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: 10289496
• 负责人: Michael E Scheurer
• 金额: $ 18.71万
• 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/10289496
• 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; 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：急性儿童和青少年甲氨蝶呤神经毒性的种族差异 淋巴细胞白血病 项目摘要 改善儿童急性淋巴细胞白血病（所有）的治疗方法，包括采用风险 改编，多药化疗，导致五年生存率超过85％ 国家。抗叶酸剂甲氨蝶呤（MTX）是治愈儿科的关键组成部分。 大约10％的小儿所有患者在鞘内经历急性或亚急性神经毒性（IT）（IT） 或大剂量静脉（IV）MTX。但是，拉丁裔儿童似乎经历了与MTX相关的神经毒性 更频繁。此外，与MTX相关的神经毒性的临床管理通常涉及治疗延迟 和/或修改，这可能会限制抗白血病功效并影响生存。许多因素可能 促进儿科差异所有神经毒性和相关治疗结果，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种族 小儿所有结果（包括复发）的差异可以部分通过差异来解释 遗传血统，表明与抗血清血症治疗药效学和 药代动力学在祖先种群中各不相同。我们的总体目标是更好地了解因素 有助于与治疗相关的毒性差异和所有人的拉丁裔儿童的治疗结果。 我们的总体假设是，潜在的种系遗传学，肿瘤生物学和健康的社会决定因素 在这一脆弱的儿童人群中有助于较差的结果。为了解决我们的目标，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的影响 拉丁裔和非拉丁裔白人患者之间的结果（例如，复发）。目标2：确定临床， 初始MTX神经毒性和神经毒性的社会经济，药物基因组和代谢组预测指标 MTX重新挑战后的复发，同时考虑了种族的影响。目标3：确定改变 与初始MTX神经毒性和神经毒性复发相关的白质完整性MTX恢复 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。这个项目将提供 洞悉负责增加的所有人神经毒性的因素，并可能确定 允许预防初始或后续事件的高危个体的药物基因组学和成像特征， 以及所有结果的改善。