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.
