Project 1: Understanding population-based disparities in treatment-associated hepatotoxicity during ALL therapy

Project 1: Understanding population-based disparities in treatment-associated hepatotoxicity during ALL therapy Project Summary This proposal seeks to integrate clinical, demographic, lipidomic, and genomic data to advance our understanding of disparities in treatment-related hepatoxicity (TAH) during induction therapy for pediatric acute lymphoblastic leukemia (ALL). Improved treatment regimens for pediatric (ALL) have resulted in survival rates exceeding 90%; however, nearly a quarter of patients experience TAH. Our preliminary evidence identified striking population-based disparities in the incidence of TAH during the initial induction phase of ALL therapy. Specifically, Latino patients appear particularly vulnerable to dose-limiting TAH, potentially compromising treatment efficacy and contributing to well-established disparities in pediatric ALL relapse and survival. This proposal pursues the central hypothesis that differences in both inherited genetic and modifiable clinical risk factors contribute to population-based disparities in TAH. Our preliminary data suggests severe TAH can be reliably predicted using a novel hepatotoxicity risk model, plasma lipid dysregulation is an emerging biomarker for TAH risk, and murine models of ALL can provide functional insight into the etiology of TAH. Informed by our preliminary data, the specific research aims of this project will examine: 1) whether consistent and recognizable alterations in plasma lipid profiles involved in liver function contribute to TAH during pediatric ALL induction therapy; 2) to what extent consideration of clinical, demographic, genetic, and lipidomic data can inform the prediction of TAH in heterogenous pediatric ALL populations; and 3) how genetic variation and dyslipidemia contribute to TAH using a murine model of ALL. This project, which is jointly led by investigators with expertise in pediatric oncology (Drs. Huynh and Orgel), molecular epidemiology (Dr. Brown) and murine models of ALL (Dr. Mittelman), builds on the rich resources available in the multi-institutional REDIAL consortium. Leveraging the Prospective (n=1,369) and U54 Continuation (n=1,000) REDIAL Cohorts, this project will systematically evaluate risk for severe TAH in newly diagnosed cases of pediatric ALL. Therefore, this innovative proposal will establish one of the largest prospective investigations of TAH in a cohort of pediatric patients with ALL that is representative of the Texas and California populations. The comprehensive research plan outlined in this proposal will address key gaps in our understanding of disparities in the incidence and etiology of TAH and serve as a unique resource of preliminary data to support future research endeavors. Ultimately, we anticipate that this line of research will inform risk-stratified approaches to safely deliver curative induction chemotherapy to children and adolescents treated for ALL to improve their overall survival.