The evaluation of the impact of NUDT15 variants on thiopurine metabolism in Japanese children with acute lymphoblastic leukemia

Purpose This study aimed to evaluate the impact of Nudix hydrolase 15 (NUDT15) variants on thiopurine metabolites, DNA-incorporated thioguanine nucleotides (DNA-TG), erythrocyte thioguanine nucleotides (Ery-TGNs) and methyl mercaptopurine nucleotide (Ery-MMPN) levels, and the association among the levels of these 6-MP metabolites in Japanese children with acute lymphoblastic leukemia (ALL). Methods DNA-TG, Ery-TGNs, and Ery-MMPN levels were measured in 20 Japanese patients with childhood ALL (171 sampling points) on consecutive clinical visits, using liquid chromatography with tandem mass spectrometry. NUDT15 was genotyped using Sanger sequencing. Results Three NUDT15 intermediate metabolizers (IM, *1/*2 or *1/*3) and two poor metabolizers (PM, *3/*3) were identified. DNA-TG/dose was significantly higher in PM than in normal metabolizers (NM). Intra-patient coefficients of variation (CV) of DNA-TG levels were similar in NUDT15 genotypes, and inter-patient CV was higher in IM and PM than in NM. The DNA-TG/Ery-TGNs ratio was higher in IM and PM than in NM (p < 0.01). The ranges of DNA-TG/dose and DNA-TG/Ery-TGNs ratio were not different within NUDT15 phenotypes. In NUDT15 NM, patients with high Ery-TGNs/dose showed high DNA-TG/dose. Absolute lymphocyte count was significantly correlated with DNA-TG, Ery-TGNs, and Ery-MMPN levels (p < 0.001). White blood cell counts were significantly correlated with Ery-TGNs levels (p < 0.02), and the levels of aspartate and alanine aminotransferases were significantly correlated with Ery-MMPN levels (p < 0.001). Conclusion NUDT15 phenotype is a strong factor for thiopurine trialability in Japanese children with ALL. Ery-TGNs levels may associate with difference of individual response.