Novel and Replicated Clinical and Genetic Risk Factors for Toxicity From High-Dose Methotrexate in Pediatric Acute Lymphoblastic Leukemia

Authors

Mark Zobeck
M Brooke Bernhardt
Kala Y Kamdar
Karen R Rabin
Philip J Lupo
Michael E Scheurer

Publication Date

3-1-2023

Journal

Pharmacotherapy

DOI

10.1002/phar.2779

PMID

36764694

PMCID

PMC10085626

PubMedCentral® Posted Date

3-1-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Child, Methotrexate, Retrospective Studies, Bayes Theorem, Creatinine, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Risk Factors, Liver-Specific Organic Anion Transporter 1, Methotrexate, leukemia, nephrotoxicity, pharmacogenomics, pediatrics

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/m

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.

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