One in four children in remission from acute lymphocytic leukemia (ALL) may not be adhering to the recommended daily regimen of oral 6-mercaptopurine (6MP) to avert a relapse, especially those in African American and Asian families, according to a new study by the Children's Oncology Group (COG), the National Cancer Institute-supported collaboration between investigators at multiple institutions. The study is now online ahead of print in Blood (DOI: 10.1182/blood-2014-01-552166).
For the study, led by Smita Bhatia, MD, Director of the Center for Cancer Survivorship at City of Hope, a team of researchers tracked daily adherence to daily doses of 6MP among 298 children with ALL from 77 participating pediatric hospitals across the country.
Adherence was measured for five months using a monitoring device that electronically reported every time the cap on a bottle of 6MP was opened. The subjects were also tested each month for levels of erythrocyte thioguanine nucleotide, a biomarker of 6MP.
As many as 95 percent of children treated for ALL enter remission within a month of cancer therapy, but an estimated 20 percent relapse. To minimize this risk, patients are treated with an oral chemotherapy agent like 6MP every day for two years. But even skipping 10 days out of 100 days can make the children significantly more vulnerable to a relapse, Bhatia explained in an interview.
The results showed that the risk of ALL relapse was 3.1-fold higher when a daily oral 6MP regimen was followed less than 90 percent of the time.
Most striking were the racial differences in compliance, with African American children adhering to the daily regimen least often, with 46 percent failing to take at least 90 percent of their medication. Although children of Asian descent took their medication more consistently, 28 percent of them also fell below the 90 percent threshold, and while non-Hispanic white children had the best compliance rate, 14 percent failed to meet the criterion for relapse prevention.
“While we don't yet know why children of different races have significantly different survival rates for ALL, we do know that adherence to maintenance medication is critical to these children's survival,” she said.
The findings counter somewhat the widely held belief that compliance is directly linked to lower income and less educated parents. Questionnaires completed by parents and caregivers showed that while the African American children came largely from low-income, single-family households with lower parental education level, most Asian children came from higher-income, nuclear families with well-educated parents.
“Despite representing both sociodemographic extremes, neither group adhered to their medication as consistently as the non-Hispanic white children,” Bhatia said. “We were surprised that the adherence was so low for Asian children; however they came from different geographic and cultural backgrounds. Currently we are carefully examining our data for potential explanations.”
Adherence rates were found to be significantly higher among Asian and African American children where a single adult (usually mothers) acted as the full-time caregiver and medication administrator, while more African American children came from households with relatively lower levels of maternal education, and those in single-parent, multiple-children households had more trouble adhering to a daily treatment. Asian children were more vulnerable if they came from low-income households, while non-Hispanic whites did not take their medication as consistently if the father had a low education level.
Regardless of these factors, the most common reason for children not taking their 6MP medication was forgetfulness, Bhatia said.
“In an overwhelming majority, the primary reason given was that they forget to take their pills each day.” One possible reason could be that children in remission typically do not have any symptoms. “They are healthy and back to school, and involved in all of the typical activities of children their age, which can make it difficult to remember to take their daily medication. Also, the disease does not return immediately if they skip some doses.”
Bhatia and her team have developed a web-based platform that can send daily text reminders to parents and caregivers supervising and dispensing children's medication. The intervention is currently being tested in a randomized trial across 78 COG institutions.
“Physicians need to play a greater role as well, and that starts with increased awareness of non-adherence,” she added. “They need to take the time to emphasize the need for compliance with a daily regimen.”
The team is also developing an adherence risk calculator to help physicians identify which children may be at higher risk of not taking their medication.
More Awareness, Better Communication
Asked for her opinion for this article, Nina Kadan-Lottick, MD, MSPH, Associate Professor of Pediatrics and St. Baldrick's Team Brent Scholar in the Section of Pediatric Hematology-Oncology at Yale University School of Medicine, said the findings shed more light on research she and others have done on racial and socioeconomic disparities and non-adherence to anti-relapse medication among ALL patients.
“I was not surprised by the findings, but I expect most of my colleagues will be—especially the extent of the problem, even in non-Hispanic white children and those from well-educated, intact families,” she said.
In 2003, Kadan-Lottick and colleagues (Kristen K. Ness, MPH; Bhatia; and James G. Gurney, PhD) published a study in the Journal of the American Medical Association (290:2008-2014) in which they analyzed data from NCI's Surveillance, Epidemiology, and End Results (SEER) database on racial disparities and survival rates between 1973 and 1999 among 4,952 young ALL patients.
The results showed that while five-year survival increased as new anti-relapse medications become available, non-Caucasian children had worse survival rates. This contrasted with an earlier study at St. Jude Children's Research Hospital that found no racial differences in survival among ALL patients who received appropriate treatment.
“What is important to understand is that the St. Jude researchers provided free treatment and follow-up care for these children, many of whom were from lower-income African-American families,” Kadan-Lottick said. “This helps to illustrate the importance of family income in explaining the higher rates of non-adherence and poorer survival that have elsewhere been reported among such children.”
The new paper is important, she said, because it breaks down non-adherence by racial and sociodemographic variables, providing guidance for physicians and nurses to better identify potentially at-risk patients so they can direct more attention at educating them and their caregivers about the necessity of rigorously following their daily anti-relapse medication regimen.
“It is interesting that there were different predictors, not just economic income or parental education levels. For example, making the mother the primary dispenser of the medication appears to have a strong effect on compliance and having some form of reminder, especially by smart phones—this is very practical,” Kadan-Lottick said. “Telemedicine is a great solution.”
It is also important that health workers realize that parents and caregivers of children with ALL in remission have a lot of other challenges each day.
“Managing these patients takes a lot of work,” she said. For parents, in addition to dealing with jobs, work chores, and other children, a child in remission from ALL is often taking a number of other drugs, such as those for fighting infections, ulcers, constipation, and other conditions that are more prevalent in ALL patients in remission.
“For physicians, telling a parent that their child must take their anti-relapse medication every day seems simple, but for parents this requires a lot of organization.”
Equally important, she added, is that there are often cultural differences that can stand in the way of imparting and emphasizing treatment information to parents from Asian countries with ALL children, and making sure that they understand this information about medication adherence.
In many Asian cultures, Kadan-Lottick noted, direct personal questions, especially about one's family, are not considered polite, nor is asking a physician to clarify something they may not understand. Moreover, members of many Asian cultures will often give an affirmative answer to a question from a health practitioner even if they do not understand the question or the directions being given.
“There are belief barriers that must be overcome in order to get the point across, and there is the potential for misunderstanding,” she said. “Direct questions about the primary pill administrator, the role of extended family members, and the home environment all require an understanding of cultural differences and the ability to communicate in terms that are understood.”