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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. KEYWORDS Chronic myeloid leukemia; BCR-ABL fusion gene; Insertional mutation; Tyrosine kinase inhibitors; Effect; Safety; Literature analysis
慢性粒细胞白血病(Chronic myeloid leukemia,CML)是一种累及多能造血干细胞的恶性克隆性疾病,费城染色体(Philadelphia chromosome,亦称“Ph染色体”)为该症的特征性遗传学标志。Ph染色体是9号染色体上ABL原癌基因移位至22号染色体,与后者断端的断裂点簇集区(BCR)连接所形成的BCR-ABL融合基因。根据BCR断裂位点的不同,可编码形成P210和P190两种融合蛋白,均具有极强的酪氨酸激酶活性,可使信号蛋白持续磷酸化,从而影响细胞的增殖、分化、凋亡及黏附,最终导致CML的发生[1]。CML的自然病程分为慢性期(CP)、加速期(AP)和急变期(BC),其中CML- BC期为该症的终末阶段,最常见的包括急粒变和急淋变,此外还可见急粒及急淋混合变、急性巨核细胞变等类型[2]。
近年来,BCR-ABL靶向的酪氨酸激酶抑制剂(TKI)是CML患者临床治疗的首选药物。2001年上市的伊马替尼为第一代TKI,可靶向抑制BCR-ABL的表达,迄今仍是CML的一线治疗药物[3]。然而有报道指出,在应用伊马替尼的过程中,约有15%~20%的患者治疗无效或复发,且可能与其耐药有关[4]。第二代TKI(达沙替尼、尼洛替尼和伯舒替尼)和第三代TKI(普纳替尼)的陆续上市,为治疗伊马替尼耐药或不耐受以及既往治疗无效的Ph阳性CML患者提供了新的选择[3]。新一代TKI具有更多的作用靶点和更强的BCR-ABL靶向抑制活性,在伊马替尼耐药突变型CML患者的治疗中具有一定优势,但仍然存在一些安全性问题,如严重的骨髓抑制、中枢神经系统出血、消化道出血、心脏和动脉血管闭塞、肝毒性等,故临床应予以足够的重视[5-6]。
有研究指出,BCR-ABL激酶域突变是导致伊马替尼耐药的重要机制之一[7]。该突变通常为点突变,此外还可见插入突变和缺失突变[7]。目前,研究者已发现140余个相关突变位点,其中BCR-ABL35INS是该激酶域内较为常见的插入突变,为外显子8/9剪接位点474氨基酸后存在碱基(片段大小为35 bp)插入突变(p.Cys475Tyrfs*11)[8-9]。最近研究报道,BCR-ABL35INS突变可能介导伊马替尼耐药,但其耐药情况及具体机制尚不明确[10]。为此,本研究通过对国内外文献报道的BCR-ABL35INS突变型CML患者的临床资料进行统计,对其应用TKI治疗的效果与安全性进行汇总与分析,旨在为该突变型CML患者的治疗提供用药参考。
1 资料与方法
1.1 文献来源及检索策略
组合检索中国知网、万方数据知识服务平台、Medline、COSMIC数据库等,检索时限为2007年1月-2018年12月。中文检索词:“BCR-ABL插入突变”“ABL1 35ins突变”“BCR-ABL c.1423_1424ins35”“ABL1 p.C475Tyrfs*11”,英文检索词:“BCR-ABL insertional mutation”“ABL1 35ins mutation”“BCR-ABL c.1423_1424ins35”“ABL1 p.C475Tyrfs*11”。此外,在所查阅文献的参考文献中以上述检索词进行手工检索,以免漏查。
1.2 纳入与排除标准
1.2.1 纳入标准 (1)均为BCR-ABL35INS突变相关的病例报道;(2)对BCR-ABL35INS突变型CML患者的病例资料和治疗过程有较为详细的描述;(3)文献中BCR- ABL35INS突变型患者应用過TKI治疗。
1.2.2 排除标准 (1)摘要和全文均不能获取的文献;(2)资料不全、重复发表或综述文献。
1.3 数据收集及处理
收集患者的性别、年龄、确诊CML至检测到BCR- ABL35INS突变的时间、应用TKI治疗情况(治疗方案、患者依从性及停药情况)、治疗效果(包括分子生物学缓解情况和疾病进展情况)以及TKI的安全性数据(包括不良反应)等信息,相关数据使用Excel 2010软件处理。
2 结果
按照上述纳入与排除标准,共检索到相关文献15篇;剔除资料不全及重复发表的文献后,最终纳入文献9篇[8-16],涉及相关病例70例,均为国外病例。
2.1 BCR-ABL35INS突变型CML患者的基本资料
70例BCR-ABL35INS突变型CML患者中,男性39例(占55.7%),女性31例(占44.3%);年龄9~76岁,中位年龄49.2岁;从确诊CML至检测到BCR-ABL35INS突变的时间为0~233个月,中位时间为19个月。
2.2 BCR-ABL35INS突变型CML患者的治疗情况及效果
