Association of DNA Thioguanine Nucleotide Concentration and Outcome During Maintenance Therapy for Childhood ALL
In a substudy of a European phase III trial (Nordic Society of Pediatric Hematology and Oncology ALL2008) reported in The Lancet Oncology, Nygaard Nielsen et al found that higher leukocyte DNA-incorporated thioguanine nucleotide (DNA-TGN) levels were associated with an improved relapse-free survival among patients receiving mercaptopurine and methotrexate maintenance for childhood acute lymphoblastic leukemia (ALL).
Study Details
The substudy involved measurement of DNA-TGN and mercaptopurine and methotrexate metabolites in samples from 918 eligible patients with non–high-risk disease from the phase III trial (n = 1,509) who had at least a single DNA-TGN measurement. Patients eligible for the substudy were aged 1.0 to 17.9 years and had reached maintenance therapy in first remission. Maintenance therapy consisted of mercaptopurine at 75 mg/m² once daily and methotrexate at 20 mg/m² once per week targeted to a leukocyte count of 1.5 to 3.0 × 109/L.
Association With Relapse-Free Survival
Median follow-up was 4.6 years. Relapse-free survival was significantly associated with a higher DNA-TGN concentration (adjusted hazard ratio = 0.81 per 100 fmol/μg DNA increase, P = .029). No significant association with relapse-free survival was observed for levels of erythrocyte TGN, erythrocyte methotrexate polyglutamates, or erythrocyte methylated mercaptopurine metabolites. Relapse-free survival was also associated with age at diagnosis and sex but not with white blood cell count at diagnosis.
Among 42 event-free patients in an exploratory cohort and 304 event-free patients in a validation cohort who had at least 5 metabolite measurements, levels of erythrocyte TGN, erythrocyte methylated mercaptopurine metabolites, and erythrocyte methotrexate polyglutamates were all positively associated with levels of DNA-TGN (all P < .0001).
The investigators concluded: “Our results suggest the need for intervention trials to identify clinically applicable strategies for individualised drug dosing to increase DNA-TGN concentration and randomised studies to investigate whether such strategies improve cure rates compared with current dose adjustments based on white blood cell counts.”
The study was funded by the Danish Cancer Society, Childhood Cancer Foundation (Denmark), Childhood Cancer Foundation (Sweden), Nordic Cancer Union, Otto Christensen Foundation, University Hospital Rigshospitalet, and Novo Nordisk Foundation.
Kjeld Schmiegelow, DrMedSci, of the University Hospital Rigshospitalet, Copenhagen, is the corresponding author of The Lancet Oncology article.
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