Improving Outcome Disparities for Latino Children and Adolescents with Acute Lymphoblastic Leukemia

摘要 急性淋巴细胞性白血病(ALL)是儿童最常见的癌症，尽管治愈率 在过去的50年里，种族差距有所改善，但仍然存在。特别是，拉丁裔的发病率最高， 是美国白血病存活率最低的国家之一。造成这种差异的根本原因是多因素的， 包括肿瘤和宿主生物学的差异，以及社会/行为因素，如有限的医疗保健 进入。宿主药物基因组学和其他导致治疗相关毒性增加的生物因素 是造成种族结果差异的一个关键且未得到充分研究的原因。不良后果都是由直接的 与治疗相关的发病率和死亡率，以及提供足够强度的抗病毒药物的能力受损 白血病治疗。 P20计划的总体目标是减少拉丁裔儿童和青少年之间的结果差异 通过识别导致毒性增加的宿主生物因素，并为建立 首批致力于儿童白血病的卓越研究专门项目(孢子)之一。两个人 初步研究项目将确定与两种主要治疗相关毒性的风险相关的因素， 肝毒性和神经毒性，对治疗结果产生不利影响，并不成比例地发生在 拉丁裔。最终的孢子将通过(1)采取预防和治疗策略来扩展这项工作 以及(2)调查其他临床有效治疗相关毒性的种族差异。该计划将 通过行政核心(核心A)进行管理。生物质谱仪将由核心B处理，以及 统计分析将由Core C提供。开发研究计划将促进 旨在了解和/或减少所有成果中基于族裔的差距的创新试点项目。我们 将利用由6种癌症组成的缩小急性白血病(REDIAL)联盟的种族差异 该中心将提供3,000份临床数据和临床数据、骨髓、 近2000例新诊断的ALL儿童和青少年的血液和脑脊液样本 以下是两个新颖的综合项目。 我们协同整合的团队将确定与肝毒性相关的关键生物学因素 神经毒性，导致种族结果差异的重要因素。更广泛地说，该计划将进一步 加强和扩大REDIAL联盟及其宝贵的种族多样性数据集和生物储存库， 并对其用于开发风险预测模型进行建模，该模型识别存在毒性风险的拉丁裔患者，并 阐明潜在的生物学机制。这项工作将为未来的孢子奠定基础， 调查所有疗法的额外毒性，并将这些发现转化为有效的开发 干预策略。这种有效的货币投资将导致结果的显著减少 拉美裔儿童和青少年与ALL之间的差距。

Summary Acute lymphoblastic leukemia (ALL) is the most common cancer in children and, although cure rates have improved over the past 50 years, ethnic disparities persist. In particular, Latinos have the highest incidence and among the lowest survival rates for leukemia in the U.S. The underlying causes of this disparity are multi-factorial, including differences in tumor and host biology, as well as social/behavioral factors such as limited healthcare access. Host pharmacogenomics and other biological factors resulting in increased treatment-related toxicities are a key and under-studied cause of ethnic disparities in outcomes. Adverse outcomes result both from direct treatment-associated morbidity and mortality, and from compromised ability to deliver sufficiently intensive anti- leukemic therapy. The overall goals of this P20 program are to reduce outcome disparities among Latino children and adolescents by identifying host biological factors that result in increased toxicities, and to lay the groundwork for establishment of the first Specialized Programs of Research Excellence (SPORE) devoted to pediatric leukemia. The two primary Research Projects will identify factors associated with risk for two key treatment-related toxicities, hepatotoxicity and neurotoxicity, which adversely impact treatment outcomes and occur disproportionately in Latinos. The eventual SPORE will expand upon this work by (1) pursuing prevention and treatment strategies and (2) investigating ethnic disparities in other clinically impactful treatment-related toxicities. The Program will be administered through the Administrative Core (Core A). Biospecimens will be processed by Core B, and statistical analysis will be provided by Core C. A Developmental Research Program will foster development of innovative pilot projects that aim to understand and/or reduce ethnicity-based disparities in ALL outcomes. We will leverage the Reducing Ethnic Disparities in Acute Leukemia (REDIAL) Consortium, comprising 6 cancer centers in the southwestern U.S., which will provide clinical data from 3,000 and clinical data, bone marrow, blood and cerebrospinal fluid samples from nearly 2,000 children and adolescents with newly diagnosed ALL for the following two novel and integrated Projects. Our synergistically integrated team will define key biological factors associated with hepatotoxicity and neurotoxicity, important contributors to ethnic outcome disparities. More broadly, this Program will further strengthen and expand the REDIAL Consortium, with its invaluable ethnically diverse dataset and biorepository, and model its use for development of risk prediction models that identify Latino patients at risk for toxicities and illuminate the underlying biology mechanisms. This work will form the foundation for a future SPORE that will investigate additional toxicities of ALL therapy, and translate these findings into development of effective intervention strategies. This efficient monetary investment will result in significant reductions in outcome disparities in Latino children and adolescents with ALL.