含大剂量甲氨蝶呤方案治疗血液肿瘤主要不良事件影响因素的分析

Analysis of factors influencing major adverse events in patients with hematologic neoplasms and treated with high-dose methotrexate regimens

目的探讨含大剂量甲氨蝶呤(HDMTX)方案治疗血液系统肿瘤主要不良事件的影响因素。方法通过医院信息系统收集2014年1月至2016年2月在北京协和医院住院期间所有使用含HDMTX方案化疗的血液系统肿瘤患者病历资料,结合血液科临床药师为这些患者建立的HDMTX治疗结束48h内不良事件监测档案进行回顾性分析,采用单因素、多因素分析方法分析年龄、体重指数(BMI)、甲氨蝶呤(MTX)给药剂量、输注时间、给药前肝肾功能指标、停药后20hMTX血药浓度、化疗方案等因素对Ⅱ级及以上不良事件的影响。结果纳入分析的患者共324例,男性179例,女性145例;中位年龄43(14~77)岁;急性淋巴细胞白血病72例,非霍奇金淋巴瘤208例,朗格汉斯组织细胞增生症44例。324例患者共行含HDMTX方案化疗1050例次。HDMTX开始治疗至停药后48h内,共有159例患者发生≥Ⅱ级不良事件289例次,Ⅱ级及以上不良事件发生率为49.07%,发生不良事件例次占用药例次的27.52%。不良事件以血清丙氨酸转氨酶(ALT)水平升高居首位[发生率为25.62%(83/324),构成比为10.38%(109/1050)];其次是恶心、呕吐[发生率为11.73%(38/324),构成比为5.43%(57/1050)];再次是血清肌酐(Scr)水平升高[发生率为8.64%(28/324),构成比2.76%(29/1050)]。多因素分析结果显示,MTX剂量、输注时间、给药前血清ALT水平是给药后ALT升高的显著性影响因素;BMI、停药后20hMTX血药浓度和给药前血清总胆红素(TBil)是给药后Scr升高的显著性影响因素;给药前血清TBil水平是给药后血清TBil升高的显著性影响因素;停药后20hMTX血药浓度是口腔黏膜炎的显著性影响因素;MTX剂量、输注时间和GDP/ML方案(吉西他滨+地塞米松+顺铂+HDMTX+培门冬酶)是神经系统不良事件的显著性影响因素。结论应用含HDMTX方案化疗,基础肝、肾功能不良和输注24h方案可能是肝、肾损伤的风险因素;超重可能是肾损伤的风险因素;GDP/ML方案、输注4h方案和MTX剂量较大可能是神经系统不良事件的风险因素;停药后20hMTX血药浓度高可能是肾损伤和口腔黏膜炎的风险因素。

Objective To explore the factors influencing major adverse events in patients with hematologic neoplasms and treated with high-dose methotrexate (HDMTX) chemotherapy regimens.MethodsMedical records of all inpatients with hematologic neoplasms treated with HDMTX chemotherapy regimens in Peking Union Medical College Hospital from January 2014 to February 2016 were collected by Hospital Information System and retrospectively analyzed in combination with the adverse events surveillance files within 48 hours after HDMTX treatment, established by clinical pharmacists of hematology department. The effects of age, body mass index (BMI), methotrexate (MTX) dosage, time of intravenous infusion, liver and kidney function before administration, blood drug concentration of 20 hours after completion of one treatment cycle, and chemotherapy regimens on adverse events of ≥grade II were analyzed by single factor and multiple factor analysis.ResultsA total of 324 inpatients were entered in the study, including 179 males and 145 females with a median age of 43 (14-77) years. There were 72 inpatients with acute lymphoblastic leukemia, 208 with non-Hodgkin lymphoma, and 44 with Langerhans cell histiocytosis. A total of 1 050 cycles of HDMTX were administered to the 324 patients. Within 48 hours after the HDMTX treatment, 159 patients had 289 times of adverse events of ≥grade II. The incidence of adverse events of ≥grade II was 49.07% and the adverse events accounted for 27.52% of the treatment cycles. Elevated serum alanine aminotransferase (ALT) was the most common adverse event [the incidence was 25.62%(83/324) and the constituent ratio was 10.38%(109/1 050)], followed by nausea and vomiting [ the incidence was 11.73%(38/324) and the constituent ratio was 5.43%(57/1 050)]and elevated serum creatinine (Scr) level [the incidence was 8.64%(28/324) and the constituent ratio was 2.76%(29/1 050)]. Multiple factor analysis showed that MTX dosage, time of intravenous infusion, and ALT level before administration were significant factors affecting ALT elevation after administration;BMI, blood drug concentration of 20 hours after completion of one treatment cycle, serum total bilirubin (Tbil) and before administration were significant factors affecting Scr elevation after administration;serum Tbil level before administration was the only significant factor affecting Tbil elevation after administration;blood drug concentration of 20 hours after completion of one treatment cycle was the only significant factor in oral mucositis;MTX dosage, four-hour intravenous infusion regimen, and GDP/ML regimen (gemcitabine+dexamethasone+cisplatin+HDMTX+pegaspargase) were significant factors influencing adverse neuro-logical events.ConclusionsAfter HDMTX regimen chemotherapy, patients with baseline dysfunction of liver and kidney and a 24-hour intravenous infusion regimen may increase the risk of liver and kidney injury;overweight patients may have an increased risk of kidney injury;GDP/ML regimen, 4-hour intravenous infusion regimen, and higher MTX dosages may increase the risk of neurological adverse events;high blood concentration of 20 hours after completion of one treatment cycle may be a risk factor of kidney injury and oral mucositis.