1例慢性粒细胞白血病治疗后出现NK细胞增多的报道

<正>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,其发病机制主要为9号染色体和22号染色体易位形成Ph,从而产生BCR-ABL融合基因。该融合基因编码产生的BCR-ABL融合蛋白具有高酪氨酸激酶活性~([1])。针对CML分子发病机制的小分子酪氨酸激酶抑制剂(TKI)将CML的治疗带入了分子靶向治疗阶段,显著延长了患者的生存时间。目前临床常用的TKI类药物有伊马替尼、尼洛替     

慢性髓细胞白血病BCR/ABL1突变克隆演化和治疗策略

伊马替尼的应用使很多慢性髓细胞白血病(chronic myeloid leukemia,CML)患者获得了长期生存,但是CML的BCR-ABL1融合基因激酶区突变(kinase domain mutation,KDM)会造成耐药.KDM有多种类型,不同类型是随机出现的.带有不同KDM特征的白血病克隆有一定的演变规律.在伊马替尼用药期间,耐药程度较高的突变细胞容易发展为优势克隆.建议在治疗伊马替尼耐药的CML时,除了努力发展下一代酪氨酸激酶抑制剂以外,还可考虑用传统药物来辅助治疗.     

慢性粒细胞白血病一线治疗药物研究进展

第一代BCR-ABL酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)伊马替尼(Imatinib)是慢性粒细胞白血病(chronic myeloid leukemia,CML)慢性期的一线标准治疗.伊马替尼通过直接靶向作用于Bcr-Abl激酶,极大改善了CML病程.近期,第二代TKIs药物尼洛替尼(Nilotinib)和达沙替尼(Dasatinib)又被美国FDA批准为CML的一线治疗.本文主要就CML一线治疗的进展作一综述.     

酪氨酸激酶时代慢性粒细胞白血病治疗的选择

慢性粒细胞白血病（chronic myeloid leukemia,CML）是造血干细胞恶性克隆性增生疾病。约95%的CML患者都有特异的细胞遗传学改变,即产生BCR-ABL融合基因。甲磺酸伊马替尼的出现为CML的治疗带来了革命性的进展,但耐药及不耐受患者的出现使得二代酪氨酸激酶抑制剂（tyrosine kinase inhibiton,TKI）达沙替尼、尼洛替尼应运而生。二代TKI转化时机及如何选择二代TKI成为关注的热点。在酪氨酸激酶时代,造血干细胞地位又将如何被看待？我们应该怎样选择CML的治疗方案？     

伊马替尼治疗慢性髓系白血病耐药机制研究进展

慢性粒细胞白血病(chronic myeloid leukemia,CML)是一种克隆性造血系统恶性肿瘤,其特征性费城染色体阳性及BCR-ABL融合基因形成,而BCR-ABL融合基因是靶向治疗的位点。TKI的广泛使用,更是将CML患者的治疗带入一个全新的时代,但近年来伊马替尼(Imatinib,IM)在治疗CML的过程中,其耐药现象不断发生。因此,本文主要就BCR-ABL激酶区突变、BCR-ABL基因扩增、能量代谢异常、体内伊马替尼药代学、白血病干细胞所致伊马替尼耐药的机制研究进展进行综述。     

