Less Than 95% Adherence to Mercaptopurine Maintenance Associated With Nearly Threefold Increased Risk of Relapse in Pediatric ALL


Key Points

  • Mercaptopurine adherence < 95% was associated with a 2.7-fold increased risk of relapse in children with acute lymphoblastic leukemia.
  • Among patients with ≥ 95% adherence, relapse risk was increased by high variation in erythrocyte thioguanine nucleotide levels.

In a Children’s Oncology Group study (COG-AALL03N1) reported in JAMA Oncology, Bhatia et al found that < 95% adherence to mercaptopurine treatment was associated with a nearly threefold increase in the risk of relapse in children with acute lymphoblastic leukemia (ALL). Among adherent patients, high variability in erythrocyte mercaptopurine metabolite (thioguanine nucleotide) levels was associated with an increased relapse risk.

Study Details

The study involved 742 children with ALL treated in ambulatory care settings of 94 participating institutions between May 2005 and September 2011. All patients had a diagnosis of ALL at age ≤ 21 years; were in first continuous remission in progress at study entry; were receiving self-, parent-, or caregiver-administered oral mercaptopurine during maintenance therapy; and had completed ≥ 6 months of maintenance therapy at study entry. Patients had a median age of 5 years at diagnosis, 68% were boys, and 43% had high-risk disease.

Adherence to mercaptopurine regimens was measured over 68,716 person-days by recording each mercaptopurine bottle opening, with adherence rate defined as the ratio of days that a mercaptopurine bottle was opened to days that a mercaptopurine bottle was prescribed. Average monthly mercaptopurine dose intensity was measured over 120,439 person-days by dividing the number of actually prescribed mercaptopurine doses by the number of planned protocol doses (75 mg/m2/d). Erythrocyte thioguanine nucleotide levels were measured monthly over 6 consecutive months (total of 3,944 measurements). Median follow-up was 6.7 years.

Relapse was observed in 13.9% of patients with mean mercaptopurine adherence < 95% vs 4.7% of those with adherence ≥ 95%; after adjustment for clinical prognostic variables, patients with mean mercaptopurine adherence rates < 95% had a relapse hazard ratio [HR] of 2.7 (P = .01). Among adherent patients, high intraindividual variability in thioguanine nucleotide levels (≥ 85th percentile) was associated with an increased risk of relapse (HR = 4.4, P = .02). Adherent patients with variation in thioguanine nucleotide levels were more likely to have had variation in mercaptopurine dose intensity (odds ratio [OR] = 4.5, P = .01) and mercaptopurine interruptions (OR = 10.2, P = .003).

The investigators concluded: “These findings emphasize the need to maximize [mercaptopurine] regimen adherence and maintain steady thiopurine exposure to minimize relapse in children with ALL.”

Smita Bhatia, MD, MPH, of University of Alabama at Birmingham, is the corresponding author of the JAMA Oncology article.

The study was supported by the National Institutes of Health and American Lebanese Syrian Associated Charities. For full disclosures of the study authors, visit

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