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

Overview

Journal Front Pediatr

Specialty Pediatrics

Date 2021 Oct 18

PMID 34660484

Citations 6

Authors

Xiaoyan Mao

Runxiu Yin

Gaoyuan Sun

Yan Zhou

Chunhui Yang

Chunlian Fang

Yuhong Wu

Tingting Cui

Li Liu

Jiaxin Gan

Xin Tian

Affiliations

Soon will be listed here.

Abstract

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. , and 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- 3C (rs1142345), c.415C>T (rs116855232), and c.94C>A (rs1127354) variants-in our cohort of pediatric ALL patients. 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 3C (rs1142345), c.415C>T (rs116855232), and 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. The allele frequencies of 3C (rs1142345), c.415C>T (rs116855232), and c.94C>A (rs1127354) were 1.34%, 14.43%, and 18.79%, respectively. Only c.415C>T (rs116855232) was strongly associated with 6-MP toxicity and 6-MP tolerable dose. c.415C>T was related to leukopenia, = 0.008, OR = 2.743 (95% CI: 1.305-5.768). The T allele was significantly correlated with 6-MP tolerable dose, dose of c.415C>T wild genotype CC 39.80 ± 1.32 mg/m, heterozygotes CT 35.20 ± 2.29 mg/m, and homozygotes TT 18.95 ± 3.95 mg/m. 6-MP tolerable dose between CC and TT had a significant difference, = 0.009. Between CC and CT, and CT and TT, they had no significant difference. EFS showed no significant difference among c.415C>T genotypes. 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.

Citing Articles

Treatment of three pediatric AML co-expressing NUP98-NSD1, FLT3-ITD, and WT1.

Liu L, Nie Q, Xiao Z, Chen X, Yang C, Mao X BMC Pediatr. 2024; 24(1):483.

PMID: 39068406 PMC: 11282587. DOI: 10.1186/s12887-024-04954-1.

Association of 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 S, Huang X, He X, Mao M, Chen M, Zhang R Haematologica. 2023; 109(4):1053-1068.

PMID: 37794799 PMC: 10985454. DOI: 10.3324/haematol.2023.282761.

A Simple, Rapid, and Cost-Effective PCR Procedure for Detection of Gene Variants in Vietnamese Patients with Acute Lymphoblastic Leukemia.

Tram D, Chuong H, Phuong H, Phung N, Nguyen M, Vu H J Lab Physicians. 2023; 15(4):567-572.

PMID: 37780869 PMC: 10539051. DOI: 10.1055/s-0043-1768948.

Genetic variants of genes involved in thiopurine metabolism pathway are associated with 6-mercaptopurine toxicity in pediatric acute lymphoblastic leukemia patients from Ethiopia.

Ali A, Adam H, Hailu D, Engidawork E, Howe R, Abula T Front Pharmacol. 2023; 14:1159307.

PMID: 37251339 PMC: 10214954. DOI: 10.3389/fphar.2023.1159307.

Polymorphisms and the Incidence of Toxicities in Children with Acute Lymphoblastic Leukemia.

Svasdisant P, Glomglao W, Siraprapapat P, Inthararujikul W, Tachavanich K, Boonthimat C Mediterr J Hematol Infect Dis. 2023; 15(1):e2023024.

PMID: 36908869 PMC: 10000882. DOI: 10.4084/MJHID.2023.024.

References

Citterio-Quentin A, Moulsma M, Gustin M, Lachaux A, Boulieu R . ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response. Basic Clin Pharmacol Toxicol. 2018; 122(6):588-595. DOI: 10.1111/bcpt.12958. View

Marinaki A, Ansari A, Duley J, Arenas M, Sumi S, Lewis C . Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Pharmacogenetics. 2004; 14(3):181-7. DOI: 10.1097/00008571-200403000-00006. View

Relling M, Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui C, Stein C . Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. Clin Pharmacol Ther. 2018; 105(5):1095-1105. PMC: 6576267. DOI: 10.1002/cpt.1304. View

Azimi F, Mortazavi Y, Alavi S, Khalili M, Ramazani A . Frequency of ITPA gene polymorphisms in Iranian patients with acute lymphoblastic leukemia and prediction of its myelosuppressive effects. Leuk Res. 2015; 39(10):1048-54. DOI: 10.1016/j.leukres.2015.06.016. View

Milosevic G, Kotur N, Krstovski N, Lazic J, Zukic B, Stankovic B . Variants in TPMT, ITPA, ABCC4 and ABCB1 Genes As Predictors of 6-mercaptopurine Induced Toxicity in Children with Acute Lymphoblastic Leukemia. J Med Biochem. 2019; 37(3):320-327. PMC: 6298470. DOI: 10.1515/jomb-2017-0060. View

