慢性髓细胞白血病的酪氨酸激酶抑制剂耐药机制

近年,慢性髓细胞白血病(CML)的治疗方法不断取得进展,包括药物化疗、脾切除术、干扰素治疗、造血干细胞移植(HSCT)等方法.第一代酪氨酸激酶抑制剂(TKI)伊马替尼,可使CML患者的总体生存(OS)率与无事件生存(EFS)率均显著提高,已成为CML的一线治疗药物.然而,部分CML患者出现原发性或继发性TKI耐药,成为导致CML患者治疗失败的主要原因.探索TKI耐药机制、寻找应对TKI耐药的新策略成为CML相关研究热点.TKI耐药的机制复杂,与多种基因产物与细胞内信号分子相关,主要分为断裂点簇集区/Abelson白血病病毒(BCR/ABL)依赖途径与非BCR/ABL依赖途径,而这些耐药机制可以单独或同时存在于同一例CML患者.随着相关研究的深入,对CML患者TKI耐药机制的研究取得较大进展,笔者拟就相关研究进展进行综述.     

酪氨酸激酶抑制剂治疗儿童急性非淋巴细胞白血病的研究进展

急性非淋巴细胞白血病即急性髓系白血病(AML)是一种高度异质性疾病,信号通路异常可能为其发病机制之一,酪氨酸激酶为常见的驱动因素,其抑制剂为研究较多的治疗AML的靶向药物。儿童急性白血病领域常用的酪氨酸激酶抑制剂为伊马替尼(Gleevec)和达沙替尼(Sprycel),索拉非尼(Nexavar)较少应用。在目前AML治疗研究中,酪氨酸激酶抑制剂主要应用于c-kit及FLT3的基因异常所致疾病,也有文献报道应用于ETV6-PDGFRβ融合基因、ETV6-ABL1融合基因AML。靶向药物专一性强、不良反应少,但目前临床应用范围较窄,未来发展方向将是在基因水平为儿童白血病提供更精细的研究结果,进而期待更多更精细的研究为儿童白血病的靶向药物治疗提供理论依据。     

新型酪氨酸激酶抑制剂治疗慢性粒细胞白血病的研究进展

靶向性酪氨酸激酶抑制剂在治疗慢性粒细胞白血病中的疗效已得到临床肯定。第一代酪氨酸激酶抑制剂STI571用于治疗慢性粒细胞白血病，能改变疾病的自然进程及提高生存率。随着STI571耐药性的出现，人们开始寻找更有效的新型酪氨酸激酶抑制剂。本文就新型酪氨酸激酶抑制剂的研究进展作一综述。     

酪氨酸激酶抑制剂STI571治疗慢性髓细胞白血病

酪氨酸激酶抑制剂STI571(signal transduction inhibitor 571,STI571)可竞争性抑制Ph阳性慢性髓细胞白血病(CML)癌基因Bcr-Abl代谢过程中ATP或底物与酪氨酸激酶催化中心结合而发挥靶向治疗作用,临床疗效确切,毒副作用轻微。本文就其在CML治疗中的药理作用与临床研究进行综述。     

不同酪氨酸激酶抑制剂治疗慢性髓系白血病有效性和安全性的网状Meta分析

目的 系统评价不同酪氨酸激酶抑制剂(TKIs)治疗慢性髓系白血病(CML)的有效性和安全性.方法 计算机检索PubMed、EMbase、The Cochrane Library、CNKI、WanFang Data和CBM数据库,搜集氟马替尼、尼洛替尼、达沙替尼和伊马替尼治疗CML的随机对照试验(RCT),检索时限均从建...     

