NUDT15 is a key genetic factor for prediction of hematotoxicity in pediatric patients who received a standard low dosage regimen of 6-mercaptopurine

Khaeso, Kanyarat; Komwilaisak, Patcharee; Chainansamit, Su-on; Nakkam, Nontaya; Suwannaying, Kunanya; Kuwatjanakul, Pitchayanan; Hikino, Keiko; Dornsena, Areerat; Kanjanawart, Sirimas; Laoaroon, Napat; Vannaprasaht, Suda; Taketani, Takeshi; Tassaneeyakul, Wichittra

doi:10.1016/j.dmpk.2021.100436

Cited by 2 publications

(2 citation statements)

References 43 publications

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“…However, the correlation between NUDT15 * 5 and NUDT15 * 6 with thiopurine-related myelosuppression remain contested. 50 Our study suggested that the difference in the risk for 6-MP-associated leukopenia in NUDT15 c.52G>A variant carriers and wild-type patients was not statistically significant. The influence of NUDT15 c.52G>A gene polymorphism on 6-MP-associated leukopenia was less than NUDT15 c.415C>T in our study.…”

Section: Discussionmentioning

confidence: 54%

Association of <i>NUDT15</i> gene polymorphism with adverse reaction, treatment efficacy, and dose of 6-mercaptopurine in patients with acute lymphoblastic leukemia: a systematic review and meta-analysis

Du,

Huang,

et al. 2023

haematol

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6-mercaptopurine (6-MP) serves as the backbone in the maintenance regimens of acute lymphoblastic leukemia (ALL). We aimed to evaluate the influence of NUDT15 gene polymorphism on the risk of myelosuppression, hepatotoxicity and interruption of 6-MP, as well as treatment efficacy and dose of 6-MP in ALL patients. A total of 24 studies with 3374 patients were included in this meta-analysis. We found 9-fold higher risk of 6-MP induced leukopenia (OR: 9.00, 95% CI: 3.73-21.74) and 2.5-fold higher risk of 6-MP induced neutropenia (OR: 2.52, 95% CI: 1.72-3.69) for NUDT15 c.415C>T variant carriers in the dominant model. Moreover, we found that the dose intensity of 6-MP in ALL patients with one NUDT15 c.415C>T variant alleles (CT) was 19% less than that in wild type patients (CC) (MD: 19.43%, 95% CI: -25.36%, -13.51%). The tolerable dose intensity of 6-MP in NUDT15 c.415C>T homozygote variant (TT) and heterozygote variant (CT) carriers was 49% and 15% less than that in wild type patients, respectively. The NUDT15 c.415C>T variants group (CT+TT) had 7 times (OR: 6.98, 95% CI: 2.83-17.22) higher risk of developing 6-MP intolerance than the CC group. However, NUDT15 c.415C>T polymorphism did not appear significantly associated with hepatotoxicity, treatment interruption or relapse incidence. We concluded that NUDT15 c.415C>T was a good predictor for 6-MP induced myelosuppression in ALL patients. The dose intensity of 6-MP in ALL patients with NUDT15 c.415C>T variants was significantly lower than that in wild type patients. This research provided a basis for further investigation into relations between NUDT15 gene and adverse reaction, treatment efficacy and dose intensity of 6-MP.

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Section: Discussionmentioning

confidence: 54%

Association of <i>NUDT15</i> gene polymorphism with adverse reaction, treatment efficacy, and dose of 6-mercaptopurine in patients with acute lymphoblastic leukemia: a systematic review and meta-analysis

Du,

Huang,

et al. 2023

haematol

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“…Similarly, ABCC4 SNP rs2274407 was found to be related to the increased 6-TGN to 6-MP dose ratio ( Choi et al, 2019 ). In addition, a study in Thai ALL pediatric patients found that the average absolute neutrophil count (ANC) at the 6 th month of the maintenance phase was significantly lower in ABCC4 SNP rs3765534 carriers, compared to patients carrying wild-type alleles, and the risk of grade 4 neutropenia was higher in ABCC4 GA carriers than wild-type patients, but was not statistically significant ( Khaeso et al, 2022 ). Of note, the allele frequency of variants in ABCC4 showed ethnic difference ( Table 2 ), and more evidence needs to be accumulated to establish the potential association between ABCC4 variants and 6-MP-induced adverse effects in the future.…”

Section: Pharmacogenetics Of Thiopurinesmentioning

confidence: 99%

Optimizing thiopurine therapy in children with acute lymphoblastic leukemia: A promising “MINT” sequencing strategy and therapeutic “DNA-TG” monitoring

Guo

Zhao²,

Dong³

et al. 2022

Front. Pharmacol.

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Thiopurines, including thioguanine (TG), 6-mercaptopurine (6-MP), and azathioprine (AZA), are extensively used in clinical practice in children with acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases. However, the common adverse effects caused by myelosuppression and hepatotoxicity limit their application. Metabolizing enzymes such as thiopurine S-methyltransferase (TPMT), nudix hydrolase 15 (NUDT15), inosine triphosphate pyrophosphohydrolase (ITPA), and drug transporters like multidrug resistance-associated protein 4 (MRP4) have been reported to mediate the metabolism and transportation of thiopurine drugs. Hence, the single nucleotide polymorphisms (SNPs) in those genes could theoretically affect the pharmacokinetics and pharmacological effects of these drugs, and might also become one of the determinants of clinical efficacy and adverse effects. Moreover, long-term clinical practices have confirmed that thiopurine-related adverse reactions are associated with the systemic concentrations of their active metabolites. In this review, we mainly summarized the pharmacogenetic studies of thiopurine drugs. We also evaluated the therapeutic drug monitoring (TDM) research studies and focused on those active metabolites, hoping to continuously improve monitoring strategies for thiopurine therapy to maximize therapeutic efficacy and minimize the adverse effects or toxicity. We proposed that tailoring thiopurine dosing based on MRP4, ITPA, NUDT15, and TMPT genotypes, defined as “MINT” panel sequencing strategy, might contribute toward improving the efficacy and safety of thiopurines. Moreover, the DNA-incorporated thioguanine nucleotide (DNA-TG) metabolite level was more suitable for red cell 6-thioguanine nucleotide (6-TGNs) monitoring, which can better predict the efficacy and safety of thiopurines. Integrating the panel “MINT” sequencing strategy with therapeutic “DNA-TG” monitoring would offer a new insight into the precision thiopurine therapy for pediatric acute lymphoblastic leukemia patients.

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NUDT15 is a key genetic factor for prediction of hematotoxicity in pediatric patients who received a standard low dosage regimen of 6-mercaptopurine

Cited by 2 publications

References 43 publications

Association of <i>NUDT15</i> gene polymorphism with adverse reaction, treatment efficacy, and dose of 6-mercaptopurine in patients with acute lymphoblastic leukemia: a systematic review and meta-analysis

Association of <i>NUDT15</i> gene polymorphism with adverse reaction, treatment efficacy, and dose of 6-mercaptopurine in patients with acute lymphoblastic leukemia: a systematic review and meta-analysis

Optimizing thiopurine therapy in children with acute lymphoblastic leukemia: A promising “MINT” sequencing strategy and therapeutic “DNA-TG” monitoring

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