Zhou H, Li L, Yang P, Yang L, Zheng J, Zhou Y . Optimal predictor for 6-mercaptopurine intolerance in Chinese children with acute lymphoblastic leukemia: NUDT15, TPMT, or ITPA genetic variants?. BMC Cancer. 2018; 18(1):516. PMC: 5932771. DOI: 10.1186/s12885-018-4398-2. View

Buaboonnam J, Sripatanatadasakul P, Treesucon A, Glomglao W, Siraprapapat P, Narkbunnam N . Effect of NUDT15 on incidence of neutropenia in children with acute lymphoblastic leukemia. Pediatr Int. 2019; 61(8):754-758. DOI: 10.1111/ped.13905. View

Cao Q, Zhu Q, Shang Y, Gao M, Si J . Thiopurine methyltransferase gene polymorphisms in Chinese patients with inflammatory bowel disease. Digestion. 2009; 79(1):58-63. DOI: 10.1159/000205268. View

Moradveisi B, Muwakkit S, Zamani F, Ghaderi E, Mohammadi E, Zgheib N . , , and Genetic Polymorphisms Predict 6-Mercaptopurine Toxicity in Middle Eastern Children With Acute Lymphoblastic Leukemia. Front Pharmacol. 2019; 10:916. PMC: 6718715. DOI: 10.3389/fphar.2019.00916. View

10.

Pui C, Mullighan C, Evans W, Relling M . Pediatric acute lymphoblastic leukemia: where are we going and how do we get there?. Blood. 2012; 120(6):1165-74. PMC: 3418713. DOI: 10.1182/blood-2012-05-378943. View

11.

Takatsu N, Matsui T, Murakami Y, Ishihara H, Hisabe T, Nagahama T . Adverse reactions to azathioprine cannot be predicted by thiopurine S-methyltransferase genotype in Japanese patients with inflammatory bowel disease. J Gastroenterol Hepatol. 2009; 24(7):1258-64. DOI: 10.1111/j.1440-1746.2009.05917.x. View

12.

Rosdiana D, Setiabudy R, Andalusia R, Gatot D, Louisa M, Bardosono S . Genetic Variability and Its Association with Hematotoxicity in Indonesian Children with Acute Lymphoblastic Leukemia in Maintenance Therapy. Pharmgenomics Pers Med. 2021; 14:199-210. PMC: 7868246. DOI: 10.2147/PGPM.S288988. View

13.

Kato M, Manabe A . Treatment and biology of pediatric acute lymphoblastic leukemia. Pediatr Int. 2017; 60(1):4-12. DOI: 10.1111/ped.13457. View

14.

Shen S, Cai J, Xue H, Pan C, Gao Y, Tang Y . Long-term results of the risk-stratified treatment of childhood acute lymphoblastic leukemia in China. Hematol Oncol. 2018; 36(4):679-688. DOI: 10.1002/hon.2541. View

15.

Liang D, Yang C, Liu H, Jaing T, Chen S, Hung I . NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia. Pharmacogenomics J. 2015; 16(6):536-539. DOI: 10.1038/tpj.2015.75. View

16.

Levinsen M, Rotevatn E, Rosthoj S, Nersting J, Abrahamsson J, Appell M . Pharmacogenetically based dosing of thiopurines in childhood acute lymphoblastic leukemia: influence on cure rates and risk of second cancer. Pediatr Blood Cancer. 2014; 61(5):797-802. DOI: 10.1002/pbc.24921. View

17.

Schmiegelow K, Nielsen S, Frandsen T, Nersting J . Mercaptopurine/Methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction. J Pediatr Hematol Oncol. 2014; 36(7):503-17. PMC: 4222610. DOI: 10.1097/MPH.0000000000000206. View

18.

Lee J, Shim Y, Kim D, Jung N, Ha J . The Effect of , , , and Genetic Variations on Mercaptopurine Treatment of Pediatric Acute Lymphoblastic Leukemia. Children (Basel). 2021; 8(3). PMC: 7998516. DOI: 10.3390/children8030224. View

19.

Yang S, Hong M, Baek J, Choi H, Zhao W, Jung Y . A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014; 46(9):1017-20. PMC: 4999337. DOI: 10.1038/ng.3060. View

20.

Tanaka Y, Kato M, Hasegawa D, Urayama K, Nakadate H, Kondoh K . Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia. Br J Haematol. 2015; 171(1):109-15. DOI: 10.1111/bjh.13518. View