The effects of NUDT15 and TPMT variants on mercaptopurine treatment in Vietnamese pediatric acute lymphoblastic leukemia patients

• Published in: Pediatric hematology and oncology Vol. 39; no. 6; pp. 561 - 570
• Main Authors: Nghia, Huynh, Than, Huynh Huu, Dong, Cao Van, Oanh, Tran Thi Kieu, Truc, Vo Thi Thanh, Ngan, Cai Thi Thu, Ngon, Huynh Thien, Binh, Nguyen Tan, Dung, Phu Chi, Anh Vu, Hoang, Xinh, Phan Thi
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 18-08-2022
• Subjects: 6-Mercaptopurine; ALL; NUDT15; TPMT; Vietnamese; ALL; Vietnamese; 6-Mercaptopurine; TPMT; NUDT15
• ISSN: 0888-0018; 1521-0669
• DOI: 10.1080/08880018.2022.2035027

6-mercaptopurine (6-MP) plays a critical role in the treatment of pediatric acute lymphoblastic leukemia (ALL). NUDT15 and TPMT gene variants have been strongly associated with myelotoxicity caused by using 6-MP. Therefore, the purpose of this study is to investigate the frequency of NUDT15 and TPMT polymorphisms, as well as the impact of NUDT15 variants on the use of 6-MP to treat pediatric ALL in Vietnam. Sanger sequencing was applied to detect NUDT15 and TPMT gene variants in 70 pediatric ALL patients. Duration of drug interruption, level of neutropenia, and 6-MP tolerance dose were recorded. NUDT15 variants were detected from 23 out of 70 (32.9%) patients. Three well-known haplotype variants were identified as NUDT15 *2 (p.V18_V19insGV and p.R139C), *3 (p.R139C), and *6 (p.V18_V19insGV); besides, a novel NUDT15 p.R11Q was not previously reported. The NUDT15 wild-type, heterozygous variant, and homozygous variant genotypes were 67.1%, 30.1%, and 2.8%, respectively. Two TPMT heterozygous polymorphisms were TPMT*3C and *6, accounted for 2.8%. Patients with intermediate and low activity NUDT15 were given the median 6-MP tolerance dose of 55.2 and 37.2 versus 69.5 mg/m
2
/day of patients with NUDT15 normal activity (p = 0.0001). Patients with homozygous variant diplotype were drastically sensitive to 6-MP, with an average dose intensity of 49.6%, compared to 73.6% and 92.7% of those with heterozygous and wild-type diplotype, respectively (p = 0.0001). Our results suggest that 6-MP dose adjustment should be based on NUDT15 variants in pediatric Vietnamese ALL patients.