Mercaptopurine Ingestion Habits, Red Cell Thioguanine Nucleotide Levels, and Relapse Risk in Children With Acute Lymphoblastic Leukemia: A Report From the Children’s Oncology Group Study AALL03N1

Abstract

Children with acute lymphoblastic leukemia (ALL) are generally instructed to take mercaptopurine (6-MP) in the evening and without food or dairy products. This study examines the association between 6-MP ingestion habits and 6-MP adherence, red cell thioguanine nucleotide (TGN) levels, and risk of relapse in children with TMPT wild-type genotype. MethodsParticipants included 441 children with ALL receiving oral 6-MP for maintenance. Adherence was monitored over 48,086 patient-days using the Medication Event Monitoring System; nonadherence was defined as adherence rate , 95%. 6-MP ingestion habits examined included: takes 6-MP with versus never with food, takes 6-MP with versus never with dairy, and takes 6-MP in the evening versus morning versus varying times. ResultsMedian age at study was 6 years (range, 2 to 20 years); 43.8% were nonadherent. Certain 6-MP ingestion habits were associated with nonadherence (taking 6-MP with dairy [odds ratio (OR), 1.9; 95% CI, 1.3 to 2.9; P = .003] and at varying times [OR, 3.4; 95% CI, 1.8 to 6.3; P = .0001]). After adjusting for adherence and other prognosticators, there was no association between 6-MP ingestion habits and relapse risk (6-MP with food: hazard ratio [HR], 0.7; 95% CI, 0.3 to 1.9; P = .5; with dairy: HR, 0.3; 95% CI, 0.07 to 1.5; P = .2; taken in evening/night: HR, 1.1; 95% CI, 0.2 to 7.8; P = .9; at varying times: HR, 0.3; 95% CI, 0.04 to 2.7; P = .3). Among adherent patients, there was no association between red cell TGN levels and taking 6-MP with food versus without (206.1 6 107.1 v 220.6 6 121.6; P = .5), with dairy versus without (220.1 6 87.8 v 216.3 6 121.3; P =.7), or in the evening/night versus morning/ midday versus varying times (218.8 6 119.7 v 195.5 6 82.3 v 174.8 6 93.4; P = .6). ConclusionCommonly practiced restrictions surrounding 6-MP ingestion might not influence outcome but may hinder adherence. Future recommendations regarding 6-MP intake during maintenance therapy for childhood ALL should aim to simplify administration.

Adherence to 6-Mercaptopurine in children and adolescents with Acute Lymphoblastic Leukemia

“…Reports on non-adherence to oral 6-MP have relied on small cohorts of patients and been based largely on self-report [ 13 , 20 – 23 ]. However, this approach can be susceptible to misrepresentation and may overestimate a patient's adherence [ 17 , 18 , 24 ].…”

Parvoviral disease in childhood cancer: Clinical outcomes and impact on therapy at a tertiary cancer center in India

“…22,23 Our study lacks a well-defined control group against which these delays could be gauged as being significant or not, but even absolute adherence rates of <95% to acute lymphoblastic leukemia maintenance regimens have been shown to be associated with increased risk of relapse. 21 However, more prolonged follow-up would be required to see the effect of PB19 infection on long-term outcomes in this cohort of patients. In two instances, definitive treatment, i.e., HSCT, could not be delivered as the patients relapsed while undergoing treatment for sustained symptomatic parvoviremia.…”

“…Intensified/dose-dense regimens and strict adherence to oral medications are imperative to achieve and maintain durable remission rates in both childhood leukemias 21 and solid tumors. 22,23 Our study lacks a well-defined control group against which these delays could be gauged as being significant or not, but even absolute adherence rates of <95% to acute lymphoblastic leukemia maintenance regimens have been shown to be associated with increased risk of relapse.…”

Use of Allopurinol to Mitigate 6-Mercaptopurine Associated Gastrointestinal Toxicity in Acute Lymphoblastic Leukemia

“…Historically, 6-MP has been given in the evenings without food based on studies suggesting improved event-free survival for ALL patients when 6-MP is taken in the evening compared to the morning (20,21). However, more recent studies challenge these claims with no notable change in relapse risk or 6-TGN levels based on administration habits related to timing or co-administration with food, as long as 95% or more of the daily doses are taken (22,23). Twice daily administration has also been shown to maintain 6-TGN levels similar to daily dosing while reducing 6-MMP levels so long as the total daily dose is maintained (24).…”