Dasatinib用于治疗对伊马替尼耐药的Ph染色体阳性白血病

背景:Bcr-Abl酪氨酸激酶抑制剂伊马替尼(imatinib)可有效治疗Ph染色体阳性白血病,但是会复发,主要是由于白血病亚型的副产物与伊马替尼耐药的Bcr-Abl突变。我们研究了以大部分伊马替尼耐药的Bcr-Abl突变体为靶点的B c r-Abl抑制剂dasatinib在治疗慢性骨髓性白血病(CML)和Ph阳性急性淋巴细胞白血病(ALL)患者中的作用。方法:患有CML或者Ph阳性ALL且对伊马替尼不能耐受或者对伊马替尼耐药的患者被收录入Ⅰ期剂量递增研究(dose-escalationstudy)中。口服dasatinib(15～240mg/d),每日1次或2次,每4周为1个疗程。结果:在40例慢性期CML患…     

FTY720:治疗急变期慢性髓样白血病和费城染色体阳性淋巴细胞白血病的新选择

BCR-ABL癌蛋白过度的激酶活性可导致慢性髓样白血病(CML)和费城染色体阳性急性淋巴细胞白血病(Ph1ALL)的发生和恶化。多数CML急变期(CML-BC)患者和Ph1ALL患者对ABL抑制剂(如伊马替尼、达沙替尼)耐药。Perrotti等发现,应用FTY720可再活化肿瘤抑制蛋白磷酸酶(PP2A),从而诱导CML-B     

第三代BCR-ABL酪氨酸激酶抑制剂普纳替尼

普纳替尼作为新一代酪氨酸激酶抑制剂(TKIs),对BCR-ABL阳性白血病,如慢性髓细胞白血病(CML)、费城染色体阳性急性淋巴细胞性白血病(Ph+ALL)有显著的治疗效果,甚至在对当前市场上供应的第一、二代TKIs出现耐药(如T315I突变)的情况下仍有效。目前普纳替尼已获美国FDA批准用于对其他TKIs耐药的CML与Ph+ALL患者的治疗,并在尼洛替尼与达沙替尼耐药或不耐受的T315I突变患者中进行了Ⅱ期临床研究。     

药物警戒快讯

1欧盟更新帕纳替尼（Ponatinib）的使用建议 帕纳替尼（Ponatinib）是一种抗癌药物。用于治疗成人慢性粒细胞白血病（（CML）、“费城染色体阳性”（Ph＋）急性淋巴细胞白血病（ALL）。主要用于治疗对达沙替尼或尼洛替尼治疗无效的患者,或不能耐受达沙替尼或尼洛替尼的患者,以及不适合伊马替尼后续治疗的患者。     

达沙替尼治疗伊马替尼耐药的 BCR／ABL阳性白血病

目的评价达沙替尼治疗伊马替尼耐药的BCR/ABL阳性白血病的疗效和安全性。方法对9例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-1口服治疗,评估疗效和耐受情况。结果 9例伊马替尼耐药的BCR/ABL阳性白血病,2例CML-CP患者均获得CHR,1例达CCyR;5例CML-BC患者中4例获得CHR和PCyR,1例NR;2例Ph＋ALL患者中1例检测到E255V突变,采用达沙替尼治疗达CHR和PCyR,1例诱导缓解时,同时行VDP方案化疗,继发严重感染死亡。结论达沙替尼治疗伊马替尼耐药的BCR/ABL阳性白血病患者可获得血液学甚至细胞遗传学缓解,且耐受性好。     

伯舒替尼的药理研究及临床评价

慢性髓性白血病是一造血系统疾病,与融合基因Bcr-Abl相关,尽管采用酪氨酸激酶抑制剂伊马替尼治疗取得了显著疗效,但部分患者出现耐药或不能耐受。伯舒替尼为Src和Abl激酶的双重抑制剂,主要用于治疗对伊马替尼耐药或不能耐受的慢性髓性白血病,对一些实体瘤也有效。本文综述了其药理作用、药动学、药物相互作用、临床评价及不良反应等。     

