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

Abstract

Study objective: 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. The purpose of this study is to identify clinical and genetic factors that may predict which children are at risk for creatinine increase and prolonged MTX clearance.

Design: We conducted a single-center, retrospective cohort study of pediatric patients with ALL who received 4000-5000 mg/m² of MTX. Measurements 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.

Main results: 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.

Conclusions: These predictors of MTX toxicities may allow for more precise individualized toxicity risk prediction.

Keywords: leukemia; methotrexate; nephrotoxicity; pediatrics; pharmacogenomics.

Figure 1.. Coefficient results from the multivariable, hierarchical Bayesian ordinal regression models for each SNP.

The association with creatinine increase is in the left panel and delayed MTX clearance in the right. Values are on the log-odds scale. Median coefficient value (circle), 50% compatibility interval (thick line segment), and 95% compatibilty interval (thin line segment) are shown. MTX, methotrexate.

Figure 2.. Distribution of values for creatinine increase from baseline (left) and MTX clearance hours (right) by genotype for the three SNPs with the largest association.

The grey shaded area shows the density of distribution of creatinine increase values. The points underneath the shaded area represent individual dose values. The right shoulder of the box represents the 75% for the data values. The right tip of the thin line segment represents 1.5 times the interquartile range beyond the 75%. Thick vertical lines signify that all values contained in the box and whiskers fall on the ≤ 25% creatinine increase category or the 48-hour clearance time for MTX for the left and right plots, respectively. MTX, methotrexate; SNPs, single nucleotide polymorphisms.