作者：江艾婷1，林佳慧1，张信华2，蔡世荣2，唐可京1，夏延哲1

单位：1.中山大学附属第一医院药学部，广东 广州 510080；2.中山大学附属第一医院胃肠外科中心，广东 广州 510080

Authors: Jiang Aiting1, Lin Jiahui1, Zhang Xinhua2, Cai Shirong2, Tang Kejing1, Xia Yanzhe1

Unit:  1.Department of Pharmacy, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China；2.Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, Guangdong, China

摘要：

目的  描述真实世界中胃肠间质瘤患者服用伊马替尼的血液学毒性的发生情况，并探索发生血液学毒性的影响因素。方法  收集中山大学附属第一医院2017年7月至2021年12月566例胃肠间质瘤患者的详细病例资料，统计患者接受伊马替尼治疗后各级血液学毒性发生率，并分析性别、年龄、肿瘤原发部位、疾病治疗阶段、伊马替尼血浆谷浓度对各类血液学毒性发生的影响。采用受试者操作特征曲线评估伊马替尼血浆谷浓度预测发生严重血液学毒性的效能。结果  最常见的血液学毒性是贫血，发生率为56.4%，其次是白细胞减少（47.0%），中性粒细胞减少和淋巴细胞减少发生率相似（31.4%和30.9%），血小板减少发生率较低（3.5%）。3级及以上的各项血液学毒性发生率均在5%以下。单因素二元Logistic回归分析显示，女性是发生中性粒细胞减少（OR=1.697，95%CI 1.187~2.428，P=0.004）的危险因素。多因素二元Logistic回归分析显示，女性是发生白细胞减少（OR=2.333，95%CI 1.658~3.283，P<0.001）的独立危险因素；女性（OR=1.450，95%CI 1.021~2.058，P=0.038）、≥60 岁（OR=1.868，95%CI 1.308~2.666，P=0.001）、血浆谷浓度四分位区间上升是发生贫血的独立危险因素，血浆谷浓度每上升1个四分位区间，发生贫血的风险变为原来的1.278倍（95%CI 1.095~1.492，P=0.002）。受试者操作特征曲线结果显示，伊马替尼血浆谷浓度预测严重贫血的最佳截断值为1428 μg/L，敏感度、特异度、约登指数、曲线下面积分别为0.500，0.725，0.225 、0.622（P=0.029）。结论  伊马替尼在治疗胃肠间质瘤中的安全性较好，血液学毒性通常是轻微的，多为1~2级，少数3级及以上。对使用伊马替尼进行治疗的胃肠间质瘤患者应定期检测血常规，做好包括治疗药物监测在内的药学监护，及时发现和处理伊马替尼引起的血液学毒性。

关键词： 伊马替尼；胃肠间质瘤；血液学毒性；影响因素

Abstract：

Objective   To describe the occurrence of hematologic toxicity in patients with gastrointestinal stromal tumors receiving imatinib in the real world, and to explore influence factors of hematologic toxicity. Method  The characteristics and imatinib treatment data of 566 patients with gastrointestinal stromal tumors from July 2017 to December 2021 in the First Affiliated Hospital of Sun Yat-sen University were collected, and the incidence of hematological toxicity after receiving imatinib was counted. The effects of gender, age, tumor primary location, treatment stage and imatinib plasma trough concentration on hematological toxicity were analyzed. The efficiency of imatinib plasma trough concentration in predicting severe hematological toxicity was evaluated using receiver operating characteristic curve. Result  The most common hematological toxicity was anemia (56.4%), followed by leukopenia (47.0%), similar incidence of neutropenia and lymphocytopenia (31.4% and 30.9%), and low incidence of thrombocytopenia (3.5%). The incidences of hematological toxicities of grade 3 or above were less than 5%. Univariate binary Logistic regression analysis showed that female was a risk factor for neutropenia (OR=1.697, 95%CI 1.187-2.428, P=0.004). Multivariate binary Logistic regression showed that female was an independent risk factor for leukopenia (OR=2.333, 95%CI 1.658-3.283, P<0.001). Female (OR=1.450, 95%CI 1.021-2.058, P=0.038), age≥60 years old (OR =1.868, 95% CI 1.308-2.666, P=0.001), imatinib plasma trough concentration quartile increase were independent risk factors of anemia. For each quartile increase in imatinib plasma trough concentration, the risk of anemia became 1.278 times greater (95%CI 1.095-1.492, P=0.002). The optimal cutoff value of imatinib plasma trough concentration for predicting severe anemia was 1428 μg/L, with the sensitivity, specificity, Jorden index and area under the curve were 0.500, 0.725, 0.225 and 0.622, respectively (P=0.029). Conclusion  Imatinib had good safety in the treatment of gastrointestinal stromal tumors. Hematological toxicities were usually mild, mostly grade 1-2, with a few of grade 3 or above. For patients with gastrointestinal stromal tumor received imatinib, regular blood routine and pharmaceutical care including therapeutic drug monitoring should be performed to detect and manage hematological toxicity in time.

Key Words:  Imatinib; Gastrointestinal stromal tumor; Hematological toxicity; Influence factor

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