伊马替尼治疗Ph阳性进展期慢性粒细胞白血病

目的:观察伊马替尼治疗Ph阳性进展期慢性粒细胞白血病(CML)的疗效和耐药情况,研究改善伊马替尼耐药的方法。方法:32例Ph阳性进展期CML病人,其中加速期12例,急变期20例,每日口服伊马替尼600或800mg,持续3～9mo。结果:CML加速期病人血液学完全缓解率和总有效率分别为42%和83%,主要细胞遗传学缓解率25%,持续完全血液学缓解病例占25%。CML急变期各类型病人血液学完全缓解率和总有效率分别为20%和55%,主要细胞遗传学缓解率15%,持续完全血液学缓解病例占10%。CML急变期原发耐药和继发耐药分别为45%和20%,联合化疗与暂停伊马替尼对继发耐药可暂时改善其耐药性,但药物有效时间明显缩短。结论:伊马替尼对初治或复治的CML加速期和急变期病人均有效,可作为非移植CML治疗的标准一线方案,伊马替尼治疗CML急变期的原发耐药和继发耐药率较高,联合化疗和暂停伊马替尼可暂时改善其耐药性。     

慢性粒细胞白血病临床治疗药物选择

目的:为慢性粒细胞白血病患者治疗药物选择提供参考。方法:查阅国内外相关文献,综述分析已上市的临床用于治疗慢性粒细胞白血病的一线药物,包括酪酸激酶抑制剂伊马替尼、达沙替尼、尼罗替尼、博舒替尼、帕纳替尼和非酪酸激酶抑制剂高三尖杉酯碱的标准使用剂量、药效学、毒副作用、药物禁忌、药物相互作用。结果:第一代酪氨酸激酶抑制剂伊马替尼对未使用过其他酪氨酸激酶抑制剂治疗的初始患者有很好的疗效,但患者用药后很容易发生Bcr-Abl基因突变而耐受或者耐药。第二代酪氨酸激酶抑制剂达沙替尼、尼罗替尼、博舒替尼对大部分Bcr-Abl基因突变有效,对伊马替尼产生耐受或者耐药的患者有较好的治疗效果,但是均对T315I突变无效。第三代酪氨酸激酶抑制剂帕纳替尼对大部分Bcr-Abl基因突变有效,而且是目前唯一对T315I突变有效的已上市激酶抑制剂,但有严重的致血管阻塞、心脏衰竭和肝毒性的风险。另外,非酪氨酸激酶抑制剂高三尖杉酯碱主要用于难治性白血病患者。结论:在临床治疗中,应根据患者病情的发展阶段,用药、耐药情况及药物本身的疗效和毒副作用等综合评估,合理选择药物进行治疗,充分发挥药物疗效和提高药物使用安全性。     

针对Abl-T315I突变的Bcr-Abl蛋白激酶抑制剂的研究进展

Bcr-Abl融合基因与慢性粒细胞白血病(CML)的发病发展密切相关.直接作用于Bcr-Abl蛋白的小分子药物是目前治疗CML的重要方法,受到广泛的关注.伊马替尼作为首个上市的Bcr-Abl蛋白激酶抑制剂,在靶向治疗慢性粒细胞白血病上取得了很大成功,但Bcr-Abl基因的突变导致其出现耐药性,尤其以Abl-T315I突变的耐药程度最高.本文综述了近年正在开发中的针对Abl-T315I突变的Bcr-Abl蛋白激酶抑制剂.     

Bcr-Abl酪氨酸激酶抑制剂联合用药治疗慢性粒细胞白血病研究进展

以伊马替尼为代表的酪氨酸激酶抑制剂对慢性粒细胞白血病(CML)的治疗产生了重要影响,但其耐药性已成为CML治疗领域的关键问题。伊马替尼、尼洛替尼、达沙替尼以及普纳替尼等Bcr-Abl酪氨酸激酶抑制剂与其他药物联合使用,可以协同抑制Bcr-Abl及其磷酸化蛋白的表达,显著降低STAT5、CRKL、ERK5等信号通路的磷酸化水平,改善肿瘤微环境,降低肿瘤细胞多药耐药性,已在基础研究和临床Ⅰ期研究中取得阶段性成果,为治疗CML提供新策略。     

Is AMN-107 a step forward from imatinib in the treatment of chronic myeloid leukaemia?

The Philadelphia (Ph) chromosome was the first consistent chromosome abnormality identified in cancer. It is found in 90% of patients with chronic myeloid leukaemia (CML) and in a subset of patients with acute lymphoblastic leukaemia. The effectiveness of the Bcr-Abl kinase inhibitor imatinib in these conditions reduces with advancing disease and/or the development of resistance to imatinib. AMN-107 inhibited the proliferation of haematopoietic cells expressing the mutants in Ph+ CML and acute lymphoblastic leukaemia with concentrations causing 50% inhibition of approximately 12 nM, making it more potent than imatinib. AMN-107 was also effective against several imatinib-resistant Bcr-Abl mutants, but not T3151. In mice transduced with Bcr-Abl, AMN-107 reduced mortality and tumour burden. In mice transduced with the E255V imatinib-resistant mutant of Bcr-Abl, AMN-107 delayed the onset of leukaemia. As AMN-107 is more potent and more selective for Bcr-Abl than imatinib, it may represent a step forward in the treatment of CML, but further animal (and then clinical) studies are needed to test this.     

New tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia

Imatinib mesylate, Abl tyrosine kinase inhibitor, has improved the treatment of Bcr-Abl-positive leukemia such as chronic myeloid leukemia (CML) and Philadelphia chromosome positive acute lymphoblastic leukemia (Ph(+)ALL). However, resistance is often reported in patients with advanced-stage disease. Several novel tyrosine kinase inhibitors, which have been developed to override imatinib resistance mechanisms such as overexpression of Bcr-Abl and point mutations within the Abl kinase domain, are currently competing. Inhibitors of Abl tyrosine kinase are divided into two main groups, namely, ATP-competitive and ATP non-competitive inhibitors. Moreover, ATP-competitive inhibitors are fall into two subclasses, i.e. the Src/Abl inhibitors, and 2-phenylaminopyrimidin-based compounds. Dasatinib (formerly BMS-354825), AP23464, SKI-606 and PD166326 are classified as Src/Abl inhibitors while AMN107 and NS-187 (INNO-406) belong to the latter subclass of inhibitors. Among these agents, clinical studies on dasatinib and AMN107 had started earlier than the others and favorable results are accumulating. Clinical studies of other compounds including NS-187 (INNO-406) will be performed in rapid succession. Because of its strong affinity, most ATP competitive inhibitors may be effective against imatinib-resistant patients. However, to date, an ATP-competitive inhibitor that can inhibit the phosphorylation of T315I Bcr-Abl has not yet been developed. To address this problem, ATP non-competitive inhibitors such as ON012380, Aurora kinase inhibitor VX-680 and p38 MAP kinase inhibitor BIRB-796 have been developed. It may be necessary for the improvement of CML and Ph(+)ALL treatment to be taken into consideration of the combination therapy with novel ATP-competitive inhibitors and these agents.     

Rutin: therapeutic potential and recent advances in drug delivery

The Philadelphia (Ph) chromosome was the first consistent chromosome abnormality identified in cancer. It is found in 90% of patients with chronic myeloid leukaemia (CML) and in a subset of patients with acute lymphoblastic leukaemia. The effectiveness of the Bcr-Abl kinase inhibitor imatinib in these conditions reduces with advancing disease and/or the development of resistance to imatinib. AMN-107 inhibited the proliferation of haematopoietic cells expressing the mutants in Ph⁺ CML and acute lymphblastic leukaemia with concentrations causing 50% inhibition of ~ 12 nM, making it more potent than imatinib. AMN-107 was also effective against several imatinib-resistant Bcr-Abl mutants, but not T3151. In mice transduced with Bcr-Abl, AMN-107 reduced mortality and tumour burden. In mice transduced with the E255V imatinib-resistant mutant of Bcr-Abl, AMN-107 delayed the onset of leukaemia. As AMN-107 is more potent and more selective for Bcr-Abl than imatinib, it may represent a step forward in the treatment of CML, but further animal (and then clinical) studies are needed to test this.     

Cross-talk between Bcr-Abl tyrosine kinase, protein kinase C and telomerase-a potential reason for resistance to Glivec in chronic myelogenous leukaemia

To prevent the resistance to Glivec in patients with chronic myelogenous leukaemia (CML), it is necessary to get a good understanding of its potential mechanisms. The present hypothesis accents on the mechanisms whereby Bcr-Abl tyrosine kinase remains inhibited by Glivec, but alternative signalling pathways become activated-the potential reason associates with activation of telomerase after long-term treatment with Glivec and recovery of cell proliferation and immortality. The hypothesis is based on the observations about differences in telomere dynamics and telomerase activity between chronic and blast phases of CML patients, as well as about the potential effect of Glivec on the cross-talk between telomerase, Bcr-Abl tyrosine kinase and protein kinase C family-key enzymes in CML. It proceeds from recently published data, demonstrating that protein kinase C activates and c-Abl tyrosine kinase inhibits telomerase. During optimization of chemical structure, Glivec loose its effect on protein kinase C and enhances the effect on Bcr-Abl tyrosine kinase, resulting in a high potential to activate telomerase indirectly through its effect on both kinases. Experimental preclinical data are given in confirmation of this hypothesis.     

