Prediction of methotrexate neurotoxicity using clinical, sociodemographic, and area-based information in children with acute lymphoblastic leukemia

TL;DR

This study uses machine learning to predict neurotoxicity from methotrexate in children with leukemia, aiming to improve personalized treatment.

Contribution

A novel risk prediction model for methotrexate-related neurotoxicity using clinical and demographic data in pediatric ALL patients.

Findings

Neurotoxicity occurred in 8.7% of patients, with older age and Latino ethnicity as significant risk factors.

The random forest model achieved 77% accuracy in predicting neurotoxicity with 73% sensitivity and 69% specificity.

The model may help reduce neurotoxicity burden through personalized treatment strategies.

Abstract

Methotrexate is a critical component of pediatric acute lymphoblastic leukemia (ALL) therapy that can result in neurotoxicity which has been associated with an increased risk of relapse. We leveraged machine learning to develop a neurotoxicity risk prediction model in a diverse cohort of children with ALL.

We included children (age 2-20 years) diagnosed with ALL (2005-2019) and treated in Texas without pre-existing neurologic disease. Clinical information was obtained by medical record review. Neurotoxicity occurring post-induction and prior to maintenance therapy was defined as neurologic episodes occurring within 21 days of methotrexate. Suspected cases were independently confirmed by 2 pediatric oncologists. Demographic and clinical factors were compared using logistic regression. The dataset was randomly split (80/20) for training and testing. random forest (RF) with boosting and downsampling using 5-repeat, 10-fold cross-validation was used to construct a predictive model.

Neurotoxicity developed in 115 (8.7%) of 1325 eligible patients. Several factors including older age at diagnosis (OR = 1.19, 95% CI: 1.15-1.24) and Latino ethnicity (OR = 2.79, 95% CI: 1.83-4.35) were associated with neurotoxicity. The RF had an area under the curve of 0.77 with a train error rate of 0.29 and a test error rate of 0.24. The overall sensitivity was 0.73, and specificity was 0.69.

In one of the largest studies of its kind, we developed a novel risk prediction model of methotrexate-related neurotoxicity. Ultimately, a validated model may help guide the development of personalized treatment strategies to reduce the burden of neurotoxicity in children diagnosed with ALL.

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