Ethnic disparities in methotrexate neurotoxicity among children and adolescents with ALL

项目2：急性胰腺炎儿童和青少年甲氨蝶呤神经毒性的种族差异 淋巴细胞性白血病 项目摘要 改进儿童急性淋巴细胞性白血病(ALL)的治疗，包括采用风险- 在大多数发达国家，经过调整的多药剂化疗导致五年存活率超过85% 国家。抗叶酸剂甲氨蝶呤(MTX)是治疗儿科ALL方案的关键成分。 大约10%的儿童ALL患者在鞘内(IT)后经历了急性或亚急性神经毒性 或大剂量静脉注射甲氨蝶呤。然而，拉丁裔儿童似乎经历了与MTX相关的神经毒性 更频繁地。此外，甲氨蝶呤相关神经毒性的临床处理通常涉及治疗延误。 和/或修饰，这可能限制抗白血病疗效并影响生存。可能有许多因素 导致儿科所有神经毒性和相关治疗结果的差异，包括临床 特征、药物基因组学、疾病特征和社会经济因素。值得注意的是，种族和民族 儿科所有结果的差异，包括复发，可以部分解释为潜在的 遗传祖先，提示参与抗白血病治疗的变异的频率和药效学 药代动力学在不同的祖先群体中不同。我们的总体目标是更好地理解这些因素 导致急性淋巴细胞白血病拉美裔儿童在治疗相关毒性和治疗结果方面的差异。 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 在这一脆弱的儿童群体中，造成更差的结果。为了实现我们的目标，我们建议 三个具体目标。目的1：比较急性甲氨喋呤神经毒性对临床疗程和 拉美裔和非拉丁裔白人ALL患者之间的转归(例如，复发)。目标2：确定临床， 甲氨蝶呤初始神经毒性和神经毒性的社会经济学、药物基因组学和代谢组学预测因子 MTX再次挑战后的复发，同时考虑到种族的影响。目标3：找出 脑白质完整性与甲氨蝶呤首次神经毒性和甲氨蝶呤再灌注后神经毒性复发的关系 在种族差异的背景下，使用标准和新颖的成像技术是一项挑战。该项目将提供 对导致急性淋巴细胞白血病拉美裔儿童神经毒性增加的因素的洞察并可能确定 高危个体的药物基因组和成像特征，允许预防初始或后续事件， 和改善所有结果。

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.