6‐Mercaptopurine metabolic profiles and clinical outcomes in TPMT and NUDT15 phenotypes during maintenance therapy for Thai paediatric acute lymphoblastic leukaemia

Aim This study aimed to investigate the real‐world profiles of 6‐mercaptopurine (6‐MP) treatment in various TPMT/NUDT15 phenotype groups among paediatric patients with ALL. Methods We conducted a prospective cohort study of 104 paediatric patients with ALL during the maintenance phase, collecting baseline data and following up monthly for 5 months. Patients were genotyped and classified as normal (NM), intermediate (IM) or poor (PM) metabolizers based on the TPMT and NUDT15 genetic variations. Additionally, TPMT activity and metabolite concentrations (6‐thioguanine nucleotides; 6‐TGN and 6‐methylmercaptopurine nucleotides; 6‐MMPN) were also quantified. Results The patients were categorized into five TPMT/NUDT15 phenotype groups: NM/NM (73.08%), NM/IM (17.31%), NM/PM (1.92%), IM/NM (3.85%) and IM/IM (3.85%). The tolerated 6‐MP dose was lowest in the NM/PM group (18 mg/m 2 , IQR = 8–29 mg/m 2 ) and IM/IM group (25 mg/m 2 , IQR = 8–26 mg/m 2 ). The IM/IM had the highest rate of early neutropenia (75%). TPMT activity remained stable throughout the study except in the NM/PM group, which showed significant fluctuations. Patients with NM/PM had the lowest 6‐TGN level, and patients with IM/NM showed high 6‐TGN levels. Patients with NM/NM and NM/IM exhibited elevated levels of 6‐MMPN, which were associated with the occurrence of hepatotoxicity. Conclusion The TPMT and NUDT15 genes influence the side effects of 6‐MP medications. Patients who have variations in both genes are at a higher risk of experiencing toxicity. High levels of 6‐TGN are associated with TPMT variants, whereas low levels are linked to NUDT15 variants. This could facilitate more precise monitoring of toxicity.