This clinical trial is assessing compliance with long-term mercaptopurine treatment in young patients with acute lymphoblastic leukemia in remission. Assessing why young patients who have acute lymphoblastic leukemia may not take their medications as prescribed may help identify ways to assist them in taking their medications more consistently and may improve long-term treatment outcomes.
PRIMARY OBJECTIVES: I. To determine and compare adherence to maintenance mercaptopurine (6-MP) in a cohort of children with acute lymphoblastic leukemia (ALL) from four different ethnic and racial groups (Caucasians, African-Americans, Hispanics, and Asians) receiving maintenance/continuation chemotherapy, using the following assessments: serial red cell 6-MP metabolites (6-thioguanine \[6TGN\] and methyl thioinosine monophosphate \[TIMP\]); frequency of 6-MP dosing using an electronic pill monitoring system (Microelectromechanical Systems \[MEMS\]?); self-report of adherence to 6-MP by questionnaire. II. To determine the impact of adherence to 6-MP (measured using 6TGN, methyl \[Me\]TIMP, MEMS? and self-report data independently) on event-free-survival (EFS) in the entire cohort, after adjusting for known predictors of disease outcome. III. Define a critical level of adherence (measured independently by 6TGN, MeTIMP, MEMS?, self-report) that has a significant impact on EFS for the entire cohort. IV. Describe prevalence of adherence to 6-MP by ethnicity (6TGN, MeTIMP, MEMS?, Self-report). 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. VII. To evaluate the impact of adherence on ethnic/racial difference in EFS. SECONDARY OBJECTIVES: I. To assess the concordance among 6TGN and MeTIMP levels, electronic pill monitoring, and self-reported adherence in the ethnic/racial groups. OUTLINE: Patients receive an electronic pill monitoring system comprising an empty MEMS? medication bottle with TrackCap? child resistant (CR). The mercaptopurine prescription is filled using this system. Beginning on day 1 of the third or later course of maintenance therapy, patients take all doses of mercaptopurine from the MEMS? medication bottle with TrackCap? CR for at least 169 days. The MEMS? TrackCap? CR is mailed to the Coordinating Center at the end of study. Patients also receive methotrexate orally (PO) as indicated by their individual chemotherapy regimen. NOTE: \*Study closed to accrual for Caucasian and Hispanic patients as of 8/14/2009. After completion of study, patients are followed up every 6 months for 5 years and then annually for up to 10 years.
Study Type
OBSERVATIONAL
Enrollment
720
Receive an electronic pill monitoring system comprising an empty MEMS medication bottle with TrackCap
Correlative studies
Given PO
Adherence to 6-MP as measured by 6TGN and MethylTIMP levels
Will initially perform an exploratory data analysis on distributions across the four groups using side-by-side boxplots, histograms, and summary quantities (mean, median, quartiles, standard deviations, inter-quartile-range, etc.). If central values summarize across-group differences well, then mean and median of the distribution will be compared between 6 pairs of the four ethnic groups using the two-sample t-test and the Mann-Whitney U-test. Will perform these tests adjusting for 6 pairwise multiple comparisons among the four groups using the Bonferroni?s correction method.
Time frame: 169 days
Adherence as measured by frequency of 6-MP dosing as a continuous variable using MEMS? defined as the number of days the MEMS? Cap openings are recorded, taken as a percentage of days doses were prescribed during the study period
Will initially perform an exploratory data analysis on distributions across the four groups using side-by-side boxplots, histograms, and summary quantities (mean, median, quartiles, standard deviations, inter-quartile-range, etc.). If central values summarize across-group differences well, then mean and median of the distribution will be compared between 6 pairs of the four ethnic groups using the two-sample t-test and the Mann-Whitney U-test. Will perform these tests adjusting for 6 pairwise multiple comparisons among the four groups using the Bonferroni?s correction method.
