伊马替尼血药浓度监测指导慢性粒细胞白血病患者的研究

Study on Monitoring of Imatinib Serum Level Guides Management of Chronic Myelogenous Leukemia Patients

目的:观察是否可以通过对伊马替尼(Imatinib,IM)进行血药浓度监测提高疗效,减少药物不良反应。方法:选取2013~2018年就诊于我院的慢性粒细胞白血病(chronic myelogenous leukemia,CML)患者,分为试验组(药物监测组),对照组(常规经验治疗组)。对服药3个月、6个月、12个月、18个月,进行疗效及不良反应评估及比较。结果:共有51人入选此次临床试验。其中试验组35人,对照组16人。结果:服用伊马替尼400mg/d时,血药浓度568. 00~3 989. 66ng/ml,均数(标准差):1 716. 46ng/ml (788. 96);服用伊马替尼300mg/d时,血药浓度720. 89~1 497. 11ng/ml,均数(标准差):971. 67ng/ml (204. 02)。达到主要分子学反应(major molecular response,MMR)的伊马替尼血药浓度高于未达到稳态时的伊马替尼血药浓度。两组不良反应评级有统计学差异。试验组III级及以上不良反应发生率明显小于对照组。结论:伊马替尼的稳态血浆药物谷浓度存在较大个体差异,这种个体差异与疗效和不良反应存在相关性。通过治疗药物监测(therapeutic drug monitoring,TDM)可以在确保疗效的同时,减少伊马替尼在治疗慢性粒细胞白血病中的不良反应。结果尚需大样本临床试验进一步验证。伊马替尼药物代谢个体差异的原因需要大样本遗传药理学研究进一步探讨。

Objective:To assess if therapeutic drug monitoring(TDM)of imatinib used for chronic myelogenous leukemia(CML)patients led to improve clinical outcome and reduce side effects compared to empiric adjustments.Methods:Patients followed between 2013 to 2018 at CML Center of Xiangya Hospital are performed.Primary outcomes are composite remission at 3,6,12 and 18 months in those with empiric adjustments versus TDM-guided optimization.Results:There are 51 patients who are included in the study.Among them,35 are in the experimental group and 16 are in the control group.The results show that when taking imatinib 400 mg/d,the serum level is 568.00~3 989.66 ng/ml,the mean(standard deviation):1 716.46 ng/ml(788.96);when taking imatinib 300 mg/d,serum level is 720.89~1 497.11 ng/ml,mean(standard deviation):971.67 ng/ml(204.02).The serum level at the time of achieving a stable molecular response is higher than that the time when the stable molecular response is not achieved.There are significant differences in adverse reaction ratings between the two groups.The incidence of adverse reactions of grade III and above in the experimental group is significantly smaller than that of the control group.Conclusions:There is a large individual difference in the steady serum level of imatinib,and this individual difference is related to efficacy and adverse reactions.TDM can reduce the adverse effects while ensuring efficacy in the treatment of CML patients.The results still require further validation of large sample clinical trials.The reasons for individual differences in imatinib drug metabolism require further investigation of large sample pharmacogenetics studies.