Effects of TPMT, NUDT15, and ITPA Genetic Variants on 6-Mercaptopurine Toxicity for Pediatric Patients With Acute Lymphoblastic Leukemia in Yunnan of China

Mao, Xiaoyan; Yin, Runxiu; Sun, Ge; Zhou, Yan; Yang, Chunhui; Fang, Chunlian; Wu, Yuhong; Cui, Tingting; Liu, Li; Gan, Jiaxin; Tian, Xin

doi:10.3389/fped.2021.719803

Cited by 9 publications

(23 citation statements)

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“…18 The correlation between ITPA polymorphisms and elevated transaminase is uncertain. 4,6,14 In the univariate analysis of the current investigation, the incidence of transaminitis in patients with homITPA was significantly higher than in those with hetITPA and wild-type ITPA. Fortunately, this cohort did not exhibit severe transaminitis (> 20 times) or severe hepatic dysfunction, including coagulopathy.…”

Section: Methodsmentioning

confidence: 55%

“…11 As for ITPA, its allele frequency in this study was 0.23, consistent with other studies on Asian populations. 4,12 Neutropenia is among the most common complications for those treated with thiopurine agents. The polymorphisms of the genes involved in thiopurine metabolism account for the neutropenia of patients treated with such agents.…”

Section: Methodsmentioning

confidence: 99%

“…They are thiopurine methyltransferase (TPMT), prevalent in European populations, and nudix (nucleoside diphosphate linked moiety X) type motif 15 (NUDT15), prevalent in Asian populations. 3,4 Inosine triphosphate pyrophosphatase (ITPA), another enzyme in the multistep thiopurine pathway, prevents the accumulation of methylthioinosine triphosphate, a toxic thiopurine metabolite, thereby catalyzing inosine triphosphate to inosine monophosphate. 5,6 ITPA 94 C>A genotypes were found to have markedly decreased ITPA activity.…”

mentioning

confidence: 99%

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Itpa Polymorphisms and the Incidence of Toxicities in Children With Acute Lymphoblastic Leukemia

Svasdisant¹,

Glomglao²,

Siraprapapat³

et al. 2023

Mediterr J Hematol Infect Dis

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Background: 6-Mercaptopurine (6-MP), a thiopurine agent, is an indispensable medication for treating pediatric acute lymphoblastic leukemia (ALL). However, its side effects of neutropenia and hepatotoxicity might interrupt treatment, resulting in poor outcomes. Inosine triphosphate pyrophosphatase (ITPA), an enzyme in the thiopurine pathway, may prevent the accumulation of toxic thiopurine metabolites. Studies on ITPA and thiopurine-associated toxicities are scarce. Methods: This study retrospectively investigated 1- to 15-year-old children with ALL who received 6-MP during the maintenance phase of treatment between 2000 and 2020. Toxicity during the first year of maintenance therapy and the mean dose of 6-MP were analyzed. Results: The 209 patients had a median age of 4.8 (0.3-14.8) years. Of these, 124 patients (59.3%) had wildtype ITPA, 73 patients (34.9%) had heterozygous ITPA 94C>A (hetITPA), and 12 patients (5.7%) had homozygous ITPA 94C>A (homITPA), with an allele frequency of 0.23. The incidence of neutropenia among ITPA polymorphisms did not significantly differ (P = 0.813). In patients harboring homITPA, transaminitis was more frequent than other polymorphisms but without a significant difference (P = 0.063). The mean dose of 6-MP for patients with homITPA was significantly lower than that for patients with hetITPA or wildtype ITPA (P = 0.016). Conclusions: HomITPA had a higher incidence of transaminitis and required a significantly larger dose reduction of 6-MP than wildtype ITPA. Further study is warranted to elucidate the effects of ITPA polymorphisms on toxicity in patients with ALL treated with 6-MP.

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Section: Methodsmentioning

confidence: 55%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Itpa Polymorphisms and the Incidence of Toxicities in Children With Acute Lymphoblastic Leukemia

Svasdisant¹,

Glomglao²,

Siraprapapat³

et al. 2023

Mediterr J Hematol Infect Dis

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“…Second, we were not able to impute all single-nucleotide polymorphisms, which probably affect DNA-TG production and thiopurine toxicity. The conclusions on the variants, such as ITPA [32][33][34] and ABCC4, 15,35 are controversial and the other omitted TPMT or NUDT15 variants are exceedingly rare. 6,31,36,37 A larger sample size is needed to prove DNA-TG as an independent marker when considering these variants.…”

Section: Articlementioning

confidence: 99%

DNA‐Thioguanine Nucleotides as a Marker for Thiopurine Induced Late Leukopenia after Dose Optimizing by NUDT15 C415T in Chinese Patients with IBD