Dasatinib: a review of its use in the treatment of chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia

Dasatinib (Sprycel?) is an orally administered small molecule inhibitor of multiple tyrosine kinases, including BCR-ABL and SRC family kinases, which is indicated for the treatment of adults with newly diagnosed chronic-phase chronic myeloid leukaemia (CML), CML (chronic-, accelerated- or blast-phase) with resistance or intolerance to prior therapy, including imatinib, or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) with resistance or intolerance to prior therapy. Dasatinib is ≈325-fold more active than imatinib in inhibiting wild-type ABL kinase in vitro and is active against a wide variety of imatinib-resistant BCR-ABL mutants, except for T315I. This article reviews the efficacy and tolerability of dasatinib in the treatment of patients with newly diagnosed chronic-phase CML or imatinib-resistant or -intolerant CML or Ph+ ALL, as well as summarizing its pharmacological properties. In clinical trials, oral dasatinib was effective in achieving major or complete cytogenetic responses in both newly diagnosed and imatinib-resistant or -intolerant chronic-phase CML. Dasatinib was likewise effective in achieving major or overall haematological responses in imatinib-resistant or -intolerant, accelerated- or blast-phase CML, or Ph+ ALL. Responses were rapidly achieved within 1-3 months and were durable over 1-5 years of follow-up. The majority of adverse events with dasatinib were of mild to moderate severity. Fluid retention (including pleural effusion) was the most common adverse event. Haematological abnormalities were common and cytopenias were the most common grade 3/4 adverse events. Dasatinib 100?mg administered once daily was as effective as dasatinib 70?mg administered twice daily, and was better tolerated, being associated with lower incidences of pleural effusion and grade 3/4 thrombocytopenia, in particular. Dasatinib was more effective than high-dose imatinib in the treatment of patients with imatinib-resistant chronic-phase CML and was more effective than standard dosages of imatinib, as well as being associated with less frequent fluid retention, in patients with newly diagnosed chronic-phase CML. Dasatinib was generally equally effective in patients with or without BCR-ABL mutations at baseline. Therefore, oral dasatinib is a highly effective once-daily therapy for the first-line treatment of newly diagnosed patients with chronic-phase CML, as well as for the treatment of patients with imatinib-resistant or -intolerant chronic- and advanced-phase CML or Ph+ ALL.     

Preclinical and clinical profile of imatinib mesilate,a potent protein-tyrosine kinase inhibitor for CML therapy

Imatinib mesilate (Glivec) is a protein-tyrosine kinase inhibitor that potently inhibits the Bcr-Abl tyrosine kinase as well as the receptors for platelet-derived growth factor (PDGF) and stem cell factor (SCF), c-Kit, at in vitro and cellular kinase assay levels. Since Bcr-Abl tyrosine kinase plays a key role in chronic myelogenous leukemia (CML) patients, treatment with imatinib mesilate that potently inhibits Bcr-Abl tyrosine kinase could be a promising therapeutic approach to CML. Imatinib mesilate was shown to inhibit proliferation of bcr-abl-positive cell lines and suppress the formation of bcr-abl-positive colonies in cells derived from bone marrow of CML patients. This compound induced apoptosis in a variety of bcr-abl-positive cells. Moreover, in vivo data indicated that imatinib mesilate suppress growth and formation of bcr-abl-positive tumors in mice. As the profile expected from the preclinical studies, imatinib mesilate showed impressive hematological and cytogenic responses in the clinical trials, including interferon-alpha-resistant or intolerant patients.     

Drug evaluation: Nilotinib - a novel Bcr-Abl tyrosine kinase inhibitor for the treatment of chronic myelocytic leukemia and beyond

Chronic myelocytic leukemia (CML) is caused by the constitutively active tyrosine kinase Bcr-Abl. Inhibitors ofBcr-Abl have significantly improved the treatment of CML. Most notable is the inhibitor imatinib, which produces remissions in all phases of CML and is the current standard of care. However, imatinib resistance occurs in a significant proportion of patients, mainly through the development of mutations in the Bcr-Abl tyrosine kinase domain that impair imatinib binding. Attempts to circumvent resistance to imatinib led to the discovery of nilotinib (Tasigna; Novartis AG), a novel, potent and selective oral Bcr-Abl kinase inhibitor. Preclinical and clinical investigations have demonstrated that nilotinib effectively overcomes imatinib resistance. Efficacy has been observed in models of CML and other myeloproliferative disorders that are driven by Bcr-Abl and related kinases. In a phase II clinical trial in CML, major cytogenetic response rates were 52 and 33% for chronic- and accelerated-phase disease, respectively. Nilotinib has been filed for approval in the US and EU for use in Philadelphia-positive leukemias in patients who are resistant or intolerant to imatinib. Nilotinib is undergoing clinical trials in patients with newly diagnosed CML, acute lymphoblastic leukemia and gastrointestinal stromal tumors, among other indications.     

