ArticleJournal of the National Cancer Institute2024
Additive effects of TPMT and NUDT15 on thiopurine toxicity in children with acute lymphoblastic leukemia across multiethnic populations.
Article in Journal of the National Cancer Institute, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 2 of them syntheses that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
26 citing papers in PubMed, 2 syntheses or guidelines pooled it, 34 citations in OpenAlex.
- Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2025 Update.Clinical pharmacology and therapeutics · 2026Guideline
- Innovating Thiopurine Therapeutic Drug Monitoring: A Systematic Review and Meta-Analysis on DNA-Thioguanine Nucleotides (DNA-TG) as an Inclusive Biomarker in Thiopurine Therapy.Clinical pharmacokinetics · 2024Pooled it
- Personalized Therapy with Mercaptopurine in Acute Lymphoblastic Leukemia: Current Advances and Challenges.Current treatment options in oncology · 2026Review
- Pharmacogenetic Predictors of Chemotherapy Treatment-Related Toxicities in Paediatric and Adolescent Acute Lymphoblastic Leukemia: A Systematic Review, Meta-Analysis and Literature-Based Candidate Prioritization.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Prevalence of TPMT and NUDT15 diplotypes in Mexican children with B-cell acute lymphoblastic leukemia.Pharmacogenetics and genomics · 2026Article
- Pharmacogenomics and Epigenetic Regulation Transforming Pediatric Precision Therapeutics.Journal of personalized medicine · 2026Review
- Therapeutic Drug Monitoring and Pharmacogenomics of Thiopurines in Inflammatory Bowel Disease: International Guidelines Revisited.Therapeutic drug monitoring · 2026Review
- The role of pharmacogenetics in the therapy regimen of acute lymphoblastic leukemia in children: recent discoveries and future perspectives.Pharmacological reports : PR · 2026Review
- Genetic Determinants of Hematopoietic Toxicity Risk in Thai Pediatric Patients Undergoing 6-Mercaptopurine Treatment.Clinical and translational science · 2026Article
- Pharmacogenomics of Antineoplastic Therapy in Children: Genetic Determinants of Toxicity and Efficacy.Pharmaceutics · 2026Review
- Pharmacogenomics of treatment toxicities in pediatric B-Cell ALL: toward safer precision therapy.Frontiers in pharmacology · 2026Review
- Precision Pediatric Cancer Nanomedicine: Advancing Personalized Nano Therapies to Reduce Non-Communicable Diseases Through AI-Driven 3D-Printed Drugs.International journal of nanomedicine · 2026Review
- Clinical Utility and Cost-Effectiveness of Pretreatment NUDT15 Pharmacogenetic Testing to Prevent Thiopurine-Induced Myelosuppression: A Genotype-First Reverse Phenotyping Cohort Study Within the UK NIHR Inflammatory Bowel Disease Bioresource.Alimentary pharmacology & therapeutics · 2025Article
- The NUDIX hydrolase NUDT5 regulates thiopurine metabolism and cytotoxicity.The Journal of clinical investigation · 2025Article
- The NUDIX hydrolase NUDT5 influences purine nucleotide metabolism and thiopurine pharmacology.The Journal of clinical investigation · 2025Article
- Risk stratified treatment for childhood acute lymphoblastic leukaemia: a multicentre observational study from India.The Lancet regional health. Southeast Asia · 2025Article
- Clinical Actionability of the NUDT15 *4 (p.R139H) Allele and Its Association With Hispanic Ethnicity.Clinical pharmacology and therapeutics · 2025Article
- Validation of diagnostic screening test for pharmacogenomic targets for thiopurine drugs in indian pediatric acute lymphoblastic leukemia patients.Frontiers in pharmacology · 2025Article
- The multifaceted regulatory roles of Nudix hydrolases in cancer and their therapeutic potential.Frontiers in oncology · 2025Review
- Pharmacogenomics of Chemotherapies for Childhood Cancers in Africa: A Scoping Review.Pharmacogenomics and personalized medicine · 2025Review
Corrections and comments
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Authors and funding
23 authors at 6 institutions in 4 countries.
Funding
Abstract
backgroundThiopurines such as mercaptopurine (MP) are widely used to treat acute lymphoblastic leukemia (ALL). Thiopurine-S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) inactivate thiopurines, and no-function variants are associated with drug-induced myelosuppression. Dose adjustment of MP is strongly recommended in patients with intermediate or complete loss of activity of TPMT and NUDT15. However, the extent of dosage reduction recommended for patients with intermediate activity in both enzymes is currently not clear.
methodsMP dosages during maintenance were collected from 1768 patients with ALL in Singapore, Guatemala, India, and North America. Patients were genotyped for TPMT and NUDT15, and actionable variants defined by the Clinical Pharmacogenetics Implementation Consortium were used to classify patients as TPMT and NUDT15 normal metabolizers (TPMT/NUDT15 NM), TPMT or NUDT15 intermediate metabolizers (TPMT IM or NUDT15 IM), or TPMT and NUDT15 compound intermediate metabolizers (TPMT/NUDT15 IM/IM). In parallel, we evaluated MP toxicity, metabolism, and dose adjustment using a Tpmt/Nudt15 combined heterozygous mouse model (Tpmt+/-/Nudt15+/-).
resultsTwenty-two patients (1.2%) were TPMT/NUDT15 IM/IM in the cohort, with the majority self-reported as Hispanics (68.2%, 15/22). TPMT/NUDT15 IM/IM patients tolerated a median daily MP dose of 25.7 mg/m2 (interquartile range = 19.0-31.1 mg/m2), significantly lower than TPMT IM and NUDT15 IM dosage (P < .001). Similarly, Tpmt+/-/Nudt15+/- mice displayed excessive hematopoietic toxicity and accumulated more metabolite (DNA-TG) than wild-type or single heterozygous mice, which was effectively mitigated by a genotype-guided dose titration of MP.
conclusionWe recommend more substantial dose reductions to individualize MP therapy and mitigate toxicity in TPMT/NUDT15 IM/IM patients.
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