Rosdiana Dewi Selvina, Setiabudy Rianto, Andalusia Rizka, Gatot Djajadiman, Louisa Melva, Bardosono Saptawati, Instiaty Instiaty
Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
Dharmais National Cancer Hospital, Jakarta, Indonesia.
Pharmgenomics Pers Med. 2021 Feb 3;14:199-210. doi: 10.2147/PGPM.S288988. eCollection 2021.
Hematotoxicity monitoring in children with acute lymphoblastic leukemia (ALL) is critical to preventing life-threatening infections and drug discontinuation. The primary drug that causes hematotoxicity in ALL children is 6-mercaptopurine (6-MP). Genetic variability of the drug-metabolizing enzymes of 6-MP, thiopurine -methyltransferase (), is one factor that might increase the susceptibility of children to hematotoxicity. The present study aimed to determine the variability in genotypes and phenotypes and its association with the occurrence of hematotoxicity in ALL children in maintenance therapy.
A cross-sectional study was conducted at Cipto Mangunkusumo and Dharmais National Cancer Hospital, Jakarta, Indonesia, from June 2017 to October 2018. We included ALL patients, 1-18 years, who were receiving at least one month of 6-MP during maintenance therapy according to the Indonesian protocol for ALL 2013. Direct sequencing was used to determine , and genotypes, and LC-MS/MS analysis was performed to measure the plasma concentrations of 6-MP and its metabolites. Association analysis between the genotype and hematotoxicity was evaluated using the unpaired -test or Mann-Whitney's test.
The prevalence of neutropenia, anemia, and thrombocytopenia in ALL children during maintenance therapy was 51.9%, 44.3%, and 6.6%, respectively. We found a low frequency of , which is 0.95%. No association was found between hematotoxicity and genotypes or age, nutritional status, serum albumin levels, risk stratification, the daily dose of 6-MP, and cotrimoxazole co-administration. However, hematotoxicity was associated with 6-methylmercaptopurine (6-MeMP) plasma concentrations and the ratio 6-MeMP/6-thioguanine (6-TGN). We also found no association between genotypes and phenotypes.
The 6-MeMP/6-TGN ratio is associated with hematotoxicity in ALL children during maintenance therapy but is not strong enough to predict hematotoxicity.
监测急性淋巴细胞白血病（ALL）患儿的血液毒性对于预防危及生命的感染和停药至关重要。导致ALL患儿血液毒性的主要药物是6-巯基嘌呤（6-MP）。6-MP药物代谢酶硫嘌呤甲基转移酶（）的基因变异性是可能增加儿童对血液毒性易感性的一个因素。本研究旨在确定ALL维持治疗患儿的基因型和表型变异及其与血液毒性发生的关联。
2017年6月至2018年10月在印度尼西亚雅加达的Cipto Mangunkusumo国立癌症医院和Dharmais国立癌症医院进行了一项横断面研究。我们纳入了年龄在1 - 18岁、根据2013年印度尼西亚ALL方案在维持治疗期间接受至少1个月6-MP治疗的ALL患者。采用直接测序法确定基因型，采用液相色谱-串联质谱（LC-MS/MS）分析法测定6-MP及其代谢物的血浆浓度。使用未配对检验或曼-惠特尼检验评估基因型与血液毒性之间的关联分析。
ALL患儿维持治疗期间中性粒细胞减少、贫血和血小板减少的发生率分别为51.9%、44.3%和6.6%。我们发现的频率较低，为0.95%。未发现血液毒性与基因型、年龄、营养状况、血清白蛋白水平、风险分层、6-MP每日剂量及复方新诺明联合用药之间存在关联。然而，血液毒性与6-甲基巯基嘌呤（6-MeMP）血浆浓度及6-MeMP/6-硫鸟嘌呤（6-TGN）比值有关。我们还未发现基因型与表型之间存在关联。
6-MeMP/6-TGN比值与ALL维持治疗患儿的血液毒性有关，但不足以预测血液毒性。
