Abstract

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/m²/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.

摘要

6-巯基嘌呤 (6-MP) 在小儿急性淋巴细胞白血病 (ALL) 的治疗中起关键作用。NUDT15和TPMT基因变异与使用 6-MP 引起的骨髓毒性密切相关。因此，本研究的目的是调查NUDT15和TPMT多态性的频率，以及NUDT15变异对越南使用 6-MP 治疗儿科 ALL 的影响。应用 Sanger 测序检测70 名小儿 ALL 患者的NUDT15和TPMT基因变异。记录药物中断持续时间、中性粒细胞减少水平和 6-MP 耐受剂量。NUDT15从 70 名患者中的 23 名 (32.9%) 中检测到变异。三个众所周知的单倍型变体被鉴定为NUDT15 *2 (p.V18_V19insGV 和 p.R139C)、*3 (p.R139C) 和 *6 (p.V18_V19insGV)；此外，以前没有报道过一种新的NUDT15 p.R11Q。NUDT15野生型、杂合变体和纯合变体基因型分别为 67.1%、30.1% 和 2.8%。2个TPMT杂合多态性为TPMT *3C和*6，占2.8%。中低活性 NUDT15 患者的 6-MP 耐受剂量中位数为 55.2 和 37.2，而NUDT15 活性正常的患者为 69.5 mg/m ^{2 /天（} p = 0.0001)。纯合变异双倍型患者对 6-MP 极为敏感，平均剂量强度为 49.6%，而杂合型和野生型双倍型患者的平均剂量强度分别为 73.6% 和 92.7%（p  = 0.0001）。我们的结果表明，6-MP 剂量调整应基于越南儿科 ALL 患者的NUDT15变异体。