新型酪氨酸激酶抑制剂治疗慢性粒细胞白血病的临床研究进展

酪氨酸激酶（tyrosine kinases,TK）是一类催化ATPγ-磷酸转移到蛋白质酪氨酸残基上的激酶,能催化多种底物蛋白质酪氨酸残基磷酸化,在细胞生长、增殖、分化中具有重要作用。慢性粒细胞白血病（CML）是造血干细胞恶性克隆性疾病,其发病的分子遗传学基础为染色体t（9;22）（q34;q11）易位,产生bcr／ab1融合基因。     

格列卫治疗慢性髓细胞白血病的分子机制

慢性髓细胞白血病(chronic myeloid leukemia,CML)的典型遗传学特征为(t9;22)(q34;q11)易位,导致bcr/abl融合基因形成。该基因编码的bcr/abl融合蛋白为非受体酪氨酸激酶,能激活多条信号传导通路,干扰细胞的正常基本生理活动,是CML发病的关键因素。酪氨酸激酶抑制剂格列卫能竞争性结合酪氨酸激酶的ATP结合位点,抑制该酶活性,从而有效地治疗CML,是目前公认的比较理想的靶向治疗CML的小分子药物。针对CML的某些耐药机制,现正在研究多种新型有效安全的酪氨酸激酶抑制剂。     

酪氨酸激酶抑制剂STI1571治疗慢性髓细胞白血病

酪氨酸激酶抑制剂ST1571（signal transduction inhibitor571,STI571)可竞争性抑制Ph阳性慢性髓细胞白血病（CML）癌基因Bcr-Abl代谢过程中ATP或底物与酪氨酸激酶催化中心结合而发挥靶向治疗作用，临床疗效确切，毒副作用轻微，本文就其在CML治疗中的药理作用与临床研究进行综述。     

酪氨酸激酶抑制剂治疗慢性期老年人慢性粒细胞白血病的疗效及安全性分析

目的 回顾性分析酪氨酸激酶抑制剂(TKI)治疗慢性期慢性粒细胞白血病(CML)老年患者的疗效及安全性.方法 收集2005年1月至2016年1月于华西医院血液内科就诊的发病年龄≥60岁且接受TKI治疗的慢性期CML老年患者共计52例作为研究对象.其中,33例患者的一线治疗方案选择伊马替尼(IM)治疗,2例患者一线治疗方案选择二代TKI尼洛替尼(NIL)治疗,其余17例患者接受IM治疗前经过干扰素治疗.对其治疗反应、总体生存(OS)、无事件生存(EFS)、伴随疾病情况及药物不良反应进行回顾性分析,总结TKI治疗老年CML的疗效及安全性.结果 ①随访结束时,所有患者累积完全血液学缓解(CHR)、主要细胞遗传学缓解(MCyR)、完全细胞遗传学缓解(CCyR)和主要分子学缓解(MMR)率分别为100.0％(52/52)、82.7％(43/52)、80.8％(42/52)和71.2％(37/52).所有患者1、5和10年OS率分别为100.0％、95.1％和75.3％,EFS率分别为92.3％、73.3％和51.4％.②25例患者诊断为CML时存在伴随疾病,所有52例患者查尔森合并症指数(CCI)评分均≤2分.32例CCI评分=0分与20例CCI评分＞0分的患者相比,累积CCyR、MCyR、MMR率,以及Ⅲ～Ⅳ级血液学与非血液学不良反应发生率差异均无统计学意义(x2 =0.948、0.525、0.021、0.288、0.519,P＞0.05).③50例接受IM治疗患者中,Ⅲ～Ⅳ级中性粒细胞减少、血小板减少、贫血发生率分别为16.0％(8/50)、28.0％ (14/50)及18.0％(9/50),Ⅲ～Ⅳ级非血液学不良反应发生率为28.0％(14/50),5例(10.0％,5/50)患者因为IM不耐受而选择二代TKI治疗.结论 TKI对慢性期CML老年患者具有良好的疗效及安全性,轻微的伴随疾病不影响疾病治疗.     

Treatment of chronic myelogenous leukemia with tyrosine kinase inhibitor]

STI571(imatinib) selectively inhibits the ABL-tyrosine kinase, the activity of which is activated by the formation of chimeric BCR/ABL. Phase I study in USA showed a remarkable effectiveness of STI571 in interferon-refractory chronic myelogenous leukemia with little adverse effects. STI571 will plausibly become the first choice drug prior to stem cell transplantation and interferon in the treatment of this leukemia.     

