictors of MTX toxicities may allow for more precise individualized toxicity risk prediction.