70例BCR-ABL35INS突变型CML患者在诊断CML后均采用标准化的靶向治疗方案,即起始治疗选择伊马替尼400 mg,口服,每日1次;若发生耐药,将伊马替尼的剂量增加至600~800 mg;若治疗无效或不能耐受,则更换为达沙替尼100 mg,每日1次或分2次口服,或者更换为尼洛替尼400 mg,分2次口服。在检测到BCR- ABL35INS突变后,部分患者更换为达沙替尼或尼洛替尼治疗,用法用量同前,其治疗情况见表1(同一患者可能先后接受2种TKI治疗,故用药例次数合计值大于患者总数)。所有患者的治疗效果均依据美国国家综合癌症网络(NCCN)CML临床实践指南和相关文献[3,17]进行评价,评价标准——完全分子生物学缓解(CMR):应用定量聚合酶链反应分析方法及国际标准未检测到BCR-ABL mRNA表达;主要分子生物学缓解(MMR):患者BCR- ABL基因表达<0.1%(国际标准);部分分子生物学缓解(PMR):患者BCR-ABL基因表达<10%(国际标准)。若患者基因表达降低,但下降程度未达到上述分子生物学缓解标准,则为“有分子生物学应答”,反之则为“无应答”;若有细胞遗传学指标(或细胞形态学指标)提示患者病情进展,则为“疾病进展”。患者治疗情况及效果见表1。 [ 4 ] LEE T,MA W,ZHANG X,et al. BCR-ABL alternative splicing as a common mechanism for imatinib resistance:evidence from molecular dynamics simulations[J]. Mol Cancer Ther,2008,7(12):3834-3841.
[ 5 ] ZWAAN CM,RIZZARI C,MECHINAUD F,et al. Dasatinib in children and adolescents with relapsed or refractory leukemia:results of the CA180-018 phase Ⅰdose-escalation study of the innovative therapies for children with cancer consortium[J]. J Clin Oncol,2013,31(19):2460- 2468.
[ 6 ] DOUXFILS J,HAGUET H,MULLIER F,et al. Association between BCR-ABL tyrosine kinase inhibitors for chronic myeloid leukemia and cardiovascular events,major molecular response,and overall survival a systematic review and meta-analysis[J]. JAMA Oncol,2016. DOI:10.1001/jamaoncol.2015.5932.
[ 7 ] REDAELLI S,MOLOGNI L,ROSTAGNO R,et al. Th- ree novel patient-derived BCR/ABL mutants show different sensitivity to second and third generation tyrosine kinase inhibitors[J]. Am J Hematol,2012,87(11):E125- E128.
[ 8 ] O’HARE T,ZABRISKIE M,EIDE CA,et al. The BCR- ABL35INS insertion/truncation mutant is kinase-inactive and does not contribute to tyrosine kinase inhibitor resistance in chronic myeloid leukemia[J]. Blood,2011,118(19):5250-5254.
[ 9 ] BERMAN E,JHANWAR S,HEDVAT C,et al. Resistance to imatinib in patients with chronic myelogenous leukemia and the splice variant BCR-ABL135INS[J]. Leuk Res,2016. DOI:10.1016/j.leukres.2016.08.006.
[10] MARC? S,CORT?S M,ZAMORA L,et al. A thirty-five nucleotides BCR-ABL1 insertion mutation of controversial significance confers resistance to imatinib in a patient with chronic myeloid leukemia(CML)[J]. Exp Mol Pathol,2015,99(1):16-18.