Dasatinib: a tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia

BACKGROUND: The Philadelphia chromosome is formed from a translocation of genetic material involving human chromosomes 9 and 22. The resulting gene product, BCR-ABL, encodes for an abnormal tyrosine kinase (TK) that is a factor in the pathology of chronic myelogenous leukemia (CML). Use of targeted therapy that inhibits BCR-ABL kinase activity may lead to hematologic and cytogenetic responses in affected individuals. The oral TK inhibitor dasatinib was approved in 2006 for use in patients with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) who are unable to tolerate or have not responded to other treatments. OBJECTIVE: This paper reviews the available data on dasatinib, including its pharmacokinetic and pharmacodynamic properties, findings of in vitro and in vivo studies, adverse effects, and potential place in therapy. METHODS: Pertinent information was identified through searches of MEDLINE (1966-May 2007), EMBASE (1980-first quarter 2007), and International Pharmaceutical Abstracts (1970-May 2007) using the terms dasatinib, BMS-354825, chronic myelogenous leukemia, Sprycel, Philadelphia chromosome, and acute lymphoblastic leukemia. All clinical studies and case reports published at the time of the search were included in this review. RESULTS: Observed mutations in the amino acid sequence of BCR-ABL cause the failure of treatment with existing TK inhibitors. Dasatinib has shown in vitro and in vivo activity against BCR-ABL, including mutations that are resistant to other available TK inhibitors. Preliminary results are available from several noncomparative studies of dasatinib in patients who were unable to tolerate or were resistant to previous therapies. The 5 phases of START (SRC/ABL Tyrosine kinase inhibition Activity Research Trials of dasatinib) represent the largest and most comprehensive evaluation of dasatinib in the treatment of patients in all stages of CML or Philadelphia chromosome-positive ALL who had undergone previous treatment for leukemia. Dasatanib had the greatest benefit in patients in the chronic phase of CML, with complete hematologic responses in 90% of patients, 52% of whom achieved a major hematologic response. Compared with those in the chronic phase, patients in the accelerated phase or blast crisis of CML, or with Philadelphia chromosome-positive ALL had lower responses. In the START-R trial, which compared the response to dasatinib and high-dose imatinib (800 mg/d), both regimens had comparable ability to induce a complete hematologic response (95% and 93%, respectively), although more patients achieved a major cytogenetic response with dasatinib (32% vs 7%). Adverse effects include significant myelosuppression. Dasatinib may have the potential for use in the management of nonleukemic malignancies. CONCLUSIONS: Dasatinib has a wider spectrum of activity against a broader range of BCR-ABL forms than existing TK inhibitors. It has shown clinical benefit and tolerability in patients in all phases of CML, as well as in those with Philadelphia chromosome-positive ALL. Dasatinib illustrates the potential for targeted drug development based on an understanding of the genetic alterations leading to CML and the development of resistance to treatment.     

Overview of second-generation tyrosine kinase inhibitors for patients with imatinib-resistant chronic myelogenous leukemia

Imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corporation, East Hanover, NJ) has revolutionized the treatment of chronic myelogenous leukemia (CML) with marked improvement in survival in all three phases--chronic, accelerated, and blast. Most patients with CML now receive imatinib, which produces complete cytogenetic response in more than 80% of patients. About 10% of patients who initially respond to imatinib subsequently develop resistance. Mechanisms of imatinib resistance in CML include amplification, mutations, and additional chromosomal aberration. To date, more than 30 mutations have been identified in imatinib-resistant CML. Dasatinib and AMN107, second-generation tyrosine kinase inhibitors, are highly effective therapies for patients with CML experiencing imatinib resistance and mutation and offer new options for patients who do not achieve an optimal response to imatinib therapy. Studies found that dasatinib and AMN107 form tighter bonds, overcoming imatinib resistance and producing complete hematologic and cytogenetic remissions. Long-term observations are needed to determine the effectiveness of the treatment. Primary care providers need to follow patients receiving first- or second-generation tyrosine kinase inhibitors because unforeseen toxicity may surface, requiring accurate assessment, evaluation, and management. Oncology nurses will be actively involved in the symptom management of patients. Providing guidelines for symptom management and advanced knowledge of specific test results for monitoring CML may increase positive outcomes.     

