Ethnic Differences in Survival after Childhood ALL

描述(申请人提供)：急性淋巴细胞性白血病(ALL)是最常见的儿童恶性肿瘤，五年存活率接近80%。我们已经显示出族裔和种族群体之间在存活率方面存在着非常显著的差异。在被研究的四个民族和种族中，缓解率相似(97%到99%)，但复发率 有显著差异，导致观察到的无事件生存(EFS)差异。非洲裔美国儿童的结果最差，而亚裔儿童的结果最好。拉美裔美国人的结果介于高加索人和非裔美国人之间。多变量分析显示，种族/民族背景与EFS下降独立相关，即使在控制了已知的危险因素，如确诊时的年龄、高初始白细胞计数和与不良结局相关的染色体异常后也是如此。因此，对这一大群8,447名患者的随访表明，来自不同民族和种族背景的儿童的存活率毕竟是显著不同的。观察到的不同种族结果差异的原因(S)尚不清楚。ALL的治疗需要大约两年的维持期，包括口服抗代谢药物[6-巯基嘌呤(6MP)和甲氨蝶呤(MTX)]，以实现持久缓解。在维持治疗期间，全身低剂量口服6MP(以红细胞抗代谢药物浓度为代表)已被证明会对预后产生不利影响。红细胞6MP代谢物水平在患者之间存在显著差异，这可能源于6MP的吸收、代谢或消除速度的差异，或者由于未能坚持治疗。我们假设，在维持治疗期间全身暴露于6MP的种族/种族差异，主要是由于不坚持6MP，可以解释观察到的儿童结局的差异全部由种族/民族决定。我们的目标是：1)确定接受维持化疗的四个不同民族和种族的儿童(高加索人、非裔美国人、拉美裔人和亚裔)对6MP的依从性。将通过测量红细胞6MP代谢物(6TGN，甲基TIMP)、使用电子药片监测系统(MEMS)6MP剂量的频率以及遵守6MP的自我报告来评估依从性；ii)在调整已知的疾病结局预测因素后，确定遵守6MP对整个研究队列的EFS的影响；iii)定义对整个队列的EFS有重大影响的遵守的临界水平(由6TGN、MEMS、自我报告独立衡量)；iv)使用(Iii)的定义，按种族描述遵守6MP的流行率；v)使用问卷数据描述遵守的行为和社会人口预测因素；Vi)使用MEMS数据描述该队列中的服药做法；以及vii)评估坚持服药对EFS中的族裔/种族差异的影响。我们将控制TPMT的多态和其他遗传多态(转运蛋白、修复酶、HPRT等)，以及控制种族群体之间潜在的疾病负担和生物学差异。我们的总体目标是进行一项跨民族的全面研究，以阐明观察到的种族和民族存活率差异的原因，从而建立一个框架，以便在未来采取适当的干预措施来解决这一问题(S)。

DESCRIPTION (provided by applicant): Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, with a five-year survival rate approaching 80%. We have shown highly significant differences in survival among ethnic and racial groups. The remission rates were comparable among the four ethnic and racial groups (97% to 99%) studied, but the relapse rates were significantly different, resulting in the observed difference in Event-Free Survival (EFS). African-American children had the poorest and Asians the best outcome. The outcome for Hispanics was intermediate between that for Caucasians and African-Americans. Multivariate analysis revealed racial/ethnic background to be independently associated with decreased EFS, even after controlling for known risk factors such as age at diagnosis, high initial white count and chromosomal abnormalities associated with adverse outcomes. Thus, follow-up of this large cohort of 8,447 patients documents that survival rates after ALL are significantly different for children from different ethnic and racial backgrounds. The reason(s) for the observed differences in outcome by ethnicity are not clear. Treatment of ALL requires a maintenance phase of approximately two years composed of oral administration of antimetabolites [6-Mercaptopurine (6MP) and methotrexate (MTX)] in order to achieve durable remissions. Low systemic exposure to oral 6MP during maintenance therapy (represented by red cell antimetabolite concentrations) has been shown to adversely affect prognosis. There is significant inter-patient variability in red cell 6MP metabolite levels that could stem from differences in the rates of absorption, metabolism, or elimination of 6MP, or because of failure to adhere to therapy. We hypothesize that ethnic/racial difference in systemic exposure to 6MP during maintenance therapy, due primarily to non-adherence to 6MP, could explain the observed differences in outcome of childhood ALL by race/ethnicity. We aim to i) determine adherence to 6MP in a cohort of children with ALL from four different ethnic and racial groups (Caucasians, African-Americans, Hispanics, and Asians) receiving maintenance chemotherapy. Adherence will be assessed by measuring red cell 6MP metabolites (6TGN, MethylTIMP), frequency of 6MP dosing using an electronic pill monitoring system (MEMS), and self report of adherence to 6MP; ii) determine the impact of adherence to 6MP on EFS in the entire cohort studied, after adjusting for known predictors of disease outcome; iii) define a critical level of adherence (measured independently by 6TGN, MEMS, self-report) that has a significant impact on EFS for the entire cohort; iv) using the definition from (iii), describe prevalence of adherence to 6MP by ethnicity; v) describe behavioral and socio-demographic predictors of adherence using the questionnaire data; vi) describe the pill-taking practices in this cohort using the MEMS data; and vii) evaluate the impact of adherence on ethnic/racial difference in EFS. We will control for polymorphisms in TPMT, and other genetic polymorphisms (in transporters, repair enzymes, HPRT, etc.), as well as control for potential differences in disease burden and biology among the ethnic groups. Our overall goal is to conduct a comprehensive study across ethnic groups to elucidate the reasons for the observed differences in survival by race and ethnicity, thus building a framework for appropriate intervention(s) to address this problem in the future.