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The influence of NUDT15 variants on 6-mercaptopurine-induced neutropenia in Vietnamese pediatric acute lymphoblastic leukemia.

ABSTRACT: 6-Mercaptopurine (6-MP) serves as the backbone of maintenance therapy in acute lymphoblastic leukemia. The nucleoside diphosphate-linked moiety X-type motif 15 genes (NUDT15) affects the metabolism of 6-MP and thiopurine-related neutropenia in the Asian population. This study reports the influence of these variants on 6MP-induced neutropenia in children with acute lymphoblastic leukemia (ALL). A total of 102 children were enrolled in this retrospective cohort study. NUDT15 variants on exon 1 and exon 3 were identified by Sanger sequencing. We divided the intermediate metabolizer group and the normal metabolizer group base on NUDT15 diplotypes. During the first 3 months of maintenance treatment, medical reports measured treatment-related toxicity (neutropenia) and 6-MP dose decreases. NUDT15 genotyping showed two categories of mutations: wild type (75.5%) and heterozygous variant (24.5%). Neutropenia during the early phase of maintenance therapy in the intermediate metabolizer group (68%) was significantly higher than the normal metabolizer group (18.2%) with 10-fold greater odds. Especially, the c.415C>T heterozygous variant was extremely associated with neutropenia compared with the C>C genotype (odds ratio [OR]: 12; 95% confidence interval [CI]: 3.5-41.7). The tolerated doses of 6-MP after the first 3 months of maintenance therapy related to the intermediate metabolizer group and the normal metabolizer group were 48.7 and 64.3 mg/m²/day, respectively (p < 0.001). One-fourth of individuals had NUDT15 variations. All NUDT15 heterozygous mutations cause neutropenia and need 6-MP dose optimization. Given the frequency of NUDT15 mutations in Vietnamese children and their connection with early neutropenia, testing is indicated.

SUBMITTER: Nguyen ML

PROVIDER: S-EPMC9974434 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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The influence of NUDT15 variants on 6-mercaptopurine-induced neutropenia in Vietnamese pediatric acute lymphoblastic leukemia.

Nguyen Mai-Lan ML Hoang Anh Vu AV Duong Bich Tram BT Phung Nguyen The Nguyen NTN

HGG advances 20230210 2

6-Mercaptopurine (6-MP) serves as the backbone of maintenance therapy in acute lymphoblastic leukemia. The nucleoside diphosphate-linked moiety X-type motif 15 genes (NUDT15) affects the metabolism of 6-MP and thiopurine-related neutropenia in the Asian population. This study reports the influence of these variants on 6MP-induced neutropenia in children with acute lymphoblastic leukemia (ALL). A total of 102 children were enrolled in this retrospective cohort study. NUDT15 variants ...[more]

PMID: 36873097

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Project description:Mercaptopurine (MP) is a commonly used maintenance regimen for childhood acute lymphoblastic leukemia (ALL). However, 6-MP has a narrow therapeutic index, which causes dose-limiting toxicities in hematopoietic tissues. Recent studies reported several candidate pharmacogenetic markers such as TPMT, NUDT15, ITPA, and APEX1, which predict the possibility of 6-MP related toxicities. The aim of this study is to evaluate the effect of major variants of these genes on 6-MP intolerances and toxicities in pediatric acute lymphoblastic leukemia (ALL) patients. A total of 83 pediatric ALL patients were included (56 males and 27 females). The NUDT15 c.415C>T (rs116855232), NUDT15 c.55_56insGAGTCG (rs746071566), ITPA c.94C>A (rs1127354), ITPA c.IVS2+21A>C (rs7270101), APEX c.190A>G (rs2307486), and TPMT variants were analyzed by sanger sequencing. Correlations between indexes of 6-MP-related toxicities or 6-MP intolerance (absolute neutrophil count [ANC] at several time point, days of ANC < 1 × 103/mm3, days of ANC < 0.5 × 103/mm3, frequency of febrile neutropenia, maximum AST and ALT, 6-MP dose and 6-MP dose intensity during maintenance therapy) and genetic variations were analyzed. The NUDT15 c.415C>T allele carrier showed significantly low 6-MP doses at the final maintenance therapy period than the wild type carrier (p = 0.007). The 6-MP dose intensities at the sixth and final maintenance period were also significantly low in NUDT15 c.415C>T carriers (p = 0.003 and 0.008, respectively). However, indexes for neutropenia, days of febrile neutropenia, maximum AST, and ALT levels were not associated with the presence of c.415C>T as well as other analyzed variants. When analyzing the effect of the coexistence of NUDT15 c.415C>T and ITPA c.94C>A, no significant differences were found between the NUDT15 c.415C>T carrier and carrier with both variations. The NUDT15 c.415C>T was the most useful marker to predict 6-MP intolerance among analyzed variants in our study population. Although we could not find association of those variants with 6-MP induced toxicities and the synergistic effects of those variants, a well-planed larger scale study would be helpful in clarifying new candidates and their clinical effects.