[11] PARK SH,CHI HS,KWON R,et al. Rare frameshift mutation Cys475Tyrfs*11 in the BCR/ABL kinase domain contributes to imatinib mesylate resistance in 2 korean patients with chronic myelogenous leukemia[J]. Ann Lab Med,2012,32(6):452-454.
[12] LAUDADIO J,DEININGER MW,MAURO MJ,et al. An intron-derived insertion/truncation mutation in the BCR-ABL kinase domain in chronic myeloid leukemia patients undergoing kinase inhibitor therapy[J]. J Mol Diagn,2008,10(2):177-180.
[13] YUDA J,MIYAMOTO T,ODAWARA J,et al. Persistent detection of alternatively spliced BCR-ABL variant results in a failure to achieve deep molecular response[J].Cancer Sci,2017,108(11):2204-2212.
[14] VAIDYA S,VUNDINTI BR,SHANMUKHAIAH C,et al. Evolution of BCR/ABL gene mutation in CML is time dependent and dependent on the pressure exerted by tyrosine kinase inhibitor[J]. PLoS One,2015. DOI:10.1371/journal.pone.0114828. [15] MA W,GILES F,ZHANG X,et al. Three novel alternative splicing mutations in BCR-ABL1 detected in CML patients with resistance to kinase inhibitors[J]. Int Jnl Lab Hem,2011,33(3):326-331.
[16] STRHAKOVA L,GERYKOVA BM,HOJSIKOVA I,et al. Use of direct sequencing for detection of mutations in the BCR-ABL kinase domain in Slovak patients with chronic myeloid leukemia[J]. Neoplasma,2011,58(6):548-553.
[17] HEHLMANN R,HOCHHAUS A,BACCARANI M. Chronic myeloid leukaemia[J]. Lancet,2007,370(9584):342-350.
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(收稿日期:2018-08-14 修回日期:2019-04-11)
(編辑:张元媛)
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. KEYWORDS Chronic myeloid leukemia; BCR-ABL fusion gene; Insertional mutation; Tyrosine kinase inhibitors; Effect; Safety; Literature analysis
慢性粒细胞白血病(Chronic myeloid leukemia,CML)是一种累及多能造血干细胞的恶性克隆性疾病,费城染色体(Philadelphia chromosome,亦称“Ph染色体”)为该症的特征性遗传学标志。Ph染色体是9号染色体上ABL原癌基因移位至22号染色体,与后者断端的断裂点簇集区(BCR)连接所形成的BCR-ABL融合基因。根据BCR断裂位点的不同,可编码形成P210和P190两种融合蛋白,均具有极强的酪氨酸激酶活性,可使信号蛋白持续磷酸化,从而影响细胞的增殖、分化、凋亡及黏附,最终导致CML的发生[1]。CML的自然病程分为慢性期(CP)、加速期(AP)和急变期(BC),其中CML- BC期为该症的终末阶段,最常见的包括急粒变和急淋变,此外还可见急粒及急淋混合变、急性巨核细胞变等类型[2]。
