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

总结 急性淋巴细胞白血病 (ALL) 是儿童中最常见的癌症，尽管治愈率有所下降 过去50年有所改善，但种族差异依然存在。尤其是拉丁裔的发病率最高 是美国白血病生存率最低的国家之一。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，例如有限的医疗保健 访问。宿主药物基因组学和其他生物因素导致治疗相关毒性增加 是导致种族结果差异的一个关键且尚未得到充分研究的原因。不良后果是由直接原因造成的 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治疗的能力受损 白血病治疗。 该 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，并为建立奠定基础 第一个致力于儿童白血病的专业卓越研究计划 (SPORE)。两人 主要研究项目将确定与两种关键治疗相关毒性风险相关的因素， 肝毒性和神经毒性，对治疗结果产生不利影响，且发生率不成比例 拉丁裔。最终的 SPORE 将通过 (1) 追求预防和治疗策略来扩展这项工作 (2) 调查其他具有临床影响的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。生物样本将由 Core B 处理，并且 统计分析将由核心 C 提供。发展研究计划将促进 旨在了解和/或减少所有结果中基于种族的差异的创新试点项目。我们 将利用由 6 种癌症组成的减少急性白血病种族差异 (REDIAL) 联盟 位于美国西南部的中心，将提供 3,000 名患者的临床数据以及骨髓、 来自近 2,000 名新诊断为 ALL 的儿童和青少年的血液和脑脊液样本 以下两个新颖且综合的项目。 我们的协同整合团队将定义与肝毒性和相关的关键生物学因素 神经毒性，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化数据集和生物存储库， 并对其用于开发风险预测模型进行建模，该模型可识别有毒性风险的拉丁裔患者和 阐明潜在的生物学机制。这项工作将为未来的 SPORE 奠定基础 研究 ALL 治疗的其他毒性，并将这些发现转化为有效药物的开发 干预策略。这种有效的货币投资将导致结果显着降低 患有 ALL 的拉丁裔儿童和青少年的差异。

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.