Tyrosine kinase inhibitors in acute and chronic leukemias

INTRODUCTION: Since the initial approval of imatinib much has been learned about its resistance mechanisms, and efforts have continued to improve upon BCR-ABL tyrosine kinase inhibitor therapy. Targeted therapy with TKIs has continued to be an area of active research and development in the care of acute and chronic leukemia patients. AREAS COVERED: This article reviews current approved and investigational TKI treatments for chronic myelogenous leukemia (CML), Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph + ALL) and acute myelogenous leukemia (AML). EXPERT OPINION: There are now more potent BCR-ABL TKIs approved, which allow for additional options when determining front-line and second-line CML and Ph + ALL treatments. The T315I mutation is an ever-present challenge. Ponatinib, a pan BCR-ABL TKI, while still under investigation, is very hopeful with its ability to overcome T315I mutations in resistant CML and Ph + ALL patients. Because nilotinib and dasatinib have not been directly compared, at present we recommend selecting one or the other based on the side-effect profile, drug interactions, patient comorbidities, and mutational status. FLT-3 inhibition is of particular interest in AML patients with FLT-3 internal tandem duplication mutations; this type of targeted therapy continues to be studied.     

Bafetinib, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor for the potential treatment of leukemia

Bafetinib (NS-187, INNO-406) is a second-generation tyrosine kinase inhibitor in development by CytRx under license from Nippon Shinyaku for treating Bcr-Abl+ leukemia's, including chronic myelogenous leukemia (CML) and Philadelphia+ acute lymphoblastic leukemia. It is a rationally developed tyrosine kinase inhibitor based on the chemical structure of imatinib, with modifications added to improve binding and potency against Bcr-Abl kinase. Besides Abl, bafetinib targets the Src family kinase Lyn, which has been associated with resistance to imatinib in CML. In preclinical studies, bafetinib was 25- to 55-fold more potent than imatinib in vitro and ≥ 10-fold more potent in vivo. Bafetinib inhibits 12 of the 13 most frequent imatinib-resistant Bcr-Abl point mutations, but not a Thr315Ile mutation. A small fraction of bafetinib crosses the blood-brain barrier, reaching brain concentrations adequate for suppression of Bcr-Abl+ cells. Data from a phase I clinical trial conducted in patients with imatinib-resistant or -intolerant CML have confirmed that bafetinib has clinical activity in this setting, inducing a major cytogenetic response in 19% of those patients in chronic phase. Currently, bafetinib is being developed in two phase II clinical trials for patients with B-cell chronic lymphocytic leukemia and prostate cancer, and a trial is in progress for patients with brain tumors.     

Roots of imatinib resistance: A question of self-renewal?

The BCR-ABL-fusion gene is critical for the development of chronic myeloid leukemia (CML) and BCR-ABL positive acute lymphatic leukemia (Ph+ ALL). Blocking BCR-ABL by the ABL tyrosine kinase inhibitor imatinib mesylate (IM, Gleevec) is clinically highly efficient. Treatment response is unfortunately compromised by the emergence of IM resistance, which is regularly seen in accelerated and blastic phase of CML (CML-AP/BP) and in Ph+ ALL. BCR-ABL kinase domain mutations are then considered the causative mechanism of IM resistance, because 50-60% of the IM resistant patients harbour such mutations. In contrast, IM resistance arises very rarely in patients that are treated with IM in early chronic phase of CML. This implies that BCR-ABL independent factors such as the cellular context of BCR-ABL expression and stage of disease decisively control the evolution of IM resistance. In line with this, novel Abl-kinase inhibitors such as dasatinib (DA) or nilotinib (NI) - although capable of inhibiting most of the BCR/-BL kinase mutants - still often fail to overcome resistance and do mostly not induce durable cytogenetic responses in IM resistant CML-AP/BC and Ph+ ALL patients. On the basis of available evidence it is proposed here that alternative genetic aberrations, which synergize with BCR-ABL to enable leukemic self-renewal are of causal importance for the evolution of clinical kinase inhibitor resistance. Kinase mutations may in turn reflect clonal variants of cells that emerge on the basis of an already existing IM resistant and self-renewing leukemic cell population. This model has clinical implications as it implies that even highly potent Abl-kinase inhibition can not target the genetic basis of IM resistance and will also not resolve the problem of Abl-kinase inhibitor resistance.