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

接受 ALL 治疗的儿童和青少年中治疗相关肝毒性的病因学和种族差异的影响

• 批准号: 10472698
• 负责人: Austin L Brown
• 金额: $ 8.85万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-20 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10472698
• 关键词: Acute Lymphocytic Leukemia; Acute leukemia; Address; Adolescent; Adverse event; Affect; Bilirubin; Biological; Biological Markers; Blood; Blood specimen; Body fat; Body mass index; Child; Childhood; Childhood Acute Lymphocytic Leukemia; Clinical; Complication; Data; Diagnosis; Diagnostic; Disease-Free Survival; Dose-Limiting; Ethnic Origin; Etiology; Fatty acid glycerol esters; Functional disorder; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Glucose; Goals; Hepatic; Hepatotoxicity; Incidence; Individual; Inflammation; Inherited; Intake; Intervention; Investigational Therapies; Latino; Latino Population; Leukemia Acute Lymphoblastic Chemotherapy; Lipids; Liver; Magnetic Resonance Imaging; Metabolic; Metabolic Pathway; Methods; Molecular Epidemiology; Monitor; Morbidity - disease rate; Neoadjuvant Therapy; Newly Diagnosed; Nutritional; Obesity; Pathway interactions; Patient Self-Report; Patients; Pediatric Oncology; Pediatric cohort; Pharmacogenomics; Pharmacometabolomics; Phase; Phenotype; Predisposition; Prevalence; Quality of life; Quantitative Trait Loci; Regimen; Relapse; Research; Research Personnel; Resources; Risk; Risk Factors; Role; Sampling; Severities; Survival Rate; Susceptibility Gene; Therapeutic; Toxic effect; Treatment Efficacy; Treatment Protocols; Treatment outcome; Treatment-related toxicity; Variant; Work; acute liver injury; admixture mapping; adverse outcome; amino acid metabolism; cancer therapy; case control; chemotherapy; cohort; ethnic difference; ethnic disparity; ethnic diversity; experience; genetic variant; genomic data; high risk; improved; improved outcome; innovation; insight; leukemia relapse; liver function; metabolomics; modifiable risk; multi-ethnic; multiple omics; non-alcoholic fatty liver disease; novel marker; pediatric patients; prospective; response; risk stratification; targeted delivery; therapeutic target; translational potential; treatment disparity; treatment risk

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.

项目摘要 该建议旨在整合临床，人口统计学，代谢组和基因组数据，以促进我们的 在儿科诱导治疗期间，了解与治疗相关的肝毒性（TAH）中种族差异的理解 急性淋巴细胞白血病（全部）。改进的小儿治疗方案（所有）已导致生存 比率超过90％；但是，将近四分之一的患者经历了TAH。来自我们小组的新兴证据 已经确定了TAH发病率的巨大种族差异。具体来说，有既有的拉丁裔患者 特别容易受到限制剂量的tah，在关键初始初始中可能会损害治疗功效 诱导阶段并导致小儿复发和生存的良好差异。这 提案提出了一个核心假设，即拉丁裔患者的TAH风险更大 由于遗传和可能修改的危险因素的结合而导致的患者。我们的初步数据暗示 TAH发病率的种族差异加剧，但并未完全被肥胖的种族差异所解释， 与肝功能相关的血液中的主要代谢产物的丰度很可能受 治疗暴露和遗传差异可能是TAH风险的强大生物标志物。通知 根据我们的初步数据，该项目的具体研究目的将检查：1）种族可变性在多大程度上 在肥胖和相关的肝功能障碍中，在TAH发生率的种族差异有助于 儿科所有诱导疗法； 2）是否由所有化学疗法引起的一致和可识别的变化 在参与肝功能的代谢组途径中，可以预测TAH。 3）遗传变异如何 修改了对tah的个人敏感性。该项目由具有专业知识的调查员共同领导 小儿肿瘤学（Huynh和Orgel博士）和分子流行病学（Brown Dr.）建立在丰富的资源的基础上 可在种族多样化的，多机构的降低急性白血病（REDIAIL）的种族差异 财团。利用回顾性（n = 2,958）和预期（n = 1,369）REDIAIL COHORTS，该项目 将系统地评估并遵循另外600例新诊断的小儿所有病例。因此，这个 创新的提案将在多种族队列中建立对TAH最大的预期调查之一 儿科患者全部。这里概述的全面研究计划将解决我们的关键差距 理解TAH的发病率和病因中种族差异，并作为独特的资源 初步数据以支持未来的研究努力。最终，我们预计这项工作将为风险提供信息 - 分层的方法可以安全地为拉丁裔儿童和青少年提供治疗诱导化疗 治疗所有人，以改善其整体生存。