ArticlePharmacotherapy2025
Evaluation of methotrexate Pharmacogenomic variation to predict acute neurotoxicity in children with acute lymphoblastic leukemia.
Article in Pharmacotherapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers, 2 of them syntheses that pooled it.
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Who cites it
6 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- The impact of gene polymorphisms on the response of methotrexate-based treatments.European journal of clinical pharmacology · 2026Pooled it
- Reduced folate carrier 1 G80A polymorphism is correlated with elevated methotrexate-induced toxicity in pediatric acute lymphoblastic leukemia patients: a systemic meta-analysis.World journal of surgical oncology · 2026Pooled it
- Phenotype-Specific Pharmacogenetic Patterns of Methotrexate Neurotoxicity in Pediatric Acute Lymphoblastic Leukemia.Journal of clinical medicine · 2026Article
- Mitochondrial Genomic Alterations in Pediatric Acute Lymphoblastic Leukemia: Implications for Methotrexate-Induced Neurotoxicity and Ethnic Disparities.Cancer medicine · 2026Article
- Pharmacogenomics Applied to Acute Leukemias: Identifying Clinically Relevant Genetic Variants.Biomedicines · 2025Review
- Development and application of machine learning models for hematological disease diagnosis using routine laboratory parameters: a user-friendly diagnostic platform.Frontiers in medicine · 2025Article
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Authors and funding
25 authors.
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Abstract
backgroundMethotrexate is an important component of curative therapy in childhood acute lymphoblastic leukemia (ALL), but the role of genetic variation influencing methotrexate clearance and transport in toxicity susceptibility in children with ALL is not well established. Therefore, we evaluated the association between suspected methotrexate pharmacogenomic variants and methotrexate-related neurotoxicity.
methodsThis study included children (aged 2-20 years) diagnosed with ALL (2005-2019) at six treatment centers in the southwest United States. Clinical information was abstracted from medical records. Suspected neurotoxic events occurring within 21 days of intravenous and/or intrathecal methotrexate delivered between the end of induction and start of maintenance therapy were independently reviewed by at least two pediatric oncologists. Germline DNA was genotyped and 97 methotrexate pharmacogenomic variants of interest with at least grade 3 evidence were identified using the Pharmacogenomics Knowledge Base. Associations between variants and neurotoxicity were assessed by logistic regression. Data were randomly split (80/20) and random forest was constructed to estimate the ability of the variants to correctly classify neurotoxicity.
resultsOf the 763 patients included in the study, 8.2% (n = 63) developed methotrexate-associated neurotoxicity. In logistic models, none of the 97 available pharmacogenomic variants reached adjusted statistical significance. However, two variants, rs17222723 (odds ratio [OR] = 2.83 [ref. = T allele], 95% confidence interval [CI]: 1.20-6.15) in ABCC2 and rs1045642 (OR = 0.66 [ref. = minor A allele], 95% CI: 0.44-0.98) in ABCB1, were nominally associated (p-value < 0.05) with neurotoxicity susceptibility. The addition of pharmacogenomic variants did not improve the predictive performance of random forest model (AUC = 0.73) compared to clinical information alone (AUC = 0.74).
conclusionOverall, our results suggest that associations between neurotoxicity susceptibility and methotrexate pharmacogenomic variants are generally modest and these variants do not significantly improve neurotoxicity risk stratification among children with ALL.
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