ABCC4, ITPA, NUDT15, TPMT and their interaction as genetic predictors of 6-mercaptopurine intolerance in chinese patients with acute lymphoblastic leukemia

Fan, Paroni O L; Leung, Kam-Tong; Chan, Kathy Yuen Yee; Leung, Albert Wing Nang; Lam, Grace Kee See; Chow, Terry T W; Cheng, Frankie Wai Tsoi; Yuen, Liz Y P; Moriyama, Takaya; Yang, Jun J.; Li, Chi Kong

doi:10.1080/08880018.2021.1973628

Cited by 7 publications

(11 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 26 , 41 Three studies defined hepatotoxicity as ALT >500 U/L, ALT >700 U/L, and ALT or AST >500 U/L, respectively. 25 , 40 , 44 The remaining two defined hepatotoxicity as the highest direct bilirubin values ≥1.5 mg/dL, and as either ALT, AST, alkaline phosphatase or total bilirubin above 2-fold upper limit of normal, respectively. 39 , 52 All above-mentioned information are listed in Online Supplementary Table S1.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, no significant difference in the incidence of hepatotoxicity (OR=2.43, 95% CI: 0.95-6.20; P =0.06) ( Figure 4C ) was observed in the recessive model either. 25 , 39 , 41 , 44 Three studies comprising 426 ALL patients were included to compare the events of hepatotoxicity in NUDT15 c.52 G>A variant carriers (GA+AA) versus wild-type patients (GG) and the result indicated that there was no significant difference in hepatotoxicity incidence in either (OR=1.09, 95% CI: 0.22-5.31; P =0.91) ( Figure 4D ). 25 , 41 , 44 …”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Association of NUDT15 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

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Association of NUDT15 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

View full text Add to dashboard Cite

show abstract

“…Regarding the pharmacogenomics of the ABCC4 gene, the association of certain variants with 6-mercaptopurine intolerance has been described in Chinese children with ALL, while an association with hematologic toxicity was found in an Egyptian population with ALL ( 35 , 36 ). Similarly, we found a risk association between high-grade hematologic adverse events and the ABCC4 rs2274409 variant.…”

Section: Discussionmentioning

confidence: 99%

Association between genetic variants of membrane transporters and the risk of high-grade hematologic adverse events in a cohort of Mexican children with B-cell acute lymphoblastic leukemia

Escalante-Bautista,

Cerecedo,

Jiménez-Hernández

et al. 2024

Front. Oncol.

View full text Add to dashboard Cite

BackgroundAdvances in the understanding of the pathobiology of childhood B-cell acute lymphoblastic leukemia (B-ALL) have led towards risk-oriented treatment regimens and markedly improved survival rates. However, treatment-related toxicities remain a major cause of mortality in developing countries. One of the most common adverse effects of chemotherapy in B-ALL is the hematologic toxicity, which may be related to genetic variants in membrane transporters that are critical for drug absorption, distribution, and elimination. In this study we detected genetic variants present in a selected group genes of the ABC and SLC families that are associated with the risk of high-grade hematologic adverse events due to chemotherapy treatment in a group of Mexican children with B-ALL.MethodsNext generation sequencing (NGS) was used to screen six genes of the ABC and seven genes of the SLC transporter families, in a cohort of 96 children with B-ALL. The grade of hematologic toxicity was classified according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, Subsequently, two groups of patients were formed: the null/low-grade (grades 1 and 2) and the high-grade (grades 3 to 5) adverse events groups. To determine whether there is an association between the genetic variants and high-grade hematologic adverse events, logistic regression analyses were performed using co-dominant, dominant, recessive, overdominant and log-additive inheritance models. Odds ratio (OR) and 95% confidence intervals (95% CI) were calculated.ResultsWe found two types of associations among the genetic variants identified as possible predictor factors of hematologic toxicity. One group of variants associated with high-grade toxicity risk: ABCC1 rs129081; ABCC4 rs227409; ABCC5 rs939338, rs1132776, rs3749442, rs4148575, rs4148579 and rs4148580; and another group of protective variants that includes ABCC1 rs212087 and rs212090; SLC22A6 rs4149170, rs4149171 and rs955434.ConclusionThere are genetic variants in the SLC and ABC transporter families present in Mexican children with B-ALL that can be considered as potential risk markers for hematologic toxicity secondary to chemotherapeutic treatment, as well as other protective variants that may be useful in addition to conventional risk stratification for therapeutic decision making in these highly vulnerable patients.

show abstract

“…Moreover, ALL patients with intermediate active NUDT15 and ABCC4 variants experienced higher 6-MP intolerability, compared with the group with either of the variants ( Tanaka et al, 2018 ). In a very recent study, the co-occurrence of the ABCC4 (c.912G > T, rs2274407) and ITPA (c.94C > A) variants in 145 Chinese children with ALL witnessed a significant positive association with 6-MP intolerance ( Fan et al, 2022 ). Meanwhile, ABCC4 c.2128G > A (rs3765534) carriers experienced a significant increase in the DNA-TG to 6-MP dose ratio, which was associated with a high risk of leukopenia ( Fan et al, 2022 ).…”

Section: Pharmacogenetics Of Thiopurinesmentioning

confidence: 99%

“…In a very recent study, the co-occurrence of the ABCC4 (c.912G > T, rs2274407) and ITPA (c.94C > A) variants in 145 Chinese children with ALL witnessed a significant positive association with 6-MP intolerance ( Fan et al, 2022 ). Meanwhile, ABCC4 c.2128G > A (rs3765534) carriers experienced a significant increase in the DNA-TG to 6-MP dose ratio, which was associated with a high risk of leukopenia ( Fan et al, 2022 ). Similarly, ABCC4 SNP rs2274407 was found to be related to the increased 6-TGN to 6-MP dose ratio ( Choi et al, 2019 ).…”

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.

View full text Add to dashboard Cite

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.

show abstract

ABCC4, ITPA, NUDT15, TPMT and their interaction as genetic predictors of 6-mercaptopurine intolerance in chinese patients with acute lymphoblastic leukemia

Abstract: Supplemental Figure.1. 6-MP Dose Intensity in Patients with both ABCC4 c.912G>T and ITPA c.94C>A variants. 6-MP dose intensity were compared in patients with (n=11) and without both variants (n=134) using Mann Whitney U test. "+" indicates mean values.

Cited by 7 publications

References 29 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

Association between genetic variants of membrane transporters and the risk of high-grade hematologic adverse events in a cohort of Mexican children with B-cell acute lymphoblastic leukemia

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

Contact Info

Product

Resources

About