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.

项目概要 该提案旨在整合临床、人口统计、代谢组学和基因组数据，以推进我们的研究 了解儿科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）。改善儿科 (ALL) 治疗方案已提高了患者的生存率 率超过90%；然而，近四分之一的患者会经历 TAH。我们小组的新证据 已经发现 TAH 发病率存在显着的种族差异。具体来说，拉丁裔 ALL 患者出现 特别容易受到剂量限制性 TAH 的影响，在关键的初始阶段可能会损害治疗效果 诱导阶段并导致儿科 ALL 复发和生存方面的明显差异。这 该提案追求的中心假设是，与非拉丁裔患者相比，拉丁裔患者发生 TAH 的风险更大 由于遗传性和潜在可改变的危险因素的组合而导致的患者。我们的初步数据表明 TAH 发病率的种族差异加剧，但不能完全用肥胖的种族差异来解释，并且 血液中与肝功能相关的关键代谢物的丰度，可能受到以下因素的影响 治疗暴露和遗传性基因变异可能作为 TAH 风险的强大生物标志物。消息灵通 根据我们的初步数据，本项目的具体研究目标将考察：1）种族变异程度 肥胖和相关肝功能障碍导致 TAH 发病率存在种族差异 儿童 ALL 诱导治疗； 2) ALL化疗引起的变化是否一致且可识别 涉及肝功能的代谢组学途径可预测 TAH； 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业知识的研究人员共同领导 儿科肿瘤学（Huynh 博士和 Orgel 博士）和分子流行病学（Brown 博士）建立在丰富的资源之上 可在种族多样化、多机构减少急性白血病种族差异 (REDIAL) 中获得 财团。该项目利用回顾性 (n=2,958) 和前瞻性 (n=1,369) 重拨队列 将系统评估和跟踪另外 600 例新诊断的儿科 ALL 病例。因此，这个 创新提案将在多种族队列中建立最大规模的 TAH 前瞻性研究之一 患有 ALL 的儿科患者。这里概述的全面研究计划将解决我们的关键差距 了解 TAH 发病率和病因的种族差异，并作为 支持未来研究工作的初步数据。最终，我们预计这项工作将为风险提供信息 为拉丁裔儿童和青少年安全提供治疗性诱导化疗的分层方法 对 ALL 进行治疗以提高其总体生存率。