A Systems Epidemiology Approach for Predicting Methotrexate Neurotoxicity in Pediatric Acute Leukemia

项目摘要 急性淋巴细胞白血病（ALL）是儿童时期最常见的癌症。虽然存活率 虽然近几十年来儿童ALL有所改善，但种族差异仍然存在。与大多数其他种族相比， 拉丁美洲人的儿童ALL发病率较高，生存率较差。这些疾病的病因 差异是复杂的，尚未完全理解，但种族特异性的生物变异性有助于增加 治疗相关毒性是导致结果差异的一个重要但研究不足的原因。比如说 抗代谢药甲氨蝶呤是治愈性ALL化疗的关键成分， 约10%的患者出现临床神经毒性。然而，我们小组的新证据表明， 在神经毒性的发生率方面发现了显著的种族差异。特别是，拉丁裔ALL患者似乎 特别容易受到剂量限制性临床神经毒性的影响，可能影响治疗效果， 导致儿童ALL复发率和生存率的明显差异。本项目的总体目标 是通过确定预测增加的宿主因素来减少拉丁美洲儿童和青少年之间的差异 在毒性方面。我们的初步研究提供了证据表明轻度到中度的急性神经症状， 包括经常发生但在临床环境中没有常规评估的疼痛， 临床甲氨蝶呤神经毒性。我们的数据进一步表明脑脊液代谢物的水平， 受治疗和遗传变异的共同影响，以及改变的白色物质完整性的神经影像学生物标志物 为甲氨蝶呤相关神经损伤的机制提供了新的见解。根据我们初步的 数据，本项目的具体研究目标将检查：1）在多大程度上前瞻性收集的患者- 报告的神经系统症状可在临床上出现前识别出具有临床前毒性的患者， 明显的神经毒性，2）将基因组学与中枢神经系统的前瞻性分析相结合的综合方法 神经系统代谢组学途径可以识别神经毒性的分子预测因子，以及3）潜在的 新的神经影像学技术在识别与未来脑梗死相关的白色物质完整性改变中的应用 神经毒性风险。该项目建立在种族多样性、多机构、 减少急性白血病种族差异（REDIAL）联盟。利用REDIAL队列， 储存生物样本，该项目系统地评估和跟踪额外的新诊断病例 儿科ALL因此，这一创新提案将建立一个最大的前瞻性调查， 神经毒性在一个多种族的急性淋巴细胞白血病患儿队列。综合研究计划概述 在这项建议中，将解决我们在理解种族差异的发病率和病因方面的关键差距， 神经毒性最终，我们预计这一系列研究将为风险分层方法提供信息， 为接受ALL治疗的拉丁裔儿童和青少年提供治疗性化疗，以提高他们的总体生存率。

PROJECT ABSTRACT Acute lymphoblastic leukemia (ALL) is the most common cancer diagnosed in childhood. Although survival rates for childhood ALL have improved in recent decades, ethnic disparities persist. Compared to most other ethnic groups, Latinos experience both a higher incidence of childhood ALL and poorer survival. The etiology of these disparities is complex and not fully understood, but ethnic-specific biological variability contributing to increased treatment-related toxicities are an important, under-studied cause of disparities in outcomes. For example, the antimetabolite agent methotrexate, a key component of curative ALL chemotherapy, results in dose-limiting clinical neurotoxicity in approximately 10% of patients. However, emerging evidence from our group has identified striking ethnic disparities in the incidence of neurotoxicity. Specifically, Latino patients with ALL appear particularly vulnerable to dose-limiting clinical neurotoxicity, potentially compromising treatment efficacy and contributing to well-established disparities in pediatric ALL relapse and survival. The overall goal of this project is to reduce disparities among Latino children and adolescents by identifying host factors that predict an increase in toxicity. Our preliminary studies provide evidence that mild to moderate acute neurological symptoms, including pain, which occur frequently but are not routinely assessed in clinical settings, often precede the onset of clinical methotrexate neurotoxicity. Our data further suggest that levels of cerebrospinal fluid metabolites, jointly influenced by therapy and genetic variation, and neuroimaging biomarkers of altered white matter integrity provide novel insights into mechanisms of methotrexate-related neurologic injury. Informed by our preliminary data, the specific research aims of this project will examine: 1) to what extent do prospectively collected patient- reported neurologic symptoms identify patients with preclinical toxicity prior to the development of clinically evident neurotoxicity, 2) whether integrative approaches combining genomics with prospective profiling of central nervous system metabolomic pathways can identify molecular predictors of neurotoxicity, and 3) the potential utility of novel neuroimaging techniques to identify alterations in white matter integrity associated with future neurotoxicity risk. This project builds on the rich resources available in the ethnically diverse, multi-institutional Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium. Leveraging the REDIAL Cohort with banked biological samples, this project with systematically evaluate and follow additional newly-diagnosed cases of pediatric ALL. Therefore, this innovative proposal will establish one of the largest prospective investigations of neurotoxicity in a multi-ethnic cohort of pediatric patients with ALL. The comprehensive research plan outlined in this proposal will address key gaps in our understanding ethnic disparities in the incidence and etiology of neurotoxicity. Ultimately, we anticipate that this line of research will inform risk-stratified approaches to safely deliver curative chemotherapy to Latino children and adolescents treated for ALL to improve their overall survival.