Susceptibility to 6-mercaptopurine toxicity related with NUDT15 and ABCC4 variants in Japanese childhood acute lymphoblastic leukemia.

6-Mercaptopurine (6-MP) is one of the main components for the treatment of childhood acute lymphoblastic leukemia (ALL). However, many patients require a dose reduction of 6-MP due to its severe toxicities. NUDT15 variants are one of the factors that cause 6-MP intolerability in Asians. In each patient with heterozygous variants of NUDT15, 6-MP intolerability differs. Therefore, we hypothesized that the combination of NUDT15 genotype with ABCC4 genotype, which is associated with 6-MP efflux, might enable to accurately predict 6-MP intolerability. We analyzed the association between 6-MP-related events and the genotypes of NUDT15 and ABCC4. All patients with both NUDT15 rs116855232 heterozygous variants and ABCC4 rs3765534 variants suffered from severe leukopenia and required 6-MP dose reduction to less than 35 mg/m2/day. In conclusion, genotyping NUDT15 and ABCC4 facilitates the prediction of 6-MP intolerability. The results of this study will improve personalized medicines in Japanese patients with childhood ALL.