尼罗替尼治疗对伊马替尼耐药或不耐受的慢性粒细胞白血病临床分析

目的 评价对伊马替尼耐药或不耐受的慢性粒细胞白血病(CML)患者接受尼罗替尼治疗的安全性和疗效.方法 35例对伊马替尼耐药或不耐受CML患者接受尼罗替尼治疗,400 mg,口服,每日2次,评估其疗效、不良反应、总体生存和疾病进展情况.结果 35例对伊马替尼耐药或小耐受的CML患者,中位尼罗替尼治疗时间11个月,中位随访时间19个月.尼罗替尼治疗相关的非血液学小良反应多为1～2级,主要为胆红素升高(76%)和皮疹(46%).3～4级血液学不良反应包括血小板减少(37%)、中性粒细胞减少和贫血(均为26%).患者大多可耐受.进展期(包括加速期和急变期)患者的3～4级血液学不良反廊发牛率明显高于慢性期.35例接受尼罗替尼治疗的患者中,CML慢性期患者获得主要细胞遗传学缓解率为38.5%,明显高于进展期患者(22.2%).达主要细胞遗传学缓解的中位时间为3个月.进展期患者发生疾病进展的比例明显高于慢性期.18个月预期总体生存率为(93.5±1.0)%.结论尼罗替尼为对伊马替尼耐药和不耐受的CML患者提供了一个有效并安全的治疗于段.尼罗替尼治疗慢性期CML更为安全和有效.     

儿童慢性髓性白血病酪氨酸激酶抑制剂停药的研究进展北大核心CSCD

儿童慢性髓性白血病(CML)是一种罕见的骨髓增殖性肿瘤,年发病率为(0.6~1.2)/100万,特征为9号与22号染色体易位产生Ph染色体,即t(9;22)(q34;q11),该染色体在分子水平上形成BCR-ABL融合基因。酪氨酸激酶抑制剂(TKI)能有效地抑制BCR-ABL激酶底物中酪氨酸残基的磷酸化,使该酶失活,通过阻止一系列的信号传导进而引起BCR-ABL阳性的细胞凋亡。其问世彻底改变了CML的治疗模式,也极大改善了CML患者的预后,CML患儿一线伊马替尼治疗的5年总生存率可达97%,预期寿命与正常人群相近[1-3]。     

BMS-354825:一种新的酪氨酸激酶抑制剂

Bcr-Abl酪氨酸激酶的活化与慢性粒细胞白血病(CML)发病关系密切,伊马替尼作为Bcr- Abl激酶抑制剂可使CML缓解,但目前伊马替尼耐药的病例日渐增多。BMS-354825作为Src／Abl双重抑制剂,可对伊马替尼耐药的病例产生良好效果。本文就该药物的研究进展作一综述。     

一代和二代酪氨酸激酶抑制剂治疗 对CML染色体的影响及疗效

目的 探讨一代和二代酪氨酸激酶抑制剂治疗对慢性粒细胞白血病(CML)患者染色体的影响及疗效。方法 用常规细胞遗传学法对80例Ph+的CML患者进行遗传学分析,同时对比一代和二代酪氨酸激酶抑制剂治疗后CML患者染色体的改变情况及疗效。结果 80例Ph+的CML患者中有11例合并其他的染色体数目及结构异常,其中有10例对伊马替尼耐药或不耐受。伊马替尼(TKI-Ⅰ)治疗的40例患者中有35例达到持续完全细胞遗传学缓解(complete cytogenetic remission,CCyR)(占87.5%),其中有7例3个月时获得CCyR(占17.5%),10例6个月时获得CCyR(占25%),13例12个月时获得CCyR(占32.5%),5例18个月时获得CCyR(占12.5%); 达沙替尼/尼罗替尼(TKI-Ⅱ)治疗的40例患者中有33例达到持续完全细胞遗传学缓解(CCyR)(占82.5%),其中有16例3个月时获得CCyR(占40%),9例6个月时获得CCyR(占22.5%),5例12个月时获得CCyR(占12.5%),3例18个月时获得CCyR(占7.5%)。结论 合并其他染色体异常的Ph+CML患者更容易对伊马替尼产生耐药或不耐受性,尤其是加速期和急变期,一代和二代酪氨酸激酶抑制剂对CML的治疗在长期疗效上相差不大,但近期效果二代优于一代。     

