{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T15:28:10Z","timestamp":1791300490050,"version":"4.1.0"},"reference-count":87,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T00:00:00Z","timestamp":1754352000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"2022 Research, Community Service, and Innovation (PPMI 2022) Program, School of Pharmacy, Institut Teknologi Bandung","award":["16A\/IT1.C10\/SK-KP\/2022"],"award-info":[{"award-number":["16A\/IT1.C10\/SK-KP\/2022"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>The management of acute lymphoblastic leukemia (ALL), the most common pediatric malignancy, critically relies on thiopurine therapy, such as 6-mercaptopurine (6-MP), during the maintenance phase. However, significant inter-individual response variety and high risk of myelosuppression often disrupt therapy efficacy. Pharmacogenetics offer crucial strategies to personalized therapy. While thiopurine methyltransferase (TPMT) was initially the primary focus, the discovery of nudix hydrolase 15 (NUDT15) appears as a more comprehensive determinant of thiopurine intolerance. This review aims to consolidate and critically evaluate the advancement achieved in unraveling the biological mechanism and clinical significance of NUDT15 pharmacogenetics in thiopurine therapy. Foundational studies showed the vital role of NUDT15 in the detoxification of active thiopurines, with common genetic variants (for instance, p. Arg139Cys) significantly disrupting its activity, leading to the accumulation of toxic metabolites. Observational studies consistently associated NUDT15 variants with severe myelosuppression, notably in Asian populations. Recent randomized controlled trials (RCTs) confirmed that NUDT15 genotype-guided dosing effectively reduces thiopurine-induced toxicity without interfering with the therapeutic outcome. Despite these advancements, challenges remain present, including the incomplete characterization of rare variants, limited data in the diverse Asian populations, and the need for standardized integration with metabolite monitoring. In conclusion, NUDT15 pharmacogenetics is essential for improving patient safety and thiopurine dosage optimization in the treatment of ALL. For thiopurine tailored medicine to be widely and fairly implemented, future research should focus on increasing genetic data across different populations, improving the dose adjustment algorithm, and harmonizing therapeutic guidelines.<\/jats:p>","DOI":"10.3390\/medsci13030112","type":"journal-article","created":{"date-parts":[[2025,8,5]],"date-time":"2025-08-05T15:56:16Z","timestamp":1754409376000},"page":"112","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["NUDT15 Pharmacogenetics in Acute Lymphoblastic Leukemia: Synthesizing Progress for Personalized Thiopurine Therapy"],"prefix":"10.3390","volume":"13","author":[{"given":"Isfahan Shah","family":"Lubis","sequence":"first","affiliation":[{"name":"Department of Pharmacology-Clinical Pharmacy, School of Pharmacy, Institut Teknologi Bandung, Bandung 40132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9879-6112","authenticated-orcid":false,"given":"Kusnandar","family":"Anggadiredja","sequence":"additional","affiliation":[{"name":"Department of Pharmacology-Clinical Pharmacy, School of Pharmacy, Institut Teknologi Bandung, Bandung 40132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aluicia Anita","family":"Artarini","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, School of Pharmacy, Institut Teknologi Bandung, Bandung 40132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9062-9624","authenticated-orcid":false,"given":"Nur Melani","family":"Sari","sequence":"additional","affiliation":[{"name":"Division of Hematology-Oncology, Department of Child Health, Faculty of Medicine, Universitas Padjadjaran\/Dr. Hasan Sadikin General Hospital, Bandung 40161, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nur","family":"Suryawan","sequence":"additional","affiliation":[{"name":"Division of Hematology-Oncology, Department of Child Health, Faculty of Medicine, Universitas Padjadjaran\/Dr. Hasan Sadikin General Hospital, Bandung 40161, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1264-9558","authenticated-orcid":false,"given":"Zulfan","family":"Zazuli","sequence":"additional","affiliation":[{"name":"Department of Pharmacology-Clinical Pharmacy, School of Pharmacy, Institut Teknologi Bandung, Bandung 40132, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1016\/S0140-6736(19)33018-1","article-title":"Acute Lymphoblastic Leukaemia","volume":"395","author":"Malard","year":"2020","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1038\/s41375-022-01591-4","article-title":"Maintenance Therapy for Acute Lymphoblastic Leukemia: Basic Science and Clinical Translations","volume":"33","author":"Toksvang","year":"2022","journal-title":"Leukemia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1007\/BF00279977","article-title":"Intraindividual Variation in 6-Mercaptopurine Pharmacokinetics during Oral Maintenance Therapy of Children with Acute Lymphoblastic Leukaemia","volume":"40","author":"Lafolie","year":"1991","journal-title":"Eur. 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