Time frame: Up to 169 days
Self-report of adherence to 6-MP by questionnaire, defined as the number of days doses of 6-MP are reported to being taken, as a percentage of days doses were prescribed during the study period
Will initially perform an exploratory data analysis on distributions across the four groups using side-by-side boxplots, histograms, and summary quantities (mean, median, quartiles, standard deviations, inter-quartile-range, etc.). If central values summarize across-group differences well, then mean and median of the distribution will be compared between 6 pairs of the four ethnic groups using the two-sample t-test and the Mann-Whitney U-test. Will perform these tests adjusting for 6 pairwise multiple comparisons among the four groups using the Bonferroni?s correction method.
Time frame: 169 days
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Given PO
Ancillary studies
Receive an electronic pill monitoring system comprising an empty MEMS medication bottle with TrackCap
Children's Hospital of Alabama
Birmingham, Alabama, United States
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
University of Arkansas for Medical Sciences
Little Rock, Arkansas, United States
Kaiser Permanente Downey Medical Center
Downey, California, United States
City of Hope Comprehensive Cancer Center
Duarte, California, United States
Loma Linda University Medical Center
Loma Linda, California, United States
Miller Children's and Women's Hospital Long Beach
Long Beach, California, United States
Children's Hospital Los Angeles
Los Angeles, California, United States
Mattel Children's Hospital UCLA
Los Angeles, California, United States
UCLA / Jonsson Comprehensive Cancer Center
Los Angeles, California, United States
...and 125 more locations
EFS
For each of the three types of adherence measures, will fit independent Cox?s proportional-hazard models to assess the prognostic significance of the adherence measure on EFS, after adjusting for known predictors of disease outcome, including the National Cancer Institute risk group (based on the age at diagnosis and presenting white cell count) and chromosomal abnormalities.
Time frame: Up to 10 years
Critical level of adherence (measured independently by 6TGN/MethylTIMP, MEMS?, self-report) that has a significant impact on EFS
Will fit a separate Cox regression model to each of the three adherence measures (i.e., 6TGN, MeTIMP, MEMS, and self-report). Using no more than several knots, the natural spline (a special type of cubic splines) fits a very wide range of smoothly changing adherence effects. The adherence effects on EFS will be visualized graphically. This will be the primary approach for defining the critical level of adherence. To confirm the spline analysis results, will categorize the continuous adherence measures into multiple levels and estimate the effect of each adherence level.
Time frame: Up to 10 years
Prevalence of adherence to 6-MP by ethnicity (measured independently by 6TGN/MethylTIMP, MEMS?, Self-report) that has a significant impact on EFS
Will describe the prevalence of non-adherence by race/ethnicity and compare the prevalence by using two-tailed chi-squared test (with a Yates' correction).
Time frame: Up to 10 years
Behavioral, socio-demographic predictors of adherence using the questionnaire data
The reasons for non-adherence will be assessed. The relationship between adherence to 6-MP as reported by the patients/parents and the independent behavioral variables knowledge of medications, understanding of treatment regimen, extent of treatment side effects, length of treatment, and beliefs about the efficacy of the regimen, beliefs and attitudes towards health and medical care will be evaluated descriptively first using standard parametric or non-parametric tests, and then analytically by logistic regression (dichotomous adherence) or linear regression (continuous adherence).
Time frame: Up to 10 years
Pill-taking practices using the MEMS? data
Using the MEMS? output data, the adherence report will be analyzed for: i) longest and shortest interval between doses in hours; ii) percent prescribed doses taken, and iii) percent prescribed doses taken on schedule.
Time frame: Up to 169 days
Impact of adherence (measured independently by 6TGN/MethylTIMP, MEMS, self-report) on ethnic/racial differences in EFS
Will fit independent Cox?s proportional-hazard models to assess the impact of adherence measure on EFS, after adjusting for known predictors of disease outcome, including the National Cancer Institute risk group (based on the age at diagnosis and presenting white cell count) and chromosomal abnormalities.
Time frame: Up to 10 years
Concordance among red cell thiopurine metabolite levels, electronic pill monitoring, and self-reported adherence among the ethnic/racial groups
Correlations between mean dosage- and TPMT-normalized serial red cell 6-MP metabolites and mean adherence by electronic pill monitoring system and self-report will be assessed for statistical significance by Spearman's rank correlation coefficient.
Time frame: Up to 168 days