Presentation (CTI)

OBJECTIVES: Thiopurines, including azathioprine, 6-mercaptopurine, and 6-thioguanine, are widely used in the management of inflammatory bowel disease, autoimmune disorders and selected malignancies. Inter-individual variability in thiopurine toxicity is strongly influenced by pharmacogenomic factors, particularly variants in thiopurine methyltransferase and nudix hydrolase 15. This systematic review aimed to evaluate evidence on pharmacogenomic associations of TPMT, NUDT15, and reported HLA variants with thiopurine-induced toxicity across different clinical settings.
METHODS: A systematic literature review was conducted based on the use of PubMed, Google Scholar, Scopus and Web of Science (n=720). After screening the titles and abstracts, approximately 42 articles were identified, which included observational studies, case series, and case reports. Across the included studies reporting participant numbers, a total of 11,963 participants were evaluated, comprising 11,164 adults and 799 pediatric patients. Findings were synthesized narratively due to heterogeneity in study designs and outcome definitions.
RESULTS: The included studies assessed pharmacogenomic correlations between TPMT and NUDT15 with the occurrence of toxicity induced by thiopurine in clinical settings. Most investigations targeted patients with inflammatory bowel disease, and oncology was limited. The most reported toxicity was myelosuppression, which was then followed by leukopenia and neutropenia. Several reports have recorded premature and severe haematologic toxicity with NUDT15 variations that have often led to treatment withdrawal. The variants of TPMT were mainly associated with dose-related haematologic intoxication, leukopenia in particular. Other serious effects, such as pancytopenia and fatal toxicity, were less frequently reported and were described mostly in case reports. The limited number of studies carried out did not show a consistent association of HLA variants.
CONCLUSIONS: This systematic review highlights the clinical significance of TPMT and NUDT15 pharmacogenomics in predicting thiopurine-induced toxicity, especially within IBD populations. Evidence in oncology remains limited. Adding pharmacogenomic testing may enhance thiopurine safety, although further high-quality studies are needed.