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

Abstract

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/m², IQR = 8–29 mg/m²) and IM/IM group (25 mg/m², IQR = 8–26 mg/m²). 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.