Ethnic disparities in methotrexate neurotoxicity among children and adolescents with ALL

患有 ALL 的儿童和青少年中甲氨蝶呤神经毒性的种族差异

• 批准号: 10472703
• 负责人: Michael E Scheurer
• 金额: $ 7.45万
• 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/10472703
• 关键词: Accounting; Acute; Acute Lymphocytic Leukemia; Acute leukemia; Address; Adolescent; Adoption; Age; Aphasia; Blood specimen; Characteristics; Child; Childhood Acute Lymphocytic Leukemia; Clinical; Clinical Management; Clinical Treatment; Data; Developed Countries; Development; Diagnosis; Disease; Dose; Encephalopathies; Ethnic Origin; Event; Folic Acid Antagonists; Frequencies; Genetic; Goals; Image; Incidence; Individual; Intravenous; Latino; Latino Population; MRI Scans; Magnetic Resonance Imaging; Malignant Childhood Neoplasm; Methotrexate; Modification; Molecular; Native American Ancestry; Outcome; Patient Monitoring; Patients; Pharmacogenomics; Population; Prevention; Prospective cohort; Protocols documentation; Recurrence; Relapse; Reporting; Retrospective cohort; Risk; Sampling; Seizures; Socioeconomic Factors; Subgroup; Survival Rate; Symptoms; Techniques; Treatment outcome; Treatment-related toxicity; Tumor Biology; Variant; Vulnerable Populations; base; chemotherapy; ethnic disparity; ethnic diversity; experience; improved outcome; insight; metabolomics; neural network; neuroimaging marker; neurotoxic; neurotoxicity; novel imaging technique; patient subsets; pharmacokinetics and pharmacodynamics; prospective; racial and ethnic disparities; relapse risk; sex; social health determinants; socioeconomics; tractography; treatment disparity; treatment risk; white matter

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.

项目 2：急性甲氨蝶呤儿童和青少年神经毒性的种族差异 淋巴细胞白血病 项目概要 儿童急性淋巴细胞白血病（ALL）治疗的改进，包括采用风险- 经过调整的多药化疗已使大多数发达国家的五年生存率超过 85% 国家。抗叶酸剂甲氨蝶呤 (MTX) 是儿科 ALL 治疗方案的重要组成部分。 大约 10% 的儿童 ALL 患者在鞘内 (IT) 后经历急性或亚急性神经毒性 或高剂量静脉注射 (IV) MTX。然而，拉丁裔儿童似乎经历了 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常常涉及治疗延误 和/或修饰，这可能会限制抗白血病功效并影响生存。多种因素可能 导致儿科 ALL 神经毒性和相关治疗结果（包括临床）的差异 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 儿童 ALL 结局（包括复发）的差异可以部分解释为 遗传祖先，表明参与抗白血病治疗药效学的变异频率和 不同祖先人群的药代动力学有所不同。我们的总体目标是更好地了解这些因素 导致拉丁裔 ALL 儿童中治疗相关毒性和治疗结果的差异。 我们的首要假设是，潜在的种系遗传学、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。目标 1：比较急性 MTX 神经毒性对临床治疗过程和治疗过程的影响 拉丁裔和非拉丁裔白人 ALL 患者之间的结局（例如复发）。目标 2：识别临床、 初始 MTX 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素 MTX 再次挑战后复发，同时考虑种族的影响。目标 3：识别变化 白质完整性与初始 MTX 神经毒性和 MTX 再次治疗后神经毒性复发相关 在种族差异的背景下，使用标准和新颖的成像技术进行挑战。该项目将提供 深入了解拉丁裔 ALL 儿童神经毒性增加的因素，并可能确定 高危个体的药物基因组学和影像学特征，可以预防初始或后续事件， 和改善所有结果。