Objective: To explore the features of imatinib mesylate (IM) plasma concentration during adjuvant therapy and clinical factors associated with IM plasma concentration in patients with high risk gastrointestinal stromal tumors (GIST), and to determine whether IM plasma concentration <1100 μg/L influences the efficacy of adjuvant therapy. Methods: A retrospective case control study method was used. Case inclusion criteria: (1) complete resection of lesion and GIST confirmed by pathology; (2) high risk classified according to modified National Institutes of Health classification system (2008); (3) administration of IM 400 mg/d for at least 1 month; (4) not taking the medication likely affecting IM pharmacokinetic, such as rifampicin, dilantin, and carbamazepine, within 1 month before blood collection. Data of GIST patients who visited GIST Disease - Oriented Outpatient, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology between January 2015 to December 2018 were retrospectively analyzed. After taking IM for 22-26 hours, 5 ml of peripheral venous blood was collected into EDTA anticoagulant tube. IM plasma concentration was detected by using high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Patients were divided into <1100 μg/L group and ≥1100 μg/L group according to plasma concentration. Linear regression was used to analyze the relevance between clinical features and IM plasma concentration. Parameters with normal distribution were analyzed by Pearson correlation coefficient, and parameters with non-normal distribution were analyzed by Spearman correlation. Kaplan-Meier survival curves and COX regression model were used for survival analysis. Results: Among the 85 patients enrolled in the study, 49 patients (57.6%) were male and 36 (42.4%) were female, with mean age of (51.9±11.0) years. The body mass index was (22.5±2.9) kg/m(2) and body surface area was (1.6±0.2) m(2). Thirty patients received gene test, including 23 patients with c-Kit exon 11 mutation, 4 with c-Kit exon 9 mutation, 1 with c-Kit exon 11 and 17 mutation and 2 without c-Kit or PDGFRA gene mutation. The mean IM plasma concentration was (1391.4±631.3) μg/L, and there were 32 patients with plasma concentration <1100 μg/L and 53 patients with plasma concentration ≥1100 μg/L. There were no statistically significant differences between the two groups in gender, age, body mass index, body surface area, hematological examination (white blood cells, albumin, alanine aminotransferase, aspartate aminotransferase and serum creatinine), tumor location, tumor size, mitotic counts, duration of adjuvant therapy and methods of operation (all P>0.05). Positive correlation between IM plasma concentration and serum creatinine was observed in linear regression analysis (r=0.297, P=0.007), but there were no correlations between IM plasma concentration and age (r=0.044, P=0.686), body mass index (r=0.066, P=0.547), body surface area (r=-0.010, P=0.924), white blood cells (r=-0.080, P=0.478), albumin (r=-0.065, P=0.563), alanine aminotransferase (r=0.114, P=0.308), aspartate aminotransferase (r=0.170, P=0.127) and duration of adjuvant therapy (ρ=0.060, P=0.586). There was no statistically significant difference in IM plasma concentration between patients with different genders (t=0.336, P=0.738) and patients with different surgical methods (F=0.888, P=0.451). Up to March 1, 2019. the median follow-up time was 30 (range 4-49) months. Tumor recurrence was detected in two patients with plasma concentration <1100 μg/L and two with plasma concentration ≥1100 μg/L. One recurrent patient with plasma concentration <1100 μg/L was detected to harbor c-Kit exon 11 and exon 17 mutations, and the other did not receive gene detection. Two recurrent patients with plasma concentration ≥1100 μg/L were both detected to harbor c-Kit exon 9 mutation. The 3-year relapse-free survival rate was 96.4% in the cohort, 96.2% in patients with plasma concentration <1100 μg/L, and 96.6% in patients with plasma concentration ≥1100 μg/L. No significant difference in relapse-free survival was observed between the two groups (P=0.204). Univariate Cox analysis showed that IM plasma concentration <1100 μg/L was not a risk factor for patients with high risk GIST (HR=0.238, 95% CI: 0.022-2.637, P=0.242). Conclusions: IM plasma concentration of adjuvant therapy in patients with high risk GIST varies with individual. Patients with higher level of serum creatinine are more likely to have a higher plasma concentration. A blood drug concentration standard of less than 1100 μg/L for advanced GIST patients may not influence the prognosis of patients with high risk GIST.
