Ethnic Differences in Survival after Childhood ALL

儿童期后生存率的种族差异 ALL

基本信息

批准号：
7254721
负责人：
SMITA BHATIA
金额：
$ 48.58万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-09-17 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7254721
关键词：
6-Mercaptopurine Accounting Acute Acute Lymphocytic Leukemia Acute Myelocytic Leukemia Address Adherence Affect African American Age Antimetabolites Asians Behavioral Belief Biological Availability Biology Caucasians Caucasoid Race Child Childhood Childhood Acute Lymphocytic Leukemia Children&apos s Cancer Group Chromosome abnormality Cohort Studies Count Data Data Reporting Databases Diagnosis Disease Outcome Disease remission Disease-Free Survival Dose Electronics Erythrocyte Indices Erythrocytes Ethnic Origin Ethnic group Exposure to Failure Frequencies Future Genetic Polymorphism Goals Guanine Hand Hispanics Hypoxanthine Hypoxanthines Incidence Inherited Intervention Literature Lymphoblastic Leukemia Maintenance Maintenance Therapy Malignant Neoplasms Measures Mercaptopurine/Methotrexate Metabolism Methotrexate Modeling Monitor Multivariate Analysis Newly Diagnosed Nucleotides Oral Oral Administration Other Genetics Outcome Patient Self-Report Patients Pharmaceutical Preparations Pharmacogenetics Phase Play Population Prevalence Protocols documentation Questionnaires Race Range Rate Relapse Reporting Risk Risk Factors Role Solid Neoplasm Structural Chromosomal Abnormality Survival Rate System Therapeutic Thioguanine Toxic effect absorption base burden of illness chemotherapy cohort dosage enzyme activity ethnic difference follow-up indexing methotrexate polyglutamate outcome forecast pill racial and ethnic racial/ethnic difference repair enzyme stem thiopurine methyltransferase

项目摘要

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.

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%。我们已经显示出族裔和种族群体之间的生存差异非常显着。研究的四个民族和种族群体的缓解率相当（97% 至 99%），但复发率显着不同，导致观察到的无事件生存期 (EFS) 存在差异。非裔美国儿童的结局最贫困，亚洲儿童的结局最好。西班牙裔美国人的结果介于白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（例如诊断年龄、初始白细胞计数高和与不良结果相关的染色体异常）之后也是如此。因此，对这一大群 8,447 名患者的随访表明，来自不同种族和种族背景的儿童在 ALL 后的生存率存在显着差异。观察到的不同种族结果差异的原因尚不清楚。 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。维持治疗期间口服 6MP 的全身暴露量低（以红细胞抗代谢物浓度为代表）已被证明会对预后产生不利影响。红细胞 6MP 代谢物水平存在显着的患者间差异，这可能源于 6MP 吸收、代谢或消除速率的差异，或者由于未能坚持治疗。我们假设，维持治疗期间全身暴露于 6MP 的种族/种族差异（主要是由于不遵守 6MP）可以解释观察到的儿童 ALL 结局因种族/民族而存在的差异。我们的目标是 i) 确定来自四个不同民族和种族群体（白种人、非裔美国人、西班牙裔和亚洲人）接受维持化疗的 ALL 儿童队列对 6MP 的依从性。将通过测量红细胞 6MP 代谢物（6TGN、甲基TIMP）、使用电子药丸监测系统 (MEMS) 的 6MP 给药频率以及对 6MP 依从性的自我报告来评估依从性； ii) 在调整已知的疾病结果预测因素后，确定在整个研究队列中坚持 6MP 对 EFS 的影响； iii) 定义对整个队列的 EFS 有重大影响的关键依从性水平（通过 6TGN、MEMS、自我报告独立测量）； iv) 使用 (iii) 中的定义，描述按种族划分的 6MP 遵守率； v) 使用问卷数据描述依从性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习惯； vii) 评估依从性对 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），以及控制种族群体之间疾病负担和生物学的潜在差异。我们的总体目标是进行一项跨种族的全面研究，以阐明所观察到的种族和族裔生存差异的原因，从而建立一个适当的干预框架，以在未来解决这一问题。