BCR—ABL35INS突变型慢性粒细胞白血病患者选用酪氨酸激酶抑制剂的文献分析

摘 要 目的：為BCR-ABL35INS突变型慢性粒细胞白血病（CML）患者合理选用酪氨酸激酶抑制剂（TKI）治疗提供参考。方法：以“BCR-ABL插入突变”“ABL1 35ins突变”“BCR-ABL c.1423_1424ins35”“ABL1 p.C475Tyrfs*11”“BCR-ABL insertional mutation”“ABL1 35ins mutation”等为关键词，在中国知网、万方数据知识服务平台、Medline、COSMIC数据库等中进行检索，检索时限为2007-2018年，就BCR-ABL35INS突变型CML患者的基本资料、治疗情况（治疗方案、患者依从性及停药情况）、治疗效果（分子生物学缓解情况及疾病进展情况）以及安全性数据（不良反应）等进行汇总与分析。结果：共纳入相关文献9篇，涉及BCR-ABL35INS突变型CML患者70例，均为国外病例。其中，男、女性患者分别有39、31例，中位年龄为49.2岁，从确诊CML至检测到BCR-ABL35INS突变的中位时间为19个月。检测到基因突变后，采用伊马替尼（起始剂量400 mg，口服，每日1次）治疗的共39例次，有5例患者（12.9%）获得分子生物学缓解；15例（38.5%）有分子生物学应答但疾病进展；有8例（20.5%）无应答。采用达沙替尼（100 mg，每日1次或分2次口服）治疗的共17例次，有8例（47.1%）获得分子生物学缓解。采用尼洛替尼（400 mg，分2次口服）治疗的共21例次，有3例（14.3%）获得分子生物学缓解；2例有分子生物学应答但疾病进展。上述患者因不良反应而停药的分别有7、3、7例，分别占17.9%、17.6%、33.3%，均为美国国立癌症研究所常见不良事件评价标准3～4级，且以血液系统毒性反应为主。结论：BCR-ABL35INS突变型CML患者应用伊马替尼治疗的分子生物学缓解率较低，但可能对达沙替尼更为敏感。在治疗过程中，应加强对血液系统等相关指标的监测，以保证患者用药的安全性和有效性。

关键词 慢性粒细胞白血病；BCR-ABL融合基因；插入突变；酪氨酸激酶抑制剂；效果；安全性；文献分析

Literature Analysis of the Selection of Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia Patients with BCR-ABL35INS Mutation

YAN Meiling1，2，ZHANG Meng1，HUANG Lin1，JIA Yueping3，ZHANG Yi2，FENG Wanyu1，GAO Hui’er2（1. Dept. of Pharmacy， Peking University People’s Hospital， Beijing 100044， China； 2. Dept. of Pharmacy， Tianjin First Center Hospital， Tianjin 300192， China； 3. Pediatric Department， Peking University People’s Hospital， Beijing 100044， China）

ABSTRACT OBJECTIVE： To provide reference for reasonable selection of tyrosine kinase inhibitors （TKI） in chronic myeloid leukemia （CML） patients with BCR-ABL35INS mutation. METHODS： Using “BCR-ABL insertional mutation” “ABL1 35ins mutation” “BCR-ABL c.1423_1424ins35” “ABL1 p.C475Tyrfs*11” as keywords， retrieved from CNKI， Wanfang database， Medline and COSMIC database， BCR-ABL35INS mutation CML patients were summarized and analyzed in respects of general information and treatment （treatment plan， patient compliance and drug withdrawal）， therapeutic effect （molecular biological mitigation and disease progress） and safety data （ADR） during 2007-2018. RESULTS： Totally 9 related literatures were included， involving 70 patients with BCR-ABL35INS mutation， all of them were foreign cases. Among them， 39 cases were male and 31 cases were female， with a median age of 49.2 years. The median time from the diagnosis of CML to the detection of BCR-ABL35INS mutation was 19 months. After detecting gene mutation， 39 cases were treated with imatinib （initial dose of 400 mg， po， once a day）， and molecular biological remission was achieved in 5 patients （12.9%）； 15 cases （38.5%） had molecular biological response but had disease progression； 8 patients （20.5%） had no response. Seventeen patients were treated with dasatinib （100 mg， po， once a day or 2 divided dose）， and 8 cases （47.1%） achieved molecular biological response. Twenty-one patients were treated with nilotinib （400 mg， po， 2 divided dose）， and 3 patients （14.3%） achieved molecular biological response； 2 patients achieved molecular biological response， but the disease progressed. Seven， three and seven of these patients stopped taking drugs due to adverse reactions， accounting for 17.9%， 17.6% and 33.3% respectively. All the ADRs were classified as grade 3-4 of the National Cancer Institute’s Common Terminology Criteria for Adverse Events， and most of them were hematological toxicity. CONCLUSIONS： CML patients with BCR-ABL35INS mutation are less likely to achieve molecular response on imatinib therapy but are more sensitive to dashatinib. In the course of treatment， we should strengthen the monitoring of blood system and other related indicators to ensure the safety and effectiveness of drug use.