Zhu

Chao

Yang

et al. 2022

Clin Pharma and Therapeutics

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Thiopurine dose optimization by thiopurine‐S‐methyltransferase (TPMT) or nudix hydrolase‐15 (NUDT15) significantly reduced early leucopenia in Asia. However, it fails to avoid the late incidence (> 2 months). Although laboratory monitoring of 6‐thioguanine nucleotides (6TGN) to optimize thiopurine dose was suggested in White patients the exact association between leucopenia and 6TGN was controversial in Asian patients. In the present study, we aimed to explore whether DNA‐thioguanine nucleotides (DNA‐TGs) in leukocytes, compared with 6TGN in erythrocytes, can be a better biomarker for late leucopenia. This was a prospective, observational study. Patients with inflammatory bowel disease (IBD) prescribed thiopurine from February 2019 to December 2019 were recruited. Thiopurine dose was optimized by NUDT15 C415T (rs116855232). DNA‐TG and 6TGN levels were determined at the time of late leucopenia or 2 months after the stable dose was obtained. A total of 308 patients were included. Thiopurine induced late leucopenia (white blood cells < 3.5 × 109/L) were observed in 43 patients (14.0%), who had significantly higher DNA‐TG concentration than those without leucopenia (P = 4.1 × 10–9, 423.3 (~ 342.2 to 565.7) vs. 270.5 (~ 188.1 to 394.3) fmol/μg DNA). No difference in 6TGN concentrations between leucopenia and non‐leucopenia was found. With a DNA‐TG threshold of 340.1 fmol/μg DNA, 83.7% of leucopenia cases could be identified. Multivariate analysis showed that DNA‐TG was an independent risk factor for late leucopenia. Quantification of DNA‐TG, rather than 6TGN, can be applied to gauge thiopurine therapy after NUDT15 screening in Chinese patients with IBD.

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“…были включены 149 детей с ОЛЛ, у которых определяли по лиморфизмы генов TPMT, NUDT15 и ITPA. Только у больных с наличием NUDT15 полученная доза 6МП была значимо меньше и лейкоцитопении развивались чаще, чем у больных с другими исследуемыми поли морфизмами или носителями «диких» типов (p <0,05) [21]. В другом исследовании, в которое были включе ны 100 детей с ОЛЛ, достоверных различий в получен ной дозе у больных с полиморфизмами гена TPMT и «диким» типом не выявлено [22].…”

Section: Tpmt Nudt15unclassified

Polymorphisms of the <i>TPMT</i>, <i>NUDT15</i> genes and 6-mercaptopurine toxicity profile in adult patients with Ph-negative acute lymphoblastic leukemia/lymphomas on the ALL-2016 protocol

et al. 2022

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Background. 6-mercaptopurine (6-MP) is a drug that is included in the treatment protocols for children and adults with acute lymphoblastic leukemias/lymphomas (ALL/LBL). It is known that individual differences in 6-MP tolerance can be explained by the TPMT and NUDT15 polymorphisms.Aim. To determine 6-MP toxicity profile in adult patients with Ph-negative ALL/LBL treated by ALL-2016 protocol, depending on the TPMT and NUDT15 polymorphisms.Materials and methods. The study included 54 adult patients with Ph-negative ALL/LBL (40 male and 14 female). The median age was 31 (18-51) years. T-ALL/LBL was diagnosed in 29 patients, B-ALL/LBL - in 22, acute leukemia with a mixed immunophenotype - in 3. All patients received treatment according to the multicenter study ALL-2016 (ClinicalTrials.gov, NCT03462095). polymorphisms in NUDT15 (*2, *3) and TPMT (*2, *3A, *3B, *3C) genes were detected using the allele-specific real-time polymerase chain reaction. Genomic DNA was extracted from patients peripheral blood samples. On the induction and consolidation therapy by the protocol, the received and proper 6-MP doses were calculated for all the patients. Drug toxicity was evaluated based on clinical and laboratory data.Results. TPMT and NUDT15 polymorphisms were detected in 11 (20 %) patients, more often in B-ALL - 7 (32 %) of 22 (p <0.05). A lower dose of 6-MP was received by patients with TPMT, NUDT15 polymorphisms only at consolidation IV (p = 0.01). we didn't find a correlation between the 6-MP toxicity and the polymorphisms in our patients (p >0.05).Conclusion. There were no differences in the received dose of 6-MP and the incidence of toxicity in adult patients between Ph-negative ALL/LBL with or without TPMT and NUDT15 polymorphisms treated according to ALL-2016 protocol (p >0.05). further studies including evaluation of 6-MP metabolites concentrations are required for a more complete understanding of the metabolism of this drug.

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Effects of TPMT, NUDT15, and ITPA Genetic Variants on 6-Mercaptopurine Toxicity for Pediatric Patients With Acute Lymphoblastic Leukemia in Yunnan of China

Cited by 9 publications

References 32 publications

Itpa Polymorphisms and the Incidence of Toxicities in Children With Acute Lymphoblastic Leukemia

Itpa Polymorphisms and the Incidence of Toxicities in Children With Acute Lymphoblastic Leukemia

DNA‐Thioguanine Nucleotides as a Marker for Thiopurine Induced Late Leukopenia after Dose Optimizing by NUDT15 C415T in Chinese Patients with IBD

Polymorphisms of the <i>TPMT</i>, <i>NUDT15</i> genes and 6-mercaptopurine toxicity profile in adult patients with Ph-negative acute lymphoblastic leukemia/lymphomas on the ALL-2016 protocol

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