During 6-mercaptopurine and methotrexate maintenance therapy for childhood acute lymphoblastic leukemia (ALL), there was a general increase in DNA-incorporated thioguanine nucleotides (DNA-TGN), and this increase was associated with a lower frequency of disease relapse, according to the results of a study published in Lancet Oncology
“DNA-TGN concentration seems to integrate pharmacokinetics of upstream 6-mercaptopurine and methotrexate metabolites and its measurement might provide a new strategy to improve dose adjustment in maintenance therapy and decrease relapse in childhood ALL, especially in non–high-risk patients who are positive for minimal residual disease,” wrote Stine Nygaard Nielsen, MD, of the department of pediatric and adolescent medicine at University Hospital, Rigshospitalet, Denmark, and colleagues.
“These results warrant intervention trials to identify clinically applicable strategies for individualized drug dosing to increase DNA-TGN and randomized studies to explore whether such strategies improve cure rates compared with current dose adjustments based on white blood cell counts.”
According to the study, although only a small percentage of patients with childhood ALL experience relapse, relapse is most likely to occur during maintenance therapy with 6-mercaptopurine and methotrexate.
“Large inter-individual variations in drug disposition present a challenge for clinicians determining the dose of 6-mercaptopurine and methotrexate to use; and the most common measurements, erythrocyte cytosol metabolite concentrations, are poor predictors of relapse,” the researchers wrote. “Maintenance therapy intensity is instead guided by white blood cell or neutrophil counts, which have been related to relapse rates, but are confounded by natural variation with age, ethnicity, and circadian and seasonal fluctuations.”
With this study, Nielson and colleagues wanted to determine if DNA-TGN concentrations in circulating leucocytes were associated with risk for relapse. The researchers analyzed data from analyses of 6-mercaptopurine and methotrexate metabolites in blood samples taken from 918 patients with non–high-risk childhood ALL in the NOPHO ALL2008 phase III trial. Patients were aged 1 to 17.9 years and had reached maintenance therapy in first remission. Assigned maintenance therapy was mercaptopurine 75 mg/m2 once per day and methotrexate 20 mg/m2 once per week.
DNA-TGN and erythrocyte concentration of TGN nucleotides, methylated mercaptopurine metabolites, and methotrexate polyglutamates were measured. The primary objective was association of DNA-TGN concentrations and 6-mercaptopurine and methotrexate metabolites with relapse-free survival.
With a median follow-up of 4.6 years, relapse-free survival was significantly associated with increasing DNA-TGN concentrations (adjusted hazard ratio, 0.81 per 100 fmol/mcg DNA increase, P = .029). Looking at patients with at least five blood samples available, erythrocyte concentrations of TGN, methylated mercaptopurine metabolites, and methotrexate polyglutamates were associated with DNA-TGN concentrations (P < .0001 for all).
“Although previous therapeutic drug monitoring attempts for 6-mercaptopurine–based maintenance therapy (eg, plasma 6-mercaptopurine or erythrocyte TGN) have profiled pharmacokinetics or pharmacodynamics, the clinical applicability of these surrogate markers is restricted with respect to treatment adherence, and they have not proved as useful as anticipated in a randomized trial,” the researchers wrote. “Our study supports DNA-TGN as a new therapeutic drug monitoring marker both as an endpoint for the interactions between upstream 6-mercaptopurine and methotrexate metabolites and, more importantly, for the risk of relapse.”