13 Individualized use of 6-mercaptopurine in the maintenance treatment of Chinese children with acute lymphoblastic leukemia: a multicenter randomized controlled trial

Introduction Continuous 6-mercaptopurine (6-MP) dose titration is necessary because of its narrow therapeutic index and frequently encountered dose-limiting leukopenia. An increasing number of studies confirm the significance of TPMT- and NUDT15-guided dosing with regard to thiopurines, however, data from randomized trials that directly compare standard and gene-based doses in Chinese children with ALL are currently lacking. Methodology This multicenter, randomized, open-label, active-controlled clinical trial was designed to determine whether the initial 6-MP maintenance dose according to TPMT and NUDT15 genotypes is superior to the standard-dose regimen in Chinese children with ALL. This trial randomly assigned Chinese children with low- or intermediate-risk ALL in a 1:1 ratio to receive 6-MP at TPMT- and NUDT15-based dose (n = 44, 10 to 40 mg/m2/day) or standard dose (n = 44, 50 mg/m2/day) before proceeding to maintenance therapy. Results At the primary endpoint, which was 6-MP-related leukopenia, a 2.1-fold decrease of thiopurine-related leukopenia was observed in the gene-based-dose group with an approximately 50% decrease in the standard initial 6-MP dose (odds ratio, 0.30, 95% confidence interval, 0.83 to 1.06; p = 0.009), with no significant differences in efficacy. Difference was observed for Grade 3 of the primary endpoint between the gene-based-dose and standard-dose groups (22.7% and 43.2%, respectively; OR, 0.39, 95% CI, 0.15 to 0.98; p = 0.04). Severe leukopenia (Grade 4) did not differ significantly between the gene-based-dose and standard-dose groups (2.3% and 9.1%, respectively; OR, 0.23, 95% CI, 0.025 to 2.17; p = 0.85). No significant differences were observed in the secondary endpoints of the incidence of hepatotoxicity and steady-state concentrations of active metabolites in erythrocytes between gene-based dosing and standard dosing. Conclusion Preemptive TPMT- and NUDT15-based 6-MP dose adjustment will significantly contribute toward further reducing the incidence of potentially lethal adverse drug reactions in Chinese children with ALL. This trial was registered at www.clinicaltrial.gov as #NCT04228393.