Study to Assess Compliance With Long-Term Mercaptopurine Treatment in Young Patients With Acute Lymphoblastic Leukemia in Remission

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Understanding the Ethnic and Racial Differences in Survival in Children With Acute Lymphoblastic Leukemia

Conditions
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Childhood Acute Lymphoblastic Leukemia in Remission

Intervention / Treatment
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* Behavioral: Compliance Monitoring
* Other: Laboratory Biomarker Analysis
* Drug: Mercaptopurine
* Drug: Methotrexate
* Other: Questionnaire Administration
* Other: Study of Socioeconomic and Demographic Variables


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of ALL in first remission, irrespective of risk stratification; enrollment on a Children's Oncology Group (COG) therapeutic study for ALL is not required, but the treatment plan must meet the criteria in this protocol Belongs to one of the four following ethnic/racial categories: African-American, Asian, Caucasian, or Hispanic; below please find definitions for these categories African-American: includes patients who are African-American or of sub-Saharan black African ancestry Asian: patients of Asian ancestry, including the following: Asian Indian (subcontinent), Chinese, Japanese, Korean, Native Hawaiian, Guamanian or Chamorro, Pacific Islander, Filipino, Vietnamese, Samoan, Hmong, Cambodian, Thai, Laotian, or Other Asian races Caucasian: includes White or light-skinned patients of European, North African, or Middle Eastern ancestry Hispanic: patients of Hispanic ethnicity, including the following: Mexican, Mexican American, Chicano, Cuban, Puerto Rican, or Other Spanish/Hispanic/Latino ethnicity Receiving self- or parent/caregiver-administered oral anti-metabolite chemotherapy during the maintenance/continuation phase of therapy; patients are eligible if their treatment plan calls for the following doses of 6-MP and methotrexate (MTX) during the maintenance/continuation phase: 6-MP ? 75 mg/m^2/day orally; MTX 20 mg/m^2/week orally;** (modification of 6-MP or MTX dosing based on laboratory or clinical parameters is acceptable) For guidance regarding if and when a patient being treated on or according to a specific COG (or legacy group) protocol is eligible, please refer to ?AALL03N1 Eligibility by Protocol Tool,? available in the study data forms packet on the COG website Has completed at least 24 weeks of maintenance/continuation chemotherapy, and is scheduled to receive at least 24 more weeks of maintenance/continuation chemotherapy** For guidance regarding if and when a patient being treated on or according to a specific COG (or legacy group) protocol is eligible, please refer to ?AALL03N1 Eligibility by Protocol Tool,? available in the study data forms packet on the COG website Written informed consent from the patient and/or the patient?s legally authorized guardian, obtained prior to registration and any study-related procedures, and in accordance with institutional policies approved by the United States (U.S) Department of Health and Human Services Exclusion Criteria: Patients of multi-ethnic/multi-racial backgrounds are not eligible for this study; while patients of multi-ethnic/multi-racial ancestry (e.g., Caucasian/Japanese, Hawaiian/Puerto Rican) are not eligible, patients of mixed ancestry within a race/ethnicity (e.g., Japanese/Chinese = Asian or Korean/Japanese/Hawaiian = Asian or Mexican/Puerto Rican = Hispanic) may participate as long as they fall under the general classification of African-American, Asian, Caucasian, or Hispanic

Ages Eligible for Study
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Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Health service research (electronic pill monitoring system)<br>Patients receive an electronic pill monitoring system comprising an empty MEMS^? medication bottle with TrackCap? 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 PO as indicated by their individual chemotherapy regimen. | Behavioral: Compliance Monitoring<br>* Receive an electronic pill monitoring system comprising an empty MEMS medication bottle with TrackCap<br>Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Mercaptopurine<br>* Given PO<br>* Other names: WR-2785;Drug: Methotrexate<br>* Given PO<br>* Other names: WR-19039;Other: Questionnaire Administration<br>* Ancillary studies<br>Other: Study of Socioeconomic and Demographic Variables<br>* Receive an electronic pill monitoring system comprising an empty MEMS medication bottle with TrackCap<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 169 days | 
| 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. | 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. | 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). | 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). | 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. | 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. | Up to 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 168 days |