Etiology and impact of ethnic disparities in therapy-associated hepatotoxicity among children and adolescents treated for ALL

项目摘要 这项建议旨在整合临床、人口统计学、代谢和基因组数据，以推进我们的 儿科诱导治疗中治疗相关肝毒性的民族差异 急性淋巴细胞白血病(ALL)。改进的儿科(ALL)治疗方案已导致存活率 发病率超过90%；然而，近四分之一的患者经历了TAH。来自我们小组的新证据 已经发现TAH的发病率存在显著的种族差异。具体来说，拉丁裔ALL患者出现 尤其容易受到剂量限制的TAH的影响，在关键的初始阶段可能会影响治疗效果 诱导期，并在儿科ALL复发和存活率方面造成公认的差异。这 Proposal坚持中心假设，即拉丁裔患者患TAH的风险比非拉丁裔患者更大 患者由于遗传和潜在的可改变的风险因素的组合。我们的初步数据显示 肥胖的种族差异加剧了TAH发病率的种族差异，但不能完全解释这一差异 血液中与肝功能有关的关键代谢物的丰度，可能受 治疗暴露和遗传遗传变异可能是TAH风险的强大生物标志物。知情者 通过我们的初步数据，本项目的具体研究目标将检验：1)种族差异有多大 肥胖和相关的肝功能障碍对TAH发病率的种族差异有贡献 儿科全诱导治疗；2)全化疗引起的变化是否一致和可辨认 参与肝功能的代谢途径可预测TAH；以及3)遗传变异 改变个体对TAH的易感性。该项目由具有以下专业知识的调查人员共同领导 儿科肿瘤学(Huynh和Orel博士)和分子流行病学(Brown博士)，建立在丰富的资源基础上 在种族多元化、多机构减少急性白血病的种族差距中可用(重拨) 财团。利用回顾(n=2,958)和预期(n=1,369)重定向队列，该项目 将系统地评估和跟踪另外600例新诊断的儿童ALL病例。因此，这一点 一项创新的提案将在一个多种族的队列中建立TAH最大的前瞻性调查之一 儿科患者均为ALL。这里概述的全面研究计划将解决我们在 了解TAH发病率和病因的种族差异，并作为TAH的独特来源 支持未来研究努力的初步数据。最终，我们预计这项工作将告知风险- 安全地向拉丁裔儿童和青少年提供治疗性诱导化疗的分层方法 对所有人进行治疗，以提高他们的总体存活率。

Project Summary This proposal seeks to integrate clinical, demographic, metabolomic, and genomic data to advance our understanding of ethnic 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. Emerging evidence from our group has identified striking ethnic disparities in the incidence of TAH. Specifically, Latino patients with ALL appear particularly vulnerable to dose-limiting TAH, potentially compromising treatment efficacy during the critical initial induction phase and contributing to well-established disparities in pediatric ALL relapse and survival. This proposal pursues the central hypothesis that risk of TAH is greater in Latino patients as compared to non-Latino patients due to a combination of inherited and potentially modifiable risk factors. Our preliminary data suggest ethnic disparities in TAH incidence are exacerbated but not fully explained by ethnic variation in obesity and that the abundance of key metabolites in the blood associated with liver function, which are likely influenced by treatment exposures and inherited genetic variation, may serve as powerful biomarkers of TAH risk. Informed by our preliminary data, the specific research aims of this Project will examine: 1) to what extent ethnic variability in obesity and associated hepatic dysfunction contribute to ethnic differences in the incidence of TAH during pediatric ALL induction therapy; 2) whether consistent and recognizable changes induced by ALL chemotherapy in the metabolomic pathways involved in liver function are predictive of TAH; and 3) how genetic variation modifies individual susceptibility to TAH. This Project, which is jointly led by investigators with expertise in pediatric oncology (Drs. Huynh and Orgel) and molecular epidemiology (Dr. Brown), builds on the rich resources available in the ethnically diverse, multi-institutional Reducing Ethnic Disparities in Acute Leukemia (REDIAL) consortium. Leveraging the Retrospective (n=2,958) and Prospective (n=1,369) REDIAL Cohorts, this project will systematically evaluate and follow an additional 600 newly diagnosed cases of pediatric ALL. Thus, this innovative proposal will establish one of the largest prospective investigations of TAH in a multi-ethnic cohort of pediatric patients with ALL. The comprehensive research plan outlined here will address key gaps in our understanding of ethnic 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 work will inform risk- stratified approaches to safely deliver curative induction chemotherapy to Latino children and adolescents treated for ALL to improve their overall survival.