BMS-354825：一种新的酪氨酸激酶抑制剂

Bcr—Abl酪氨酸激酶的活化与慢性粒细胞白血病（CML）发病关系密切，伊马替尼作为Bcr—Abl激酶抑制剂可使CML缓解，但目前伊马替尼耐药的病钟日渐增多。BMS354825作为Src／Abl双重抑制剂，可对伊马替尼耐药的病例产生良好效果。本文就该药物的研究进展作一综述。     

Dasatinib treatment for imatinib resistant or intolerant patients with chronic myeloid leukaemia

Chronic myeloid leukaemia (CML) is a genetically associated malignancy of haematopoietic stem cells, characterized by a t(9;22) translocation that forms the Philadelphia chromosome and creates a novel fusion gene, BCR-ABL. Treatment with molecular-targeted therapy is usually initiated with imatinib, an inhibitor of BCR-ABL tyrosine kinase. Imatinib resistance is, however, observed in some CML patients, especially in those with advanced disease. Through computerized literature searches, a systematic analysis was conducted to examine the efficacy and benefits of dasatinib therapy for imatinib resistant or intolerant CML patients in the chronic phase (CP), accelerated phase (AP) and fatal blast crisis phase (BC). In terms of major haematological and cytogenetic responses, this meta-analysis showed no significant differences in dasatinib treatment between myeloid BC-CML and lymphoid BC-CML patients with imatinib resistance or intolerance. Dasatinib therapy was, however, significantly more effective in improving major haematological and cytogenetic responses for CP-CML patients than for AP-CML patients with imatinib resistance or intolerance.     

Liposomal cytarabine for treatment of myeloid central nervous system relapse in chronic myeloid leukaemia occurring during imatinib therapy

BACKGROUND: Central nervous system (CNS) relapse in chronic myeloid leukaemia (CML) is rare and if recorded is usually found to occur in patients with lymphoblastic transformation. The BCR/ABL tyrosine kinase inhibitor imatinib is highly effective in patients with CML, but hardly crosses the blood-brain barrier. PATIENTS AND METHODS: We report on two CML patients who developed a myeloid CNS relapse during treatment with imatinib. One patient was in major cytogenetic response at the time of CNS relapse. In both cases, the myeloid origin of neoplastic cells in the cerebrospinal fluid (CSF) was demonstrable by immunophenotyping, and their leukaemic origin by detection of the BCR/ABL oncoprotein. No BCR/ABL kinase domain mutations were found. Both patients received intrathecal liposomal cytarabine (50 mg each cycle; 6 cycles). In one patient, additional CNS radiation was performed, whereas in the other, consecutive treatment with dasatinib (70 mg per os twice daily) was started. RESULTS: In response to therapy, the clinical symptoms resolved, and the leukaemic cells in the CSF disappeared in both cases. After three months of observation, both patients are in complete cytogenetic and major molecular response, without evidence for a systemic or a CNS relapse. CONCLUSIONS: 'Anatomic' resistance against imatinib in the CNS can lead to a myeloid CNS relapse. Liposomal cytarabine with or without radiation is effective as local therapy in these patients. For systemic treatment and prophylaxis, BCR/ABL kinase inhibitors crossing the blood-brain barrier such as dasatinib should be considered in patients with CNS relapse.     

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.     

Chronic myelogenous leukemia

In the therapy of chronic myelogenous leukemia (CML), interferon (IFN) brought about a big progress resulting in the good hematologic as well as cytogenetic response and prolongation of survival. Recently, imatinib, the BCR/ABL antagonist, took over the first choice drug of the treatment CML. However, IFN still has the possibility to contribute the improvement of the therapy efficacy of CML.     