目的： 探讨高危GIST患者辅助治疗的甲磺酸伊马替尼（IM）血药浓度特点和相关临床因素。 方法： 采用回顾性病例对照研究方法。病例纳入标准：（1）手术完整切除且病理诊断为GIST；（2）依据2008年改良NIH分级复发风险为高危；（3）服用IM 400 mg/d辅助治疗至少1个月；（4）采血前1个月内未合并使用利福平、苯妥英钠、卡马西平等显著影响IM药动学者。收集2015年1月至2018年12月期间在华中科技大学同济医学院附属协和医院GIST专病门诊就诊并接受IM血药浓度检测的高危GIST患者病例资料，患者服用IM后22~26 h采集5 ml外周静脉血至EDTA抗凝管中，采用高效液相色谱-串联质谱检测IM血药浓度。根据患者的IM血药浓度检测水平分为<1 100 μg/L组和≥1 100 μg/L组；对患者临床特征与血药浓度进行相关性分析，呈正态分布的参数用Pearson相关性分析，呈非正态的参数用Spearman相关性分析；采用Cox回归模型进行复发危险因素分析；使用Kaplan-Meier法绘制无复发生存曲线，两组生存率的比较采用log-rank检验。 结果： 共计有85例患者纳入研究，男性49例（57.6%），女性36例（42.4%），年龄（51.9±11.0）岁；体质指数（22.5±2.9）kg/m(2)，体表面积为（1.6±0.2）m(2)。有30例患者接受了基因检测，其中23例c-Kit外显子11突变，4例c-Kit外显子9突变，2例未检测到c-Kit或PDGFRA基因突变，1例c-Kit外显子11及17均突变。全组患者血药浓度为（1 391.4±631.3）μg/L，其中<1 100 μg/L组32例，≥1 100 μg/L组53例。两组性别、年龄、体质指数、体表面积、血液学检查（白细胞、白蛋白、丙氨酸氨基转移酶、天冬氨酸氨基转移酶及血清肌酐）、肿瘤部位、肿瘤直径、核分裂像、接受辅助治疗时间以及手术方式的比较，差异均无统计学意义（均P>0.05）。相关性分析显示，IM血药浓度仅与血清肌酐线性明显正相关（r=0.297，P=0.007），而与患者年龄（r=0.044，P=0.686）、体质指数（r=0.066，P=0.547）、体表面积（r=-0.010，P=0.924）、白细胞（r=-0.080，P=0.478）、白蛋白（r=-0.065，P=0.563）、丙氨酸氨基转移酶（r=0.114，P=0.308）、天冬氨酸氨基转移酶（r=0.170，P=0.127）和辅助治疗时间（ρ=0.060，P=0.586）均无明显相关性。IM血药浓度在不同性别（t=0.336，P=0.738）和不同手术方式（F=0.888，P=0.451）患者间的分布差异亦无统计学意义。随访截至2019年3月1日，全组中位随访时间为30（4~49）个月，IM血药浓度<1 100 μg/L组患者中有2例肿瘤复发，其中1例患者复发后行基因检测为c-Kit外显子11及17突变，1例未行基因检测；而≥1 100 μg/L组中也有2例肿瘤复发，均为首次完整切除术后基因检测结果为c-Kit外显子9突变患者。全组3年无复发生存率为96.4%，其中<1 100 μg/L组为96.2%，≥1 100 μg/L组则为96.6%，两组比较差异无统计学意义（P=0.204）。单因素分析显示，IM血药浓度<1 100 μg/L与高危GIST患者的无复发生存率无关（HR=0.238，95% CI:0.022~2.637，P=0.242）。 结论： 高危GIST患者辅助治疗IM血药浓度个体差异较大，血清肌酐水平高的患者IM血药浓度更高。IM血药浓度<1 100 μg/L并不影响高危GIST患者的预后。.
Keywords: Adjuvant therapy; Gastrointestinal stromal tumor; Imatinib; Plasma concentration.