Ethnic disparities in methotrexate neurotoxicity among children and adolescents with ALL

项目2：儿童和青少年急性甲氨蝶呤神经毒性的种族差异 淋巴细胞白血病 项目摘要 儿童急性淋巴细胞白血病（ALL）治疗的改进，包括采用风险- 适应，多剂化疗，导致五年生存率超过85%，在大多数发达国家， 国家抗叶酸剂甲氨蝶呤（MTX）是治疗小儿ALL方案的关键组成部分。 大约10%的儿童ALL患者在鞘内（IT）给药后发生急性或亚急性神经毒性 或高剂量静脉内（IV）MTX。然而，拉丁裔儿童似乎经历MTX相关的神经毒性， 更频繁。此外，MTX相关神经毒性的临床管理通常涉及治疗延迟 和/或修饰，这可能限制抗白血病功效并影响存活。可能有很多因素 导致儿科ALL神经毒性和相关治疗结局的差异，包括临床 特征、药物基因组学、疾病特征和社会经济因素。特别是，种族和族裔 儿科ALL结局（包括复发）的差异部分可以解释为 遗传祖先，表明抗白血病治疗药效学中涉及的变异频率， 药代动力学在祖先群体中不同。我们的总体目标是更好地了解 导致拉丁裔ALL儿童中治疗相关毒性和治疗结局的差异。 我们的总体假设是，潜在的生殖系遗传学、肿瘤生物学和健康的社会决定因素 导致这一弱势儿童群体的结果更差。为了实现我们的目标，我们建议 三个具体目标。目的1：比较甲氨蝶呤急性神经毒性对临床治疗过程的影响， 结果（例如，复发）之间的拉丁美洲和非拉丁美洲白色患者的ALL。目的2：确定临床， 社会经济学、药物基因组学和代谢组学对MTX初始神经毒性和神经毒性预测 MTX再激发后复发，同时考虑种族的影响。目标3：确定 白色物质完整性与MTX初始神经毒性和MTX再治疗后神经毒性复发相关 在种族差异的背景下，使用标准和新型成像技术的挑战。本项目将提供 深入了解拉丁裔ALL儿童神经毒性增加的因素， 风险个体的药物基因组学和成像特征，可预防初始或后续事件， 改善所有结果。

Project 2: Ethnic disparities in methotrexate neurotoxicity among children and adolescents with acute lymphoblastic leukemia Project Summary Improvements in the treatment of childhood acute lymphoblastic leukemia (ALL), including the adoption of risk- adapted, multi-agent chemotherapy, have resulted in five-year survival rates exceeding 85% in most developed countries. The antifolate agent methotrexate (MTX) is a critical component of curative pediatric ALL protocols. Approximately 10% of pediatric ALL patients experience acute or subacute neurotoxicity following intrathecal (IT) or high-dose intravenous (IV) MTX. However, Latino children appear to experience MTX-associated neurotoxicity more frequently. Further, the clinical management of MTX-related neurotoxicity often involves treatment delays and/or modifications, which may limit anti-leukemic efficacy and impact survival. A number of factors likely contribute to disparities in pediatric ALL neurotoxicity and related treatment outcomes, including clinical characteristics, pharmacogenomics, disease features, and socioeconomic factors. Notably, racial and ethnic disparities in pediatric ALL outcomes, including relapse, can be explained in part by underlying variation in genetic ancestry, suggesting the frequency of variants involved in antileukemia therapy pharmacodynamics and pharmacokinetics vary across ancestral populations. Our overall goal is to better understand the factors contributing to disparities in treatment-related toxicities and treatment outcomes among Latino children with ALL. Our overarching hypothesis is that underlying germline genetics, tumor biology, and social determinants of health contribute to poorer outcomes in this vulnerable population of children. To address our goal, we propose the three specific aims. Aim 1: Compare the impact of acute MTX neurotoxicity on clinical treatment course and outcomes (e.g., relapse) between Latino and non-Latino White patients with ALL. Aim 2: Identify clinical, socioeconomic, pharmacogenomic, and metabolomic predictors of initial MTX neurotoxicity and neurotoxicity recurrence following MTX re-challenge, while accounting for the impact of ethnicity. Aim 3: Identify alterations in white matter integrity associated with initial MTX neurotoxicity and neurotoxicity recurrence following MTX re- challenge using standard and novel imaging techniques, in the context of ethnic variation. This project will provide insights into the factors responsible for increased neurotoxicity in Latino children with ALL and may identify pharmacogenomic and imaging features of at-risk individuals that allow prevention of initial or subsequent events, and improvement of ALL outcomes.