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

项目摘要 该提案旨在整合临床，人口统计学，代谢组学和基因组学数据，以推进我们的研究。 了解儿科患者诱导治疗期间治疗相关肝毒性（TAH）的种族差异 急性淋巴细胞白血病（ALL）。儿童（ALL）治疗方案的改进导致生存率 发生率超过90%;然而，近四分之一的患者经历TAH。我们小组的新证据 发现了TAH发病率的显著种族差异。特别是，拉丁裔ALL患者似乎 特别容易受到剂量限制性TAH的影响，在关键的初始治疗期间可能会影响治疗效果。 诱导阶段，并导致儿童ALL复发和生存率的明显差异。这 该提案追求的中心假设是，与非拉丁裔患者相比，拉丁裔患者的TAH风险更高 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 TAH发病率的种族差异加剧，但不能完全解释为肥胖的种族差异， 血液中与肝功能相关的关键代谢物的丰度，可能受 治疗暴露和遗传性遗传变异可能是TAH风险的有力生物标志物。知情 根据我们的初步数据，本项目的具体研究目标是：1）种族差异在多大程度上 肥胖和相关肝功能障碍导致TAH发生率的种族差异， 儿童ALL诱导治疗; 2）ALL化疗是否诱导了一致和可识别的变化 参与肝功能的代谢组学途径预测TAH;以及3）遗传变异如何 改变个体对TAH的易感性。该项目由具有以下专长的调查人员共同领导： 儿科肿瘤学（Huynh和Orgel博士）和分子流行病学（Brown博士），建立在丰富的资源基础上 减少急性白血病的种族差异（REDIAL） 财团利用回顾性（n= 2，958）和前瞻性（n= 1，369）REDIAL队列，本项目 将系统地评估和随访另外600例新诊断的儿童ALL病例。因此， 创新的建议将建立一个最大的前瞻性研究之一，天阿赫在一个多种族的队列， 儿童ALL患者。本文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，并作为一个独特的资源， 初步数据，以支持未来的研究工作。最终，我们预计这项工作将告知风险- 对拉丁裔儿童和青少年安全提供治愈性诱导化疗的分层方法 治疗ALL以提高总体生存率。

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.