Ethnic Differences in Survival after Childhood ALL

儿童期后生存率的种族差异 ALL

• 批准号: 7933189
• 负责人: SMITA BHATIA
• 金额: $ 16.6万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2010-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933189
• 关键词: 6-Mercaptopurine; Accounting; 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' s Cancer Group; Chromosome abnormality; Cohort Studies; Data; 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; Hypoxanthines; Incidence; Inherited; Intervention; Literature; Maintenance; Maintenance Therapy; Malignant Neoplasms; Measures; Metabolism; Methotrexate; Modeling; Monitor; Multivariate Analysis; Newly Diagnosed; Nucleotides; Oral; Oral Administration; Other Genetics; Outcome; Patient Self-Report; Patients; Pharmaceutical Preparations; Pharmacogenetics; Phase; Play; Prevalence; Protocols documentation; Questionnaires; Race; 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; population based; racial and ethnic; racial/ethnic difference; repair enzyme; stem; thiopurine methyltransferase

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（全部）是最常见的儿童恶性肿瘤，五年生存率接近80％。我们已经显示出种族和种族群体之间的生存差异非常显着。在四个族裔和种族群体中的缓解率相当（97％至99％），但复发率 有显着差异，导致观察到的无事件生存差异（EFS）。非裔美国人的儿童拥有最贫穷，亚洲人的最佳结果。西班牙裔的结果是对高加索人和非裔美国人的结果。多变量分析表明，即使控制了已知的风险因素，例如诊断时的年龄，高初始白人计数和与不良结果相关的染色体异常，种族/族裔背景与EFS下降的独立相关。因此，对来自不同种族和种族背景的儿童的8,447名患者文件进行了大规模的随访。观察到的种族结果差异的原因尚不清楚。所有处理都需要大约两年的维护阶段，该阶段由口服抗替代物[6-羟基托嘌呤（6MP）和甲氨蝶呤（MTX）]组成，以实现持久的恢复。在维持治疗期间，全身性暴露于口服6MP（由红细胞抗代谢物浓度代表）已显示出对预后的不利影响。红细胞6MP代谢产物水平有显着的患者间变异性，可能是由于吸收率，代谢率或消除6MP的差异，或者是由于未能遵守治疗的差异。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遵守6MP，可以解释出种族/种族的儿童期结果的差异。我们的目的是）i）确定来自四个不同种族和种族群体（高加索人，非洲裔美国人，西班牙裔和亚洲人）的所有儿童的遵守，并确定接受维持化疗的四个不同种族和种族。依从性将通过测量红细胞6MP代谢产物（6TGN，甲基植物），使用电子药丸监测系统（MEMS）的6MP剂量的频率以及对6MP的自我报告进行评估； ii）在调整了已知的疾病预后预测指标后，确定对整个队列中对6MP的依从性对EFS的影响； iii）定义依从性的临界水平（由6TGN，MEMS，自我报告独立衡量），对整个队列的EFS产生了重大影响； iv）使用（iii）的定义，描述遵守6MP的普遍性； 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数据来描述该队列中的药丸实践；和vii）评估依从性对EFS种族/种族差异的影响。我们将控制TPMT中的多态性以及其他遗传多态性（在转运蛋白，修复酶，HPRT等中），并控制族裔群体中疾病负担和生物学的潜在差异。我们的总体目标是跨种族进行一项全面的研究，以阐明观察到的种族和种族生存差异的原因，从而为未来的适当干预构建框架以解决此问题。

项目成果

Effects of NT5C2 Germline Variants on 6-Mecaptopurine Metabolism in Children With Acute Lymphoblastic Leukemia.

• DOI: 10.1002/cpt.2095
• 发表时间: 2021-06
• 期刊: Clinical pharmacology and therapeutics
• 影响因子: 6.7
• 作者: Jiang C;Yang W;Moriyama T;Liu C;Smith C;Yang W;Qian M;Li Z;Tulstrup M;Schmiegelow K;Crews KR;Zhang H;Pui CH;Evans W;Relling M;Bhatia S;Yang JJ
• 通讯作者: Yang JJ