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

项目摘要 急性淋巴细胞性白血病(ALL)是儿童时期诊断的最常见的癌症。虽然存活率 近几十年来，儿童状况都有所改善，但种族差距依然存在。与大多数其他民族相比 在拉美裔群体中，拉美裔儿童ALL的发病率较高，存活率较低。这些疾病的病因 差异是复杂的，也没有被完全理解，但种族特定的生物变异性导致了 与治疗相关的毒性是一个重要的、研究不足的结果差异的原因。例如， 抗代谢药物甲氨蝶呤是治疗所有化疗的关键成分，导致剂量限制 约10%的患者出现临床神经毒性。然而，来自我们小组的新证据已经 确定了神经毒性发生率的显著种族差异。具体来说，拉丁裔ALL患者出现 特别容易受到剂量限制的临床神经毒性的影响，可能会损害治疗效果和 造成儿科复发率和存活率的明显差异。这个项目的总体目标是 是通过确定预测增长的宿主因素来减少拉丁裔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， 包括经常发生但不在临床环境中进行常规评估的疼痛，通常在发病之前 临床上甲氨蝶呤的神经毒性。我们的数据进一步表明，脑脊液代谢物的水平， 白质完整性改变的治疗和遗传变异以及神经影像生物标记物的共同影响 为甲氨蝶呤相关神经损伤的机制提供新的见解。由我们初步提供的信息 数据，本项目的具体研究目标将检验：1)前瞻性收集患者- 报告的神经学症状表明，患者在临床发展之前存在临床前毒性。 明显的神经毒性，2)将基因组学与中枢神经系统的前瞻性图谱相结合的综合方法 神经系统代谢途径可以识别神经毒性的分子预测因子，以及3)潜在的 新的神经成像技术在识别与未来相关的白质完整性改变方面的应用 神经毒性风险。这个项目建立在种族多元化、多机构的丰富资源的基础上 减少急性白血病(REDIAL)联盟的种族差异。利用重拨队列 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 所有的儿科疾病。因此，这项创新的提议将建立最大的前瞻性调查之一 多民族急性淋巴细胞白血病儿童患者的神经毒性研究。概述了全面的研究计划 在这项提案中将解决我们在认识上的主要差距，在发病率和病因方面的种族差异 神经毒性。最终，我们预计这一系列研究将提供安全的风险分层方法 为所有接受治疗的拉丁裔儿童和青少年提供根治性的化疗，以提高他们的总体存活率。

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.