近年来,BCR-ABL靶向的酪氨酸激酶抑制剂(TKI)是CML患者临床治疗的首选药物。2001年上市的伊马替尼为第一代TKI,可靶向抑制BCR-ABL的表达,迄今仍是CML的一线治疗药物[3]。然而有报道指出,在应用伊马替尼的过程中,约有15%~20%的患者治疗无效或复发,且可能与其耐药有关[4]。第二代TKI(达沙替尼、尼洛替尼和伯舒替尼)和第三代TKI(普纳替尼)的陆续上市,为治疗伊马替尼耐药或不耐受以及既往治疗无效的Ph阳性CML患者提供了新的选择[3]。新一代TKI具有更多的作用靶点和更强的BCR-ABL靶向抑制活性,在伊马替尼耐药突变型CML患者的治疗中具有一定优势,但仍然存在一些安全性问题,如严重的骨髓抑制、中枢神经系统出血、消化道出血、心脏和动脉血管闭塞、肝毒性等,故临床应予以足够的重视[5-6]。
有研究指出,BCR-ABL激酶域突变是导致伊马替尼耐药的重要机制之一[7]。该突变通常为点突变,此外还可见插入突变和缺失突变[7]。目前,研究者已发现140余个相关突变位点,其中BCR-ABL35INS是该激酶域内较为常见的插入突变,为外显子8/9剪接位点474氨基酸后存在碱基(片段大小为35 bp)插入突变(p.Cys475Tyrfs*11)[8-9]。最近研究报道,BCR-ABL35INS突变可能介导伊马替尼耐药,但其耐药情况及具体机制尚不明确[10]。为此,本研究通过对国内外文献报道的BCR-ABL35INS突变型CML患者的临床资料进行统计,对其应用TKI治疗的效果与安全性进行汇总与分析,旨在为该突变型CML患者的治疗提供用药参考。
1 资料与方法
1.1 文献来源及检索策略
组合检索中国知网、万方数据知识服务平台、Medline、COSMIC数据库等,检索时限为2007年1月-2018年12月。中文检索词:“BCR-ABL插入突变”“ABL1 35ins突变”“BCR-ABL c.1423_1424ins35”“ABL1 p.C475Tyrfs*11”,英文检索词:“BCR-ABL insertional mutation”“ABL1 35ins mutation”“BCR-ABL c.1423_1424ins35”“ABL1 p.C475Tyrfs*11”。此外,在所查阅文献的参考文献中以上述检索词进行手工检索,以免漏查。
1.2 纳入与排除标准
1.2.1 纳入标准 (1)均为BCR-ABL35INS突变相关的病例报道;(2)对BCR-ABL35INS突变型CML患者的病例资料和治疗过程有较为详细的描述;(3)文献中BCR- ABL35INS突变型患者应用過TKI治疗。
1.2.2 排除标准 (1)摘要和全文均不能获取的文献;(2)资料不全、重复发表或综述文献。
1.3 数据收集及处理
收集患者的性别、年龄、确诊CML至检测到BCR- ABL35INS突变的时间、应用TKI治疗情况(治疗方案、患者依从性及停药情况)、治疗效果(包括分子生物学缓解情况和疾病进展情况)以及TKI的安全性数据(包括不良反应)等信息,相关数据使用Excel 2010软件处理。
2 结果
按照上述纳入与排除标准,共检索到相关文献15篇;剔除资料不全及重复发表的文献后,最终纳入文献9篇[8-16],涉及相关病例70例,均为国外病例。
2.1 BCR-ABL35INS突变型CML患者的基本资料
70例BCR-ABL35INS突变型CML患者中,男性39例(占55.7%),女性31例(占44.3%);年龄9~76岁,中位年龄49.2岁;从确诊CML至检测到BCR-ABL35INS突变的时间为0~233个月,中位时间为19个月。
2.2 BCR-ABL35INS突变型CML患者的治疗情况及效果
70例BCR-ABL35INS突变型CML患者在诊断CML后均采用标准化的靶向治疗方案,即起始治疗选择伊马替尼400 mg,口服,每日1次;若发生耐药,将伊马替尼的剂量增加至600~800 mg;若治疗无效或不能耐受,则更换为达沙替尼100 mg,每日1次或分2次口服,或者更换为尼洛替尼400 mg,分2次口服。在检测到BCR- ABL35INS突变后,部分患者更换为达沙替尼或尼洛替尼治疗,用法用量同前,其治疗情况见表1(同一患者可能先后接受2种TKI治疗,故用药例次数合计值大于患者总数)。所有患者的治疗效果均依据美国国家综合癌症网络(NCCN)CML临床实践指南和相关文献[3,17]进行评价,评价标准——完全分子生物学缓解(CMR):应用定量聚合酶链反应分析方法及国际标准未检测到BCR-ABL mRNA表达;主要分子生物学缓解(MMR):患者BCR- ABL基因表达<0.1%(国际标准);部分分子生物学缓解(PMR):患者BCR-ABL基因表达<10%(国际标准)。若患者基因表达降低,但下降程度未达到上述分子生物学缓解标准,则为“有分子生物学应答”,反之则为“无应答”;若有细胞遗传学指标(或细胞形态学指标)提示患者病情进展,则为“疾病进展”。患者治疗情况及效果见表1。 [ 4 ] LEE T,MA W,ZHANG X,et al. BCR-ABL alternative splicing as a common mechanism for imatinib resistance:evidence from molecular dynamics simulations[J]. Mol Cancer Ther,2008,7(12):3834-3841.
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(收稿日期:2018-08-14 修回日期:2019-04-11)
(編辑:张元媛)