Publication: NUDT15 genetic variants are related to thiopurine-induced neutropenia in Thai children with acute lymphoblastic leukemia
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Issued Date
2020
Resource Type
File Type
application/pdf
ISSN
14622416
Other identifier(s)
2-s2.0-85084695733
Rights Holder(s)
มหาวิทยาลัยศรีนครินทรวิโรฒ
Bibliographic Citation
Pharmacogenomics. Vol 21, No.6 (2020), p.403-410
Suggested Citation
Puangpetch A., Tiyasirichokchai R., Pakakasama S., Wiwattanakul S., Anurathapan U., Hongeng S., Sukasem C. NUDT15 genetic variants are related to thiopurine-induced neutropenia in Thai children with acute lymphoblastic leukemia. Pharmacogenomics. Vol 21, No.6 (2020), p.403-410. doi:10.2217/pgs-2019-0177 Retrieved from: https://hdl.handle.net/20.500.14740/4619
Abstract
Aim: 6-Mercaptopurine (6MP) is key to the treatment of acute lymphoblastic leukemia (ALL) as part of maintenance therapy. NUDT15 was identified as a novel thiopurine regulator conferring 6MP sensitivity. The aim of this study was to evaluate the influence of NUDT15 variants on 6MP-induced neutropenia in Thai children with ALL. Materials & methodology: Genotyping of NUDT15 (c.415C>T; rs116855232) and c.36-37insGGAGTC; rs554405994) was performed by Sanger sequencing in 100 patients with ALL. Patients were classified into wild-type (group 1), heterozygous variant (group 2) and homozygous variant (group 3). Clinical and laboratory features during the first 6 months of maintenance therapy were investigated. Therapy-induced neutropenia was observed in 31 patients during the weeks 1-8 (early myelotoxicity), while therapy-induced neutropenia was observed in 47 patients during the weeks 9-24 (late myelotoxicity). Results: There were 85 wild-type patients, 14 heterozygous variant patients and one homozygous variant patient. NUDT15 variants were associated with neutropenia as compared with wild-type (odds ratio: 17.862; 95% CI: 4.198-75.992, padj = 9.5 × 10-5). Multivariate analysis showed that the low-risk group was associated with neutropenia (p = 0.014) in the first 8 weeks of 6MP therapy. Group 2 and group 3 patients had significantly lower absolute neutrophil counts compared with group 1. The adjusted dose during the first 6 months of maintenance therapy with NUDT15 genotype group 1, 2 and 3 were 50, 36.6 and 12.5 mg/m2/day, respectively. Conclusion: Taken together, our results indicate NUDT15 variants may cause neutropenia, and the 6MP dosage should be considered in patients according to the NUDT15 variants to inform personalized 6MP therapy. © 2020 Future Medicine Ltd.
Subject(s)
Mercaptopurine
Nucleoside diphosphatase
Acute lymphoblastic leukemia
Article
Child
Clinical feature
Disease association
Female
Gene
Genetic association
Genetic risk
Genetic variability
Genotype
Heterozygosity
Homozygosity
Human
Low risk population
Maintenance therapy
Major clinical study
Male
Neutropenia
Neutrophil count
NUDT15 gene
Preschool child
Retrospective study
Sanger sequencing
Thai (people)
Nucleoside diphosphatase
Acute lymphoblastic leukemia
Article
Child
Clinical feature
Disease association
Female
Gene
Genetic association
Genetic risk
Genetic variability
Genotype
Heterozygosity
Homozygosity
Human
Low risk population
Maintenance therapy
Major clinical study
Male
Neutropenia
Neutrophil count
NUDT15 gene
Preschool child
Retrospective study
Sanger sequencing
Thai (people)