Trial reportJournal of clinical oncology : official journal of the American Society of Clinical Oncology2015
Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia.
Trial report in Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 2 registered trials, which are not on this map. Cited by 230 papers, 7 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.
The trial behind it
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.
Total XV - Total Therapy Study XV for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia
Pharmacogenomic Analysis of 6-mercaptopurine in Pediatric Acute Lymphoblastic Leukemia
Who cites it
230 citing papers in PubMed, 7 syntheses or guidelines pooled it, 431 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
- Association ofHaematologica · 2024Pooled it
- Clinical ascertainment of health outcomes in Asian survivors of childhood cancer: a systematic review.Journal of cancer survivorship : research and practice · 2019Pooled it
- Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update.Clinical pharmacology and therapeutics · 2019Guideline
- Association between the c.415C > T, c.52G > A, and 36_37insGGAGTC polymorphisms ofDrug design, development and therapy · 2019Pooled it
- Association of NUDT15 c.415C>T allele and thiopurine-induced leukocytopenia in Asians: a systematic review and meta-analysis.Irish journal of medical science · 2018Pooled it
- Association of GATA3 Polymorphisms With Minimal Residual Disease and Relapse Risk in Childhood Acute Lymphoblastic Leukemia.Journal of the National Cancer Institute · 2021Trial
- DNA-thioguanine nucleotide as a treatment marker in acute lymphoblastic leukemia patients with NUDT15 variant genotypes.PloS one · 2021Trial
- Nudix hydrolase 15 deficiency and azathioprine toxicity in a liver transplant recipient: A case report.JPGN reports · 2026Article
- Personalized Therapy with Mercaptopurine in Acute Lymphoblastic Leukemia: Current Advances and Challenges.Current treatment options in oncology · 2026Review
- Operationalizing Precision Medicine in Drug Development: Predictive Biomarkers, Companion Diagnostics, and Regulatory Pathways.Clinical pharmacology and therapeutics · 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
- Targeted Protein Degradation of NUDT5 Dissociates Catalytic Inhibition from Protein Loss in 6-Thioguanine Response.Nature communications · 2026Article
- Severe Thiopurine-Induced Myelosuppression in a Pediatric Acute Lymphoblastic Leukemia Patient With the NUDT15 *1/*6 Genotype: A Brief Report.Clinical and translational science · 2026Article
- Azathioprine Toxicity in Patients With Myasthenia Gravis: A Single Center Experience.Muscle & nerve · 2026Article
- Comprehensive overview of the global pharmacogenetic and functional variability in NUDT15.Human genomics · 2026Review
- The evolving landscape of pharmacogenomics: Current achievements and future directions.Pharmacological reviews · 2026Review
- Genetic Determinants of Hematopoietic Toxicity Risk in Thai Pediatric Patients Undergoing 6-Mercaptopurine Treatment.Clinical and translational science · 2026Article
- Pharmacogenomics of Thiopurine Drugs: A Bench-To-Bedside Success Story in Thailand.Clinical and translational science · 2026Review
170 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
15 authors at 1 institution in 1 country.
Funding
Abstract
purposeMercaptopurine (MP) is the mainstay of curative therapy for acute lymphoblastic leukemia (ALL). We performed a genome-wide association study (GWAS) to identify comprehensively the genetic basis of MP intolerance in children with ALL. PATIENTS AND
methodsThe discovery GWAS and replication cohorts included 657 and 371 children from two prospective clinical trials. MP dose intensity was a marker for drug tolerance and toxicities and was defined as prescribed dose divided by the planned protocol dose during maintenance therapy; its association with genotype was evaluated using a linear mixed-effects model.
resultsMP dose intensity varied by race and ethnicity and was negatively correlated with East Asian genetic ancestry (P < .001). The GWAS revealed two genome-wide significant loci associated with dose intensity: rs1142345 in TPMT (Tyr240Cys, present in *3A and *3C variants; P = 8.6 × 10(-9)) and rs116855232 in NUDT15 (P = 8.8 × 10(-9)), with independent replication. Patients with TT genotype at rs116855232 were exquisitely sensitive to MP, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes, who tolerated 63% and 83.5% of the planned dose, respectively. The NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ancestry-related differences in MP tolerance. Of children homozygous for either TPMT or NUDT15 variants or heterozygous for both, 100% required ≥ 50% MP dose reduction, compared with only 7.7% of others.
conclusionWe describe a germline variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.