Project 2: Understanding population disparities in methotrexate neurotoxicity and its impact on short- and long-term adverse outcomes 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 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, disease features, and socioeconomic factors. Notably, racial and ethnic disparities in pediatric ALL outcomes, including relapse and certain late effects of therapy, 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 and adolescents with ALL and work toward modifying their risks. Our overarching hypothesis is that underlying germline genetics, tumor biology, and social determinants of health contribute to poorer outcomes in this vulnerable population. To address our goal, we propose the following three specific aims. Aim 1: Validate and extend risk prediction models for acute MTX neurotoxicity among a contemporary multiethnic population of children with ALL. Aim 2: Determine the impact of acute MTX neurotoxicity on ALL relapse, adjusting for currently known risk factors, using the complete REDIAL Cohort (n>4,300; 50% Latino). Aim 3: Determine the impact of acute MTX neurotoxicity on long-term neurocognitive deficits, using the Retrospective REDIAL Cohort (n=2,958; 50% Latino). This project will provide insights into the factors responsible for increased neurotoxicity and subsequent increased risk of relapse and long-term neurocognitive deficits in Latino children with ALL.