Project description:Background: 6-Mercaptopurine (6-MP) is the cornerstone of current antileukemia regimen and contributes greatly to improve the survival of pediatric acute lymphoblastic leukemia (ALL) patients. However, 6-MP dose-related toxicities limit its application. TPMT, NUDT15, and ITPA are pharmacogenetic markers predicting 6-MP-related toxicities, but their genetic polymorphisms differ from those of ethnic populations. In Yunnan province, a multiethnic region of China, we had no genetic data to predict 6-MP toxicities. In this study, we evaluated the most common variants involved in 6-MP metabolism-TPMT *3C (rs1142345), NUDT15 c.415C>T (rs116855232), and ITPA c.94C>A (rs1127354) variants-in our cohort of pediatric ALL patients. Methods: A total of 149 pediatric ALL patients in the Affiliated Children's Hospital of Kunming Medical University (Yunnan Children's Medical Center) from 2017 to 2019 were enrolled in this retrospective study. We assessed the TPMT *3C (rs1142345), NUDT15 c.415C>T (rs116855232), and ITPA c.94C>A (rs1127354) frequencies and evaluated association between genotypes and 6-MP toxicities, 6-MP dose, and event-free survival (EFS) in these ALL patients. Results: The allele frequencies of TPMT *3C (rs1142345), NUDT15 c.415C>T (rs116855232), and ITPA c.94C>A (rs1127354) were 1.34%, 14.43%, and 18.79%, respectively. Only NUDT15 c.415C>T (rs116855232) was strongly associated with 6-MP toxicity and 6-MP tolerable dose. NUDT15 c.415C>T was related to leukopenia, p = 0.008, OR = 2.743 (95% CI: 1.305-5.768). The T allele was significantly correlated with 6-MP tolerable dose, dose of NUDT15 c.415C>T wild genotype CC 39.80 ± 1.32 mg/m2, heterozygotes CT 35.20 ± 2.29 mg/m2, and homozygotes TT 18.95 ± 3.95 mg/m2. 6-MP tolerable dose between CC and TT had a significant difference, p = 0.009. Between CC and CT, and CT and TT, they had no significant difference. EFS showed no significant difference among NUDT15 c.415C>T genotypes. Conclusion: NUDT15 c.415C>T (rs116855232) was an optimal predictor for 6-MP toxicity and tolerable dose in pediatric ALL patients from Yunnan province, a multiethnic region in China, and would play an important role in precise therapy for ALL.

Project description:Background: Acute lymphoblastic leukemia (ALL) is the most common cancer seen in children worldwide and in the Middle East. Although there have been major advances in treatment approaches for childhood ALL, serious toxicities do occur but with significant inter-individual variability. The aim of this study is to measure the frequency of polymorphisms in candidate genes involved in 6-Mercaptopurine (6-MP) disposition in a combined cohort of Middle Eastern Children with ALL, and evaluate whether these polymorphisms predict 6-MP intolerance and toxicity during ALL maintenance therapy. Methods: The study includes children treated for ALL on two treatment protocols from two cohorts; one from Lebanon (N = 136) and another from Kurdistan province of Iran (N = 74). Genotyping for the following six candidate genetic polymorphisms: ITPA 94C > A (rs1127354) and IVS2+21A > C (rs7270101), TPMT*2 238G > C (rs1800462), TPMT*3B 460G > A (rs1800460) and *3C 719A > G (rs1142345), and NUDT15 415C > T (rs116855232) was performed and analyzed in association with 6-MP dose intensity and toxicity. Results: As expected, TPMT and NUDT15 variants were uncommon. As for ITPA, both polymorphisms were more common in the Lebanese as compared to the Kurdish cohort with a minor allele frequency of 0.05 for 94C > A and 0.14 for IVS2+21A > C in the Lebanese only (N = 121), and of 0.01 for either ITPA polymorphism in Kurds. The most significant toxic effects were depicted with the NUDT15 polymorphism with a median 6-MP dose intensity of 33.33%, followed by 46.65% for TPMT*3A polymorphism, followed by 65.33% for two ITPA risk allele carriers and 74% for one ITPA risk allele carriers, in comparison to a median of 100% for the homozygous wild type in the combined cohort (P < 0.001). In addition, the onset of febrile neutropenia was significantly higher in variant allele carriers in the combined cohorts. Conclusions: These data confirm the predictive role of TPMT, NUDT15, and ITPA in 6-MP intolerance in Middle Eastern children with ALL. Given the relatively high frequency of ITPA variants in our study and their significant association with 6-MP dose intensity, we recommend that physicians consider genotyping for ITPA variants in conjunction with TPMT and NUDT15 prior to 6-MP therapy in these children.

Dataset Information

The influence of NUDT15 variants on 6-mercaptopurine-induced neutropenia in Vietnamese pediatric acute lymphoblastic leukemia.

Publications

The influence of <i>NUDT15</i> variants on 6-mercaptopurine-induced neutropenia in Vietnamese pediatric acute lymphoblastic leukemia.

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