Division of Pharmacogenomics & Personalized Medicine, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand.
Laboratory for Pharmacogenomics, Somdech Phra Debaratana Medical Center (SDMC), Ramathibodi Hospital, Bangkok, 10400, Thailand.
Pharmacogenomics. 2020 Apr;21(6):403-410. doi: 10.2217/pgs-2019-0177. Epub 2020 Apr 20.
: 6-Mercaptopurine (6MP) is key to the treatment of acute lymphoblastic leukemia (ALL) as part of maintenance therapy. was identified as a novel thiopurine regulator conferring 6MP sensitivity. The aim of this study was to evaluate the influence of variants on 6MP-induced neutropenia in Thai children with ALL. : Genotyping of (c.415C>T; rs116855232) and c.36_37insGGAGTC; rs554405994) was performed by Sanger sequencing in 100 patients with ALL. Patients were classified into wild-type (group 1), heterozygous variant (group 2) and homozygous variant (group 3). Clinical and laboratory features during the first 6 months of maintenance therapy were investigated. Therapy-induced neutropenia was observed in 31 patients during the weeks 1-8 (early myelotoxicity), while therapy-induced neutropenia was observed in 47 patients during the weeks 9-24 (late myelotoxicity). : There were 85 wild-type patients, 14 heterozygous variant patients and one homozygous variant patient. variants were associated with neutropenia as compared with wild-type (odds ratio: 17.862; 95% CI: 4.198-75.992, p = 9.5 × 10). Multivariate analysis showed that the low-risk group was associated with neutropenia (p = 0.014) in the first 8 weeks of 6MP therapy. Group 2 and group 3 patients had significantly lower absolute neutrophil counts compared with group 1. The adjusted dose during the first 6 months of maintenance therapy with genotype group 1, 2 and 3 were 50, 36.6 and 12.5 mg/m/day, respectively. : Taken together, our results indicate variants may cause neutropenia, and the 6MP dosage should be considered in patients according to the variants to inform personalized 6MP therapy.
巯嘌呤（6MP）是急性淋巴细胞白血病（ALL）治疗的关键，作为维持治疗的一部分。被鉴定为一种新的硫嘌呤调节剂，赋予 6MP 敏感性。本研究旨在评估泰国 ALL 患儿中 变异对 6MP 诱导中性粒细胞减少的影响。对 100 例 ALL 患者进行了（c.415C>T；rs116855232）和 c.36_37insGGAGTC；rs554405994）的基因分型，通过 Sanger 测序。将患者分为野生型（第 1 组）、杂合变异型（第 2 组）和纯合变异型（第 3 组）。研究了维持治疗前 6 个月的临床和实验室特征。在第 1-8 周（早期骨髓毒性）观察到 31 例患者发生治疗诱导性中性粒细胞减少，而在第 9-24 周（晚期骨髓毒性）观察到 47 例患者发生治疗诱导性中性粒细胞减少。有 85 例野生型患者、14 例杂合变异型患者和 1 例纯合变异型患者。与野生型相比，变异型与中性粒细胞减少相关（比值比：17.862；95%可信区间：4.198-75.992，p=9.5×10）。多变量分析显示，低危组与 6MP 治疗的前 8 周中性粒细胞减少相关（p=0.014）。与第 1 组相比，第 2 组和第 3 组患者的绝对中性粒细胞计数明显较低。维持治疗的前 6 个月期间，基因型组 1、2 和 3 的调整剂量分别为 50、36.6 和 12.5mg/m/day。综上所述，我们的结果表明，变异可能导致中性粒细胞减少，应根据患者的 变异情况考虑 6MP 剂量，以实现个性化 6MP 治疗。
