Ethnic Differences in Survival after Childhood ALL

描述（由申请人提供）：急性淋巴细胞白血病（ALL）是最常见的儿童恶性肿瘤，五年生存率接近80%。我们已经发现，不同种族和民族之间的生存率存在非常显著的差异。研究的四个种族和人种组的缓解率相当（97%至99%），但复发率 显著不同，导致观察到的无事件生存期（EFS）差异。非洲裔美国儿童最穷，亚洲儿童最好。西班牙裔的结果介于白人和非洲裔美国人之间。多变量分析显示，种族/民族背景与EFS降低独立相关，即使在控制了已知的风险因素，如诊断时的年龄，高初始白色计数和染色体异常与不良结局相关。因此，对8，447名患者的大型队列的随访记录表明，来自不同种族和种族背景的儿童在ALL后的生存率显着不同。观察到的不同种族结局差异的原因尚不清楚。ALL的治疗需要约两年的维持期，包括口服抗代谢药[6-巯基嘌呤（6 MP）和甲氨蝶呤（MTX）]，以实现持久缓解。维持治疗期间口服6 MP的低全身暴露（以红细胞抗代谢药浓度表示）已显示对预后有不良影响。红细胞6 MP代谢物水平存在显著的患者间变异性，可能源于6 MP吸收、代谢或消除速率的差异，或由于未能坚持治疗。我们假设，维持治疗期间6 MP全身暴露的种族/人种差异（主要是由于不依从6 MP）可以解释观察到的不同种族/人种儿童ALL结局的差异。我们的目标是i）确定接受维持化疗的四个不同种族和人种（白人、非洲裔美国人、西班牙裔和亚洲人）ALL儿童队列中对6 MP的依从性。将通过测量红细胞6 MP代谢产物评估粘附性（6 TGN，甲基TIMP），使用电子药丸监测系统（MEMS）的6 MP给药频率，以及对6 MP依从性的自我报告; ii）在针对疾病结果的已知预测因子进行调整后，确定在所研究的整个队列中对6 MP依从性对EFS的影响; iii）确定遵守的临界水平（通过6 TGN，MEMS，自我报告独立测量），对整个队列的EFS有显著影响; iv）使用（iii）中的定义，按种族描述6 MP依从性的流行率; v）使用问卷数据描述依从性的行为和社会人口统计学预测因素; vi）使用MEMS数据描述该队列中的服药实践;以及vii）评价依从性对EFS中种族/种族差异的影响。我们将控制TPMT的多态性和其他遗传多态性（转运蛋白、修复酶、HPRT等），以及控制不同种族之间疾病负担和生物学的潜在差异。我们的总体目标是在不同种族群体中进行一项综合研究，以阐明观察到的不同种族和种族的生存差异的原因，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。

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.