Genetic Determinants of Hematopoietic Toxicity Risk in Thai Pediatric Patients Undergoing 6‐Mercaptopurine Treatment

The nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) has been identified as a key genetic determinant of 6-mercaptopurine (6-MP)-induced hematopoietic toxicity in populations with a high frequency of NUDT15 variants but a low frequency of thiopurine S-methyltransferase (TPMT) variants. However, evidence remains limited in populations where both genetic variants are prevalent. This study aimed to characterize the impact of NUDT15 and TPMT polymorphisms on 6-MP-induced hematopoietic toxicity in Thai pediatric patients, a population with a high prevalence of both variants. A total of 215 Thai pediatric patients undergoing maintenance-phase therapy with 6-MP were enrolled. Genotyping for TPMT and NUDT15 was performed, and phenotypes were determined based on the genotype data. The results showed that the absolute neutrophil count (ANC), white blood cell (WBC) count, and platelet count during the first 6 months of the maintenance phase were significantly lower in intermediate metabolizers (IM) of NUDT15 compared to normal metabolizers (NM). The risk of 6-MP-induced severe neutropenia increased by 6.8-24.5-fold in IM/PM of NUDT15. The suitable tolerance doses of 6-MP in the IM/PM of NUDT15 were lower than the normal starting dose while the tolerance dose of 6-MP in the indeterminate metabolizers (IDM) of NUDT15 or IM of TPMT was not significantly different from the normal starting dose. In conclusion, NUDT15 plays a more prominent role than TPMT in 6-MP-induced hematopoietic toxicity in Thai pediatric patients. Determining NUDT15 phenotypes is essential to ensure appropriate 6-MP dosage adjustments and to mitigate the risk of severe hematopoietic toxicity in this population.