Aim: 6-Mercaptopurine (6MP) is key to the treatment of acute lymphoblastic leukemia (ALL) as part of maintenance therapy. NUDT15 was identified as a novel thiopurine regulator conferring 6MP sensitivity. The aim of this study was to evaluate the influence of NUDT15 variants on 6MP-induced neutropenia in Thai children with ALL. Materials & methodology: Genotyping of NUDT15 (c.415C>T; rs116855232) and c.36_37insGGAGTC; rs554405994) was performed by Sanger sequencing in 100 patients with ALL. Patients were classified into wild-type (group 1), heterozygous variant (group 2) and homozygous variant (group 3). Clinical and laboratory features during the first 6 months of maintenance therapy were investigated. Therapy-induced neutropenia was observed in 31 patients during the weeks 1–8 (early myelotoxicity), while therapy-induced neutropenia was observed in 47 patients during the weeks 9–24 (late myelotoxicity). Results: There were 85 wild-type patients, 14 heterozygous variant patients and one homozygous variant patient. NUDT15 variants were associated with neutropenia as compared with wild-type (odds ratio: 17.862; 95% CI: 4.198–75.992, padj = 9.5 × 10-5). Multivariate analysis showed that the low-risk group was associated with neutropenia (p = 0.014) in the first 8 weeks of 6MP therapy. Group 2 and group 3 patients had significantly lower absolute neutrophil counts compared with group 1. The adjusted dose during the first 6 months of maintenance therapy with NUDT15 genotype group 1, 2 and 3 were 50, 36.6 and 12.5 mg/m2/day, respectively. Conclusion: Taken together, our results indicate NUDT15 variants may cause neutropenia, and the 6MP dosage should be considered in patients according to the NUDT15 variants to inform personalized 6MP therapy.
The response to 6-mercaptopurine (6-MP) can be altered by genetic polymorphisms in genes encoding drug-metabolizing enzymes and drug transporters. The purpose of this study was to investigate the association between genetic polymorphisms of drug-metabolizing enzymes (TPMT 719A > G (*3C), ITPA 94C > A and ITPA 123G > A) and drug transporters (MRP4 912C > A and MRP4 2269G > A) with 6-MP-related myelotoxicity and hepatotoxicity in Thai children with acute lymphoblastic leukemia (ALL). The prescribed dosage of 6-MP and its adverse effects were assessed from medical records during the first 8 weeks and 9–24 weeks of maintenance therapy. Children with the TPMT*1/*3C genotype had a higher risk of leukopenia with an odds ratio (OR) of 4.10 (95% confidence interval (CI) of 1.06–15.94; p = 0.033) compared to wild type (TPMT*1/*1) patients. Heterozygous TPMT*3C was significantly associated with severe neutropenia with an increased risk (OR, 4.17; 95% CI, 1.25–13.90); p = 0.014) during the first 8 weeks. No association was found among ITPA94C > A, ITPA123G > A, MRP4 912C > A, and MRP4 2269G > A with myelotoxicity and hepatotoxicity. The evidence that TPMT heterozygotes confer risks of 6-MP-induced myelotoxicity also supports the convincing need to genotype this pharmacogenetic marker before the initiation of 6-MP therapy.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.