Impact of 6 Mercaptopurine (6MP) Pill-Taking Habits on Adherence, Thioguanine Nucleotide (TGN) Levels and Relapse Risk in Children with Acute Lymphoblastic Leukemia (ALL): Results from a Children’s Oncology Group (COG) Study (AALL03N1)
Authors: Hageman Lindsey , Landier Wendy , Chen Yanjun , Kim Heeyoung , Kornegay Nancy , Evans William E. , Bostrom Bruce C. , Casillas Jacqueline , Dickens David , Angiolillo Anne , Lew Glen , Maloney Kelly , Mascarenhas Leo , Ritchey Arthur K. , Termuhlen Amanda , Carroll William L. , Relling Mary V. , Wong F. Lennie , Bhatia Smita 
Published: October 2019

Abstract

Background: Exposure to oral 6MP for ~2 years is critical for durable remissions in children with ALL. We have previously shown that poor 6MP adherence (rates <95%) is prevalent and increases relapse risk (JCO 30[17]:2094-101). 6MP is supplied in 50 mg tablets that may be swallowed, crushed, or chewed; patients are generally instructed to take 6MP with non-dairy liquid, in the evening on an empty stomach (~1-2h after a meal). These restrictive instructions could impose challenges in 6MP ingestion; the need for such restrictions with respect to clinical outcomes has not been examined systematically. This study examines the pill-taking habits of children with ALL and their association with adherence, risk of relapse and red cell TGN levels.
Methods: Participants included 441 patients with ALL in first remission receiving oral 6MP (75 mg/m2/d) during maintenance. Adherence was measured using Medication Event Management System (MEMS) that recorded dates/times of each 6MP bottle opening for 6 mo/pt (58,086 patient-days of MEMS data). Average adherence rate (days MEMS bottle opened/days 6MP prescribed) over the 6m study period was computed to define non-adherence (adherence rate <95%). A 37-item questionnaire elicited pill-taking habits: i) 6MP never with food vs. with food; ii) 6MP never with dairy vs. with dairy; iii) 6MP pill swallowing (whole, crushed, chewed); iv) time of day 6MP always taken (evening, night, morning, midday, varying times); v) use of a routine: established routine vs. no routine. Monthly TGN levels (~6/pt) yielded 1,395 measurements. 6MP dose intensity [DI] was defined as dose prescribed/ protocol dose, and inherited capacity to metabolize 6MP was characterized by thiopurine methyltransferase (TPMT) genotype. Only TPMT wild-type patients were included in this analysis. 38 relapses occurred after a median follow-up of 6.1 years from start of maintenance (cumulative incidence of relapse: 8.9±1.4% at 6 years).
Results: Median age at diagnosis was 6y (2-20); 67% were males; 40.3% had high-risk disease. 43.8% of the patients were non-adherent. Pill-taking habits and non-adherence: Time-varying generalized estimating equations (adjusted for age at study, ethnicity/race, income, and parental education) identified the following predictors of non-adherence: i) Taking 6MP with dairy (Odds Ratio [OR]=1.9, 95% Confidence Interval [CI]=1.3-2.9, p=0.003); ii) Taking 6MP at varying times vs. non-varying times (OR=2.4, 95%CI=1.2-4.7, p=0.008); iii) No routine (OR=1.7, 95%CI=1.1-2.7, p=0.02). Crushing the pill vs. swallowing whole was less likely to be associated with non-adherence (OR=0.7, 95%CI=0.4-0.99, p=0.05) [Fig 1A].Pill-taking habits and relapse: A proportional sub-distribution hazards model (adjusted for time from start of maintenance, NCI risk group, cytogenetics, race/ethnicity, age at study, and adherence) demonstrated no association between pill-taking habits and relapse risk: i) 6MP with food (Hazard Ratio [HR]=0.7, 95%CI=0.3-1.9, p=0.5); ii) 6MP with dairy (HR=0.3, 95%CI=0.07-1.5, p=0.2); iii) Swallowing tablet whole vs. crushing/chewing (HR=0.8, 95%CI=0.3-2.1, p=0.7); iv) 6MP in the evening/night vs. morning/mid-day (HR=1.1, 95%CI=0.2-7.5, p=0.9); v) 6MP at varying times vs. non-varying times (HR=1.0, 95%CI=0.2-4.5, p=0.9) [Fig 1B].Pill-taking habits and DI-adjusted TGN levels: Among adherent patients, there was no association between DI- and age-adjusted TGN levels and: i) 6MP with food (p=0.5); ii) 6MP with dairy (p=0.7); iii) Swallowing 6MP whole vs. chewing/crushing (p=0.4); iv) 6MP in the morning/midday vs. evening/night (p=0.5); v) 6MP at varying times vs. non-varying times (p=0.5) [Fig 1C].
Conclusions: The association between non-adherence and certain pill-taking habits identifies a subgroup of patients that either did not receive appropriate instructions or did not adhere to them; our study was not designed to discern between the two scenarios. However, pill-taking habits were not associated with either relapse risk or TGN levels. These findings suggest that the commonly-practiced restrictions surrounding 6MP ingestion (i.e., taking only in the evening without food/dairy) might not influence outcome.
Figure 1A Figure 1A.

Figure 1B Figure 1B.
Figure 1C Figure 1C.

Disclosures
Evans: St. Jude: In accordance with institutional policy (St. Jude), I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Patents & Royalties. Relling:St. Jude: In accordance with institutional policy (St. Jude), I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Patents & Royalties.