# A Systems Epidemiology Approach for Predicting Methotrexate Neurotoxicity in Pediatric Acute Leukemia

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2024 · $614,625

## Abstract

PROJECT ABSTRACT
Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in childhood. Although survival rates
for childhood ALL have improved in recent decades, ethnic disparities persist. Compared to most other ethnic
groups, Latinos experience both a higher incidence of childhood ALL and poorer survival. The etiology of these
disparities is complex and not fully understood, but ethnic-specific biological variability contributing to increased
treatment-related toxicities are an important, under-studied cause of disparities in outcomes. For example, the
antimetabolite agent methotrexate, a key component of curative ALL chemotherapy, results in dose-limiting
clinical neurotoxicity in approximately 10% of patients. However, emerging evidence from our group has
identified striking ethnic disparities in the incidence of neurotoxicity. Specifically, Latino patients with ALL appear
particularly vulnerable to dose-limiting clinical neurotoxicity, potentially compromising treatment efficacy and
contributing to well-established disparities in pediatric ALL relapse and survival. The overall goal of this project
is to reduce disparities among Latino children and adolescents by identifying host factors that predict an increase
in toxicity. Our preliminary studies provide evidence that mild to moderate acute neurological symptoms,
including pain, which occur frequently but are not routinely assessed in clinical settings, often precede the onset
of clinical methotrexate neurotoxicity. Our data further suggest that levels of cerebrospinal fluid metabolites,
jointly influenced by therapy and genetic variation, and neuroimaging biomarkers of altered white matter integrity
provide novel insights into mechanisms of methotrexate-related neurologic injury. Informed by our preliminary
data, the specific research aims of this project will examine: 1) to what extent do prospectively collected patient-
reported neurologic symptoms identify patients with preclinical toxicity prior to the development of clinically
evident neurotoxicity, 2) whether integrative approaches combining genomics with prospective profiling of central
nervous system metabolomic pathways can identify molecular predictors of neurotoxicity, and 3) the potential
utility of novel neuroimaging techniques to identify alterations in white matter integrity associated with future
neurotoxicity risk. This project builds on the rich resources available in the ethnically diverse, multi-institutional
Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium. Leveraging the REDIAL Cohort with
banked biological samples, this project with systematically evaluate and follow additional newly-diagnosed cases
of pediatric ALL. Therefore, this innovative proposal will establish one of the largest prospective investigations
of neurotoxicity in a multi-ethnic cohort of pediatric patients with ALL. The comprehensive research plan outlined
in this proposal will address key gaps in our understanding e...

## Key facts

- **NIH application ID:** 10831490
- **Project number:** 5R01CA272981-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Austin L Brown
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $614,625
- **Award type:** 5
- **Project period:** 2023-04-21 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10831490

## Citation

> US National Institutes of Health, RePORTER application 10831490, A Systems Epidemiology Approach for Predicting Methotrexate Neurotoxicity in Pediatric Acute Leukemia (5R01CA272981-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10831490. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*