Electronic Monitoring of Medication Adherence in Early Maintenance Phase Treatment for Pediatric Leukemia and Lymphoma: Identifying Patterns of Nonadherence

Treatment advances have greatly improved survival rates for pediatric cancer from 58% in the late 1970s to 89% in the early 2000s. In fact, 95% of pediatric patients will reach disease remission and 80% of patients aged 1–18 years are expected to have long-term event-free survival (National Cancer Institute, 2008). Still, pediatric cancer remains the leading cause of disease-related death for children and adolescents in the United States (National Cancer Institute, 2008). Similarities in morphology, genetics, and immunophenotypes between lymphoblastic lymphoma (LBL) and acute lymphoblastic leukemia (ALL) indicate that ALL and LBL be considered as part of a spectrum of malignant lymphoproliferative disorders (Reddy & Perkins, 2004) that require similar treatment protocols (Weiss, Bindl, Picozzi, Link, & Warnke, 1986). Maintenance therapy is vital for relapse prevention in youth with ALL and LBL and has been shown to increase survival rates (Pritchard, Butow, Stevens, & Duley, 2006). However, the complex course of maintenance therapy can be difficult for children, adolescents, and parents to manage effectively. For example, 6-mercaptopurine (6MP) is a critical component of maintenance treatment for ALL/LBL that is taken daily, on an empty stomach, typically at bedtime (Bhatia et al., 2012). Despite the importance of taking medications as prescribed, some studies have shown that as many as ≥50% of pediatric cancer patients do not adhere to their maintenance treatment regimen (Kondryn, Edmondson, Hill, & Eden, 2010). Nonadherence may contribute to preventable morbidity and mortality in pediatric patients (Festa, Tamaroff, Chasalow, & Lanzkowsky, 1992; Lau, Matsui, Greensberg, & Koren, 1998; Tebbi, 2006). In a recent Children’s Oncology Group (COG) study of 327 patients with ALL, even relatively low nonadherence rates of <95% for 6MP treatment during maintenance therapy were associated with an increased risk of relapse (Bhatia et al., 2012). Such findings heighten the need for objective and precise measurement of medication adherence during all phases of maintenance therapy. More than 20 published studies have reported data on treatment adherence in ALL and related conditions (Festa et al., 1992; Kennard et al., 2004; Kondryn et al., 2010; Lau et al., 1998). However, significant methodological problems, such as the absence of objective measures of medication adherence in recent treatment protocols, small sample sizes, and the exclusive use of self-reported adherence, limit the scientific and clinical utility of most available studies. Most studies were published more than a decade ago and are not applicable to current treatment for ALL/LBL given the substantial changes in treatment protocols that have been implemented by the COG. With only four exceptions (Bhatia et al., 2012; Kato et al., 1992; Lennard, Welch, & Lilleyman, 1995), sample sizes have been small (<60) and limited to a single institution, which limits the generalizability of study findings as well as the ability to identify subgroups of patients based on patterns of treatment adherence. Finally, most studies of pediatric patients with ALL/LBL have used physician-, parent-, and/or patient-reported adherence measures. However, it is well established that such reports tend to overestimate adherence levels (Lau et al., 1998; Riekert & Rand, 2002) and cannot validly identify dosing patterns that are relevant targets for adherence promotion. The primary measure of medication adherence in previous studies of pediatric chronic illness, including pediatric cancer, has been based on a percentage of doses taken as prescribed. However, this measure does not capture clinically relevant patterns of adherence including the timing of medication taking and provides misleading results when used as the sole measure of adherence. For example, a patient who demonstrates a significant gap in adherence (e.g., missing 5 consecutive days of medication) would have exactly the same adherence percentage as a patient who missed medication sporadically for 5 days over a comparable monitored period. Such discrepant patterns of adherence are likely to have a different impact on health outcomes, including the therapeutic action of a medication that has a half-life of several days. The timing of medication doses may be particularly important for chemotherapy agents given it is recommended that they be taken around the same time each day to avoid over- or under-dosing (Pritchard et al., 2006; Relling, 1999; Ruddy, Mayer, & Partridge, 2009). For this reason, measuring the timing between doses (i.e., interdose intervals: IDIs) based on objective observational measures (Kenna, Labbe, Barrett, & Pfister, 2005) is a potentially important variable that has not been examined in previous research. Previous studies have also suggested that there is considerable within-sample heterogeneity in patterns of adherence to pediatric cancer treatment (Kennard et al., 2004; Kondryn et al., 2010; Lau et al., 1998; Ruddy et al., 2009). Moreover, research in other pediatric chronic conditions has identified clinically relevant subgroups who demonstrate different patterns of adherence (Modi, Rausch, & Glauser, 2011). However, to our knowledge, subgroups that demonstrate different adherence patterns based on objective observational measures have not been previously identified in pediatric ALL and LBL but have important implications for tailoring and targeting adherence promotion interventions. For example, individuals who demonstrate either chronic or declining patterns of adherence that are associated with risk for relapse are prime candidates for more intensive adherence promotion intervention. Bhatia et al. (2012) identified a progressive increase in risk for relapse in a large cohort of children with ALL: As adherence to treatment decreased, especially below a level of 95%, risk for relapse increased. However, subgroups of children with different trajectories of adherence/nonadherence or variable IDIs were not assessed. The present study addressed salient methodological limitations of previous studies of oral medication adherence in maintenance phase therapy for ALL and LBL by studying a cohort of 139 pediatric patients across multiple sites enrolled in treatment protocols used by COG (2007–2012) that were currently in maintenance treatment. The primary objective of this study was to describe patterns of adherence to 6MP treatment, including heterogeneity in trajectories of adherence patterns and IDIs based on electronic monitoring, which is an objective observational method recognized as a valid adherence measure (Quittner, Modi, Lemanek, Ievers-Landis, & Rapoff, 2008). One medication (6MP) was selected as the primary medication to monitor for adherence because (1) substantial data have demonstrated its efficacy and importance in preventing relapse (Bhatia et al., 2012); and (2) it is prescribed daily over the course of maintenance therapy. A second objective of the study was to describe the interrelationships between adherence measures (e.g., overall adherence percentage, adherence subgroups, medication gaps, and IDIs) and demographic correlates of adherence.