丝氨酸/苏氨酸蛋白激酶抑制剂治疗成人急性白血病的研究

目的应用基因表达谱芯片来检测丝氨酸/苏氨酸蛋白激酶Raf-1抑制剂对急性髓系白血病（AML）细胞基因表达的影响,试图进一步探讨丝氨酸/苏氨酸蛋白激酶Raf-1抑制剂抗白血病细胞增殖的机制。方法利用cDNA基因芯片研究10例成人AML,用两种不同的荧光素cy3和cy5通过逆转录反应将白血病细胞经丝氨酸/苏氨酸蛋白激酶Raf-1抑制剂作用前后的RNA分别标记成两种探针,并与基因表达谱芯片进行杂交,通过计算机扫描分析得出这些基因在经丝氨酸/苏氨酸蛋白激酶Raf-1抑制剂处理前后的表达差异。结果基因表达谱分析两次重复实验结果,最后筛选出包括与细胞凋亡、细胞周期等相关表达差异的基因共20条,其中12条表达上调,8条表达下调。结论结果提示丝氨酸/苏氨酸蛋白激酶Raf-1抑制剂抗成人急性粒细胞白血病的作用机制与抑制白血病细胞周期和诱导白血病细胞凋亡有很大关系。     

慢性髓系白血病患者应用酪氨酸激酶抑制剂期间的生育结果

目的 观察接受酪氨酸激酶抑制剂( TKI)治疗的慢性髓系白血病(CML)患者的生育结果.方法 回顾性收集接受TKI治疗的CML患者或其配偶妊娠、生育的相关信息.结果 2例年轻女性患者和10例中位年龄为33.5(26 ～46)岁的男性患者的配偶妊娠,并生产了12名婴儿.2例女性患者在伊马替尼治疗90和91个月时发现意外怀孕,1例仅停药1个月、1例妊娠全程和产后哺乳半年期间持续服用伊马替尼.10例男性患者中,7例在伊马替尼中位治疗60( 11 ～96)个月时、3例在达沙替尼中位治疗3(2.5～7.O)个月时,发现其配偶妊娠.所有患者生育前后疾病均处于血液学、细胞遗传学或分子学缓解状态.12名婴儿中,除1名早产、低体重并有尿道下裂的畸形外(出生后手术修复),其余11名均为足月生产,未见器官畸形.目前,12例患者子女生长发育正常,中位年龄17.5(3～101)个月.结论 在TKI治疗期间,女性CML患者和男性CML患者的配偶均可产出正常婴儿,但也有发生先天畸形的可能.建议育龄期女性患者在TKI治疗中应该有效避孕,并避免哺乳.当患者发现意外妊娠后,应咨询医生,权衡服药与妊娠的风险与收益.男性患者在服用伊马替尼期间无须避孕.     

慢性髓性白血病患者门诊酪氨酸激酶抑制剂治疗规范化管理

21世纪以来,酪氨酸激酶抑制剂(TKI)在治疗慢性髓性白血病(CML)方面取得了极大的成功,使慢性髓性白血病-慢性期(CML-CP)成为一种可控制的慢性疾病.接受TKI治疗的CML患者大多数在门诊随诊监测,因此,患者的依从性及对疾病的认知能力;医师优化临床TKI选择、早期疾病监测、治疗疗效的评估等对实现免治疗缓解最终彻底清除CML干细胞方面有着重要作用.现就CML患者门诊接受TKI的规范化治疗及监测进行概述.     

慢性粒细胞白血病的治疗进展

慢性粒细胞白血病(CML)是一种造血干细胞克隆性骨髓增殖性肿瘤.尽管酪氨酸激酶抑制剂(TKI)可抑制Bcr/Abl激酶活性,并在慢性期CML治疗中取得了很好的疗效,而且耐受性良好,但TKI有很多的不良反应.目前对于CML患者和社会而言,TKI的治疗已成为一个沉重的负担.因此,迫切需要探索清除来源于Ph+恶性干细胞克隆的CML微小残留病灶有望获得CML永久治愈和长期无病生存的方法,现就其治疗进展作一综述.