NUDT15 (Nudix Hydrolase 15)

Approximately 28% of patients carried TPMT and/or NUDT15 variants associated with non-wild-type enzymatic activity, increasing the risk of mercaptopurine-induced myelotoxicity. Preemptive genotyping is essential to reduce toxicity, optimize treatment, and advance precision medicine in this population. Additionally, the two TPMT variants p.G126A and p.D137Y, currently not classified within Clinical Pharmacogenetics Implementation Consortium-defined star alleles, highlight the need for functional validation and potential clinical classification to improve pharmacogenetic interpretation in diverse populations.

Such inhibition aims to exploit cancer cell vulnerabilities by increasing the accumulation of damaged nucleotides and enhancing susceptibility to DNA-damaging agents (e.g., chemotherapy, radiotherapy) or PARP inhibitors, offering promising avenues for novel combination therapies. This review comprehensively overviews the mechanisms, diverse functions, and pathophysiological roles of NUDT in cancer biology, critically evaluating their therapeutic potential and the challenges in targeting them.

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.

However, the composite effects of these genetic variants remain unexplored at the global scale. Proper large-scale studies with multi-ethnic patients can provide a clear understanding of the TPMT/NUDT15 association and would pave the way towards the optimization of thiopurine drugs to achieve precision medicine.

Thiopurines such as 6-mercaptopurine (6-MP) are central to maintenance therapy for pediatric acute lymphoblastic leukemia (ALL), yet their narrow therapeutic index frequently causes dose-limiting myelosuppression in genetically susceptible patients...Its affordability and minimal infrastructure requirements make it suitable for integration into routine pre-treatment workflows in India, enabling genotype-guided thiopurine dosing and reducing the risk of treatment-related toxicity. This assay supports a scalable path toward equitable implementation of pharmacogenomics in resource-limited pediatric oncology settings.

Enhanced data governance and public education are also required to overcome privacy concerns and foster acceptance. Continued investment in paediatric-specific PGx research and age-specific guidelines is vital in bridging knowledge gaps and addressing developmental differences in drug metabolism.

Multivariate analysis was performed, and the dosage was adjusted for age, sex, and mercaptopurine...Preemptive NUDT15 genotyping did not significantly reduce febrile neutropenia episodes in our cohort of pediatric patients with ALL, although it allowed a potential reduction in HR patients. Clinicians should consider preemptive testing, particularly in HR and VHR patient groups, to optimize ALL treatments and reduce adverse events.

However, large-scale international collaborations can generate the necessary statistical power, including enabling more complex bioinformatic approaches, such as polygenic risk scores and more advanced machine learning strategies. In this review, we outline the necessary steps toward bridging the gap between genetic discovery and clinical practice.

The current guideline describes the gene-drug interactions for TPMT, NUDT15 and thiopurines (azathioprine, 6-mercaptopurine and thioguanine). For TPMT or NUDT15 IM treated for leukaemia, starting with the normal dose can be considered and then decrease the dose to the advised dose described above in case toxicities occur. For NUDT15 PM reduced starting dose is advised only if an alternative is not possible, due to a higher uncertainty in the calculated dose reduction for NUDT15 PM than for TPMT PM.DPWG classifies genotyping for TPMT and NUDT15 "essential" before thiopurine initiation.

Analysis of ClinPGx/PharmGKB data emphasizes ABCB1 as a potential resistance marker and supports pre-treatment genotyping of genes like TPMT and NUDT15 to prevent severe toxicities. Future advances should include the expansion of pharmacogenetic studies in underrepresented populations and the clinical validation of new markers in prospective trials, aiming to consolidate precision medicine as a routine part of the therapeutic management of acute leukemias.

This novel case highlights the risk of alarelin acetate-related hepatotoxicity. Pharmacogenomic profiling indicated that its hepatotoxicity may be related to gene polymorphisms; however, further research or larger-scale studies are needed to validate these associations.

Mercaptopurine (MP)-based maintenance therapy is essential to cure acute lymphoblastic leukemia (ALL). Dose escalation is unlikely to improve myelosuppression but will increase the risk of hepatotoxicity. Low-dose mercaptopurine combined with allopurinol can improve efficacy and reduce the risk of hepatotoxicity.