Project 2: Ethnic disparities in methotrexate neurotoxicity among children and adolescents with acute lymphoblastic leukemia Project Summary Improvements in the treatment of childhood acute lymphoblastic leukemia (ALL), including the adoption of risk- adapted, multi-agent chemotherapy, have resulted in five-year survival rates exceeding 85% in most developed countries. The antifolate agent methotrexate (MTX) is a critical component of curative pediatric ALL protocols. Approximately 10% of pediatric ALL patients experience acute or subacute neurotoxicity following intrathecal (IT) or high-dose intravenous (IV) MTX. However, Latino children appear to experience MTX-associated neurotoxicity more frequently. Further, the clinical management of MTX-related neurotoxicity often involves treatment delays and/or modifications, which may limit anti-leukemic efficacy and impact survival. A number of factors likely contribute to disparities in pediatric ALL neurotoxicity and related treatment outcomes, including clinical characteristics, pharmacogenomics, disease features, and socioeconomic factors. Notably, racial and ethnic disparities in pediatric ALL outcomes, including relapse, can be explained in part by underlying variation in genetic ancestry, suggesting the frequency of variants involved in antileukemia therapy pharmacodynamics and pharmacokinetics vary across ancestral populations. Our overall goal is to better understand the factors contributing to disparities in treatment-related toxicities and treatment outcomes among Latino children with ALL. Our overarching hypothesis is that underlying germline genetics, tumor biology, and social determinants of health contribute to poorer outcomes in this vulnerable population of children. To address our goal, we propose the three specific aims. Aim 1: Compare the impact of acute MTX neurotoxicity on clinical treatment course and outcomes (e.g., relapse) between Latino and non-Latino White patients with ALL. Aim 2: Identify clinical, socioeconomic, pharmacogenomic, and metabolomic predictors of initial MTX neurotoxicity and neurotoxicity recurrence following MTX re-challenge, while accounting for the impact of ethnicity. Aim 3: Identify alterations in white matter integrity associated with initial MTX neurotoxicity and neurotoxicity recurrence following MTX re- challenge using standard and novel imaging techniques, in the context of ethnic variation. This project will provide insights into the factors responsible for increased neurotoxicity in Latino children with ALL and may identify pharmacogenomic and imaging features of at-risk individuals that allow prevention of initial or subsequent events, and improvement of ALL outcomes.