Imatinib therapy for patients with chronic myelogenous leukemia

Imatinib mesylate (imatinib), a selective inhibitor of BCR-ABL tyrosine kinase, has shown excellent efficacy in patients with chronic myelogenous leukemia (CML) in the chronic phase, however, it does not in those in the accelerated phase or blastic crisis. In patients with CML who have undergone allogeneic stem cell transplantation, imatinib has the capability to induce hematological and even molecular response, and provides a prolonged survival among those in the chronic and accelerated phases. It has been demonstrated that major cytogenic response is a surrogate marker for survival in cases receiving imatinib. It has also been demonstrated that a genome-wide cDNA microarray enables the prediction of sensitivity to imatinib. The acquired resistance in patients who failed to respond to imatinib seemed to be induced by several point mutations in the BCR-ABL gene, which were likely to affect the binding of imatinib with BCR-ABL. Polyclonal cells which harbor distinct mutations in a single patient seemed to be selected in vivo under the selective pressure of imatinib, indicating the rationale of combined treatment with other types of agents. Recently, SPIRIT (STI571 Prospective International Randomized Trials) have been conducted, in which the efficacy of imatinib monotherapy, and imatinib combined with interferon or cytarabine were compared. New agents which inhibit the signaling pathway related to BCR-ABL, such as adaphostin (NSC680410), farnesyltransferase inhibitor SCH66336, MAP kinase inhibitor PD184352, PD98059, U0126, and antibiotic geldanamycin, have shown excellent activity combined with imatinib in vitro.     

What is imatinib-resistant chronic myeloid leukemia? Identifying and managing loss of response

Imatinib is widely recognized as the standard of care in the first-line treatment of chronic myeloid leukemia (CML); however, resistance can limit its long-term benefits. Early identification of the loss of response to imatinib is therefore important for the optimal management of patients with this type of leukemia. Cytogenetic and molecular responses during the first 12 months of treatment have been shown to predict future responses (complete cytogenetic response and major molecular response) and reduce disease progression. The degree of early reduction in BCR-ABL levels after commencing imatinib therapy is a good indicator of subsequent response. Monitoring for kinase domain mutations should also be considered in patients with suboptimal response or in those who demonstrate resistance. Modification of the treatment strategy is required if there is a loss of response. Dasatinib and nilotinib are the most extensively studied second-generation BCR-ABL tyrosine kinase inhibitors, and are currently approved for treating patients following imatinib failure.     

达沙替尼治疗伊马替尼耐药的BCR/ABL阳性白血病的临床研究

本研究评价达沙替尼治疗原发或继发伊马替尼耐药的BCR/ABL阳性白血病的疗效和安全性。对27例原发或继发伊马替尼耐药的慢性髓系白血病(CML)或Ph阳性急性淋巴细胞白血病(Ph+ALL)患者,给予达沙替尼100-140 mg/d口服治疗,评估疗效、总体生存和耐受情况。结果表明:27例伊马替尼耐药的BCR/ABL阳性白血病中位达沙替尼治疗时间8(1-66)个月,中位随访时间54(3-75)个月。27例接受达沙替尼治疗的患者中,88.8%获得完全血液学反应(CHR),44.4%获得主要细胞遗传学反应(mCyR),37%获得完全遗传学反应(CCyR),18.5%获得主要分子学反应(MMR)。伊马替尼耐药的进展期(CML-AP、CML-BC、骨髓复发Ph+ALL)患者接受达沙替尼治疗获CCyR率低于疾病稳定期(CML-CP、骨髓缓解Ph+ALL)患者(P=0.0377),且3-4级不良反应发生率明显增高。达沙替尼治疗后获得CCyR的患者生存期(OS)较未达CCyR者明显延长(63个月vs 9个月,P=0.0126)。达沙替尼治疗后最常见的3-4级不良反应包括血液学反应如血小板减少(51.8%)、中性粒细胞减少(48.1%)、贫血(33.3%)和非血液学反应如胸腔积液(18.5%)、肺部感染(18.5%)、心包积液(11.1%)。3-4级不良反应主要发生在疾病进展期时改服达沙替尼者,均发生于服药12个月内。结论:达沙替尼治疗伊马替尼耐药的BCR/ABL阳性白血病有效,且在疾病稳定期改服达沙替尼疗效和耐受性更好。