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

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 patientreported 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 ethnic disparities in the incidence and etiology of neurotoxicity. Ultimately, we anticipate that this line of research will inform risk-stratified approaches to safely deliver curative chemotherapy to Latino children and adolescents treated for ALL to improve their overall survival.