Nonadherence to Oral 6-Mercaptopurine (6MP) in a Multi-Ethnic Cohort of Children with Acute Lymphoblastic Leukemia (ALL) and Its Impact On Relapse – a Children's Oncology Group (COG) Study (AALL03N1)
Authors: Bhatia Smita , Landier Wendy , Hageman Lindsey , Kim Heeyoung , Hanby Cara , Nancy Kornegay , Bostrom Bruce C. , Casillas Jacqueline , Dickens David S , Maloney Kelly W. , Mascarenhas Leo , Meza Jane , Ritchey Arthur Kim , Termuhlen Amanda M , Carroll William L. , Wong F. Lennie , Relling Mary V. 
Published: October 2019

Abstract
Abstract 882

Background:
Nearly 20% of children with ALL relapse within 5y from diagnosis. Second-line therapies are toxic and salvage is poor. Systemic exposure to 6MP is critical for durable remissions; low systemic exposure due to nonadherence to oral 6MP could potentially increase relapse risk. We have previously reported on adherence to oral 6MP in non-Hispanic whites and Hispanics, (J Clin Oncol 2012;30:2094-101); this report extends follow-up for assessment of disease status by 68,250 person-days for non-Hispanic whites and Hispanics; it also includes adherence data for a previously unreported cohort of African American and Asian children. The goal of this report was to: i) describe adherence to oral 6MP in a multi-ethnic cohort of children with ALL; ii) identify determinants of adherence; iii) describe impact of adherence on relapse; and iv) define a clinically-relevant level of adherence needed to minimize relapse risk.

Methods:
Microprocessor chips in Medication Event Monitoring System (MEMS) caps recorded date/time of 6MP bottle openings for 6 mos/ patient. Adherence rate was defined as days of 6MP bottle opening, divided by days of prescribed 6MP (removing days when 6MP was withheld for toxicity/illness from denominator). Monthly red cell thioguanine nucleotide (TGN) levels were used to demonstrate that MEMS bottle openings were accompanied by 6MP ingestion. Analyses used Generalized Estimating Equations.

Results:
462 patients (168 Hispanics; 157 non-Hispanic whites; 69 Asians; 68 African Americans) yielded 76,055 person-days of adherence data. Median age at participation was 6y (2-20); 67% were males; 40% had high-risk disease per NCI criteria; 61% reported income <$50k/y; 14% reported single-caregiver households. Among patients with normal TPMT activity, each 1% increase in MEMS-based adherence was accompanied by a 14 unit (pmol/8·108 red cells) increase in TGN (p=0.01). Adherence declined from mo 1 (94.4%) to mo 6 (89.2%, p<0.0001). Multivariate longitudinal analysis revealed adherence to be significantly lower in adolescents (≥12y: 84.5% vs. <12y: 92.6%, p=0.0003, Fig A); patients from single-caregiver households (87.2% vs. 92.0%, p=0.03, Fig B); patients with low income (<$50k/y: 89.4% vs. ≥$50k/y: 93.8%, p=0.02, Fig C); and Hispanics (90.5±1.6%), Asians (85.3±3.7%) and African Americans (85.3±2.9%) compared with non-Hispanic whites (95.3±1.2%, p<0.0001, Fig D). Adherence for the adolescents (≥12y) from low-income (<$50k/y) families with single-caregivers was significantly lower when compared with that for <12-year-olds from high-income families with multiple caregivers (79.9% vs. 96.7%, p=0.0002); this difference was observed across all racial/ ethnic backgrounds Reasons for missing 6MP included forgetfulness (79%), logistical barriers (19%), and active refusal (2%). After a median follow-up of 5.4y, multivariate analysis (adjusting for clinical/sociodemographic factors) revealed that adherence <95% was associated with an increase in relapse risk (reference: adherence ≥95%; 94.9%-90%: Hazard Ratio [HR]=3.3, 95% Confidence Interval [CI], 1.0–11.6, p=0.06; 89.9%-85%: HR=3.4, 95%CI, 0.9–13.0, p=0.07; <85%: HR=4.5, 95%CI, 1.3–15.1, p=0.02), leading us to use <95% as the cut-point for adherence with a clinically unacceptable increase in relapse. Using this definition, 45% of the patients were non-adherers. The cumulative incidence of relapse was significantly higher among non-adherers (18.8% vs. 4.9%, p=0.0003, Fig E). Furthermore, non-adherers were at a 3.7-fold increased risk of relapse (95%CI, 1.4–10.2, p=0.01), after adjusting for sociodemographic/clinical variables. The adjusted risk of relapse attributable to non-adherence was 47% for this cohort that had entered maintenance in 1st CR.

Conclusions:
Non-adherence to 6MP is prevalent in children with ALL; 45% consume <95% of prescribed 6MP. Adolescents, Hispanic, African American and Asian children, those with low annual household income, and those from single-caregiver households are more likely to be non-adherent. Forgetfulness is the most common reason for non-adherence. Adherence rates <95% significantly increase relapse risk; 47% of relapses after entry into maintenance are attributable to non-adherence to oral 6MP. Results of this study have led to a COG-wide intervention using cell phone reminders and directly supervised therapy to enhance adherence to oral 6MP.

Disclosures:
Relling: St. Jude Children's Research Hospital: Dr. Mary Relling receives a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms and GGH polymorphisms. Dr. Mary Relling receives a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms and GGH polymorphisms. Patents & Royalties; Sigma-Tau Pharmaceuticals: Research Funding.