Department of Pharmacy Practice, Faculty of Pharmacy, Helwan University, Cairo, Egypt.
Medical Oncology Department, National Cancer Institute, Cairo University, Cairo, Egypt.
J Chemother. 2022 Oct;34(6):381-390. doi: 10.1080/1120009X.2021.2009723. Epub 2021 Dec 13.
High dose methotrexate (HDMTX) is an essential agent in chemotherapeutic regimens used in various hematological malignancies in Egyptian adults. The research for the impact of gene polymorphism on HDMTX induced toxicities and delayed elimination is an important ongoing objective in many studies, variable and conflicting results produced in the past years to clarify that impact. This study aimed to investigate the role of ABCB1 3435 C > T rs1045642 and MTHFR 677 C > T rs1801133 polymorphisms on HDMTX induced toxicity outcomes and delayed elimination in Egyptian adult patients with hematological malignancies. A prospective, observational cohort study was conducted on a total of 62 Egyptian adult patients with hematological malignancies age ≥ 18-years-old. All demographic, medical, and laboratory data were continuously collected from the patients' medical files in an up-to-date follow-up in selected clinics during the period from April 2018 to March 2020. Venous blood samples were collected for the purpose of genotyping, DNA extraction, and measurement of MTX levels. All the relevant data were statistically analyzed. The studied patients' median age was 25 years old with a range of (18-62) years. Forty-six patients were males with about 74%, and 16 were females with about 26%. Eighty-nine percent of the patients diagnosed with acute lymphoblastic leukemia 'ALL', 5% of the patients had B cell non-hodgkin lymphoma 'B-NHL' and 3% diagnosed with primary central nervous system lymphoma 'PCNSL' and Burkitt's lymphoma 'BL' Hematological, hepatic, renal and gastrointestinal toxicities observed post-HDMTX were recorded with the hematological toxicities toping on all the others, also patients with delayed elimination at 72 hours post the HDMTX dose were determined. Statistical analysis revealed a significant association between ABCB1 3435 C > T rs1045642 and HDMTX delayed elimination with about 10 times higher risk among the minor allele 'T' carriers (-value = 0.006) (odds ratio [OR]: 10.470; 95% CI: 1.961-55.904). No significant association observed between the studied gene polymorphisms: MTHFR 677 C > T rs1801133, ABCB1 3435 C > T rs1045642, and different toxicity outcomes. According to our best knowledge, this study is the first to conclude a significant association between ABCB1 3435 C > T rs1045642 gene polymorphism and HDMTX delayed elimination at 72 hours post HDMTX infusion; also, it is the first study to analyze the association between ABCB1 3435 C > T rs1045642 polymorphism with HDMTX toxicity and delayed elimination in adult Egyptian patients with hematological malignancies.
大剂量甲氨蝶呤（HDMTX）是埃及成人各种血液恶性肿瘤化疗方案中的重要药物。研究基因多态性对 HDMTX 诱导的毒性和延迟消除的影响是许多研究中的一个重要目标，过去几年产生了不同和相互矛盾的结果，以阐明这种影响。本研究旨在调查 ABCB1 3435C>T rs1045642 和 MTHFR 677C>T rs1801133 基因多态性对埃及血液恶性肿瘤成年患者 HDMTX 诱导的毒性结局和延迟消除的作用。一项前瞻性观察队列研究共纳入 62 名年龄≥18 岁的埃及血液恶性肿瘤成年患者。从 2018 年 4 月至 2020 年 3 月期间，在选定的诊所中，连续从患者的病历中收集所有人口统计学、医学和实验室数据进行最新随访。采集静脉血样进行基因分型、DNA 提取和 MTX 水平测量。对所有相关数据进行统计学分析。研究患者的中位年龄为 25 岁，范围为（18-62）岁。46 名患者为男性，约占 74%，16 名患者为女性，约占 26%。89%的患者被诊断为急性淋巴细胞白血病（ALL），5%的患者患有 B 细胞非霍奇金淋巴瘤（B-NHL），3%的患者被诊断为原发性中枢神经系统淋巴瘤（PCNSL）和伯基特淋巴瘤（BL）。在接受 HDMTX 后观察到血液学、肝、肾和胃肠道毒性，并记录了所有其他毒性的血液学毒性，还确定了在接受 HDMTX 剂量后 72 小时内有延迟消除的患者。统计分析显示，ABCB1 3435C>T rs1045642 与 HDMTX 延迟消除之间存在显著关联，在携带较小等位基因 'T' 的患者中风险增加约 10 倍（-值=0.006）（优势比 [OR]：10.470；95%CI：1.961-55.904）。未观察到研究基因多态性与不同毒性结局之间存在显著关联：MTHFR 677C>T rs1801133、ABCB1 3435C>T rs1045642。据我们所知，这是第一项研究得出 ABCB1 3435C>T rs1045642 基因多态性与 HDMTX 输注后 72 小时 HDMTX 延迟消除之间存在显著关联的结论；也是第一项分析 ABCB1 3435C>T rs1045642 多态性与埃及血液恶性肿瘤成年患者 HDMTX 毒性和延迟消除之间关联的研究。
