Evaluation of methotrexate Pharmacogenomic variation to predict acute neurotoxicity in children with acute lymphoblastic leukemia

Background: Methotrexate 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.

Methods: This 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.

Results: Of 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).

Conclusion: Overall, 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.