药物蛋白核苷酸多态性对靶向药物伊马替尼敏感性的影响

作为第一代酪氨酸激酶抑制剂（tyrosine kinase inhibitors,TKIs）,伊马替尼是临床上用于治疗慢性粒细胞白血病（chronicmyelogenous leukemia,CML）的一线药物。然而在临床治疗中,部分患者口服伊马替尼后疗效并不理想,出现伊马替尼耐药的情况。伊马替尼耐药机制比较复杂,除了TKIs的突变,国内外研究还发现ABC家族转运蛋白（ATP-binding cassette transporters,ABC）,有机阴离子转运体及有机阳离子转运体对伊马替尼药代动力学与药效学具有影响。本文主要从影响伊马替尼疗效的药物转运体基因多态性对伊马替尼治疗CML患者个体疗效差异予以综述,为进一步的临床研究提供参考依据。      

抑制Hedgehog信号通路可以阻止CML的进展

染色体易位是大多数慢性粒细胞白血病（CML）的主要发病机制，染色体易位导致断裂点簇集区（breakpoint cluster region。BCR）和酪氨酸激酶ABL1形成融合蛋白。酪氨酸激酶抑制剂伊马替尼（imatinib）可控制CML患者的病程，但是BCR—ABL1 T3151点突变的CML患者对伊马替尼等酪氨酸激酶抑制剂表现出耐药性。     

甲磺酸伊马替尼耐药机制及其逆转研究进展

甲磺酸伊马替尼作为针对bcr／abl的靶向治疗药物,因其良好的临床疗效而受到广泛关注。然而,随着甲磺酸伊马替尼临床应用范围的扩大和时间的推移,其耐药现象也逐渐显现,且多发生在慢性粒细胞白血病（CML）加速期或急变期的患者。所以,了解甲磺酸伊马替尼的耐药机制及寻找有效方案以防治耐药的发生,是目前研究的热点。在此就其耐药机制及当前防治耐药发生的策略作一综述。     

干扰素、亚砷酸联合酪氨酸激酶抑制剂治疗原发T315I突变慢性粒细胞白血病一例并文献复习

目的 探讨干扰素、亚砷酸联合酪氨酸激酶抑制剂(TKI)治疗原发T315I突变慢性粒细胞白血病(CML)的效果.方法 应用干扰素、亚砷酸联合TKI(伊马替尼)治疗1例原发T315I突变的CML患者,并进行文献复习.结果 CML加速期患者应用亚砷酸联合伊马替尼治疗1周后达完全血液学缓解;更换为干扰素联合尼洛替尼治疗6个月后,达部分细胞遗传学缓解,T315I突变消失.结论 干扰素、亚砷酸联合TKI可作为原发T315I突变CML的有效治疗手段.     

氟马替尼与伊马替尼治疗初诊慢性粒细胞白血病的有效性和安全性比较

目的：比较氟马替尼与伊马替尼治疗初诊慢性粒细胞白血病（CML）的有效性和安全性。方法采用多中心、随机、阳性药物平行对照的研究方法,对24例符合条件的初诊费城染色体阳性 CML慢性期（Ph+ CML-CP）患者给予6个周期（24周）的氟马替尼400 mg／d、600 mg／d 和伊马替尼治疗,分别在给药前及给药后2、4、6、8、10、12、16、20、24周进行血液学评价,给药前及给药后12、24周进行形态学、细胞遗传学和分子生物学评价。结果在有效性方面,治疗6个周期,氟马替尼600 mg／d 组的主要分子学缓解（MMR）率高于伊马替尼组,差异有统计学意义[44.44%（4／9）比14.29%（1／7）,P＝0.017]。治疗3个周期,氟马替尼600 mg／d 组 bcr-ablIS≤10%的患者比例高于伊马替尼组,差异有统计学意义（P＝0.002）;药代动力学／药效动力学分析也提示氟马替尼600 mg／d 较400 mg／d 更有可能使患者在早期获得分子学反应。在安全性方面,氟马替尼400 mg／d 组、氟马替尼600 mg／d 组和伊马替尼组Ⅲ～Ⅳ级不良事件的发生率差异无统计学意义（P＞0.05）。氟马替尼组较常见皮肤毒性和胃肠道反应,常见的不良事件为腹泻,未发生心脏和心血管系统不良反应,水肿的发生率低于伊马替尼组。结论氟马替尼可以安全有效地治疗初诊 Ph+ CML-CP 患者,600 mg／d 是一个较为合适的临床起始剂量。氟马替尼和伊马替尼在临床上具有相似的安全性。     

尼洛替尼一线治疗慢性髓系白血病的进展

慢性髓系白血病(CML)是一类骨髓增殖性肿瘤,其发病机制与BCR/ABL融合基因相关。酪氨酸激酶抑制剂(TKI)可显著改善CML患者的生存及预后。尼洛替尼一线治疗CML患者疗效显著、治疗反应快、缓解程度深并且安全性高。在获得持续深层分子反应后,实现停止尼洛替尼用药并达到无治疗缓解是CML治疗的新目标。此外,由于疾病耐药及突变的产生,尼洛替尼治疗失败后如何开始新的治疗值得进一步研究。     

不同基因型伊马替尼耐药的胃肠间质瘤二线靶向治疗选择

胃肠间质瘤（gastrointestinal stromal tumor ,GIST）是胃肠道最常见的间叶组织来源肿瘤。伊马替尼是转移或不可切除GIST的标准一线治疗药物。但随着临床应用时间的延长,伊马替尼耐药病例在逐渐增加。对于这组伊马替尼耐药的GIST患者二线如何选择合理的诊疗策略,是临床亟待解决的问题。目前,指南推荐二线可选择增加伊马替尼剂量和直接换用舒尼替尼治疗。针对患者个体时,是选择伊马替尼加量,还是直接换用舒尼替尼治疗,这是临床医生关注的焦点。该文对一线标准剂量伊马替尼治疗失败的不同基因型GIST患者二线靶向治疗选择进行综述。     

慢性粒细胞白血病患者血浆伊马替尼浓度检测与临床疗效分析

 目的　探讨慢性粒细胞白血病（CML）患者服用伊马替尼治疗后,伊马替尼血浆浓度在个体间的差异以及与临床疗效的关系。方法　2005年7月至2008年2月开始服用伊马替尼治疗的CML患者共51例纳入研究,其中男 34例,女 17例,服用剂量300 mg／d 9例、400 mg／d 37例,600 mg／d 5例;采用高效液相色谱法（HPLC）测定患者空腹伊马替尼血浆谷浓度;SPSS13.0软件进行统计分析。结果　伊马替尼血浆谷浓度与服用剂量有关,且个体之间差异较大,为（342～4688）ng／ml;300 mg／d剂量组的伊马替尼血浆谷浓度为（1037±514）ng／ml,低于400 mg／d剂量组的（2123±1016）ng／ml（t＝2.34,P＝0.032）;300 mg／d剂量组的治疗有效率为66.67 %（6／9）,低于400 mg／d剂量组的89.19 %（33／37）（χ2＝7.14,P＝0.008）;在300、400 mg／d剂量组中,39例治疗有效,伊马替尼血浆谷浓度高于治疗效果不理想患者,差异有统计学意义（t＝2.25,P＝0.037）;受试者工作特征曲线（ROC曲线）结果提示伊马替尼血浆谷浓度低于1050 ng／ml者,其临床疗效可能较差,敏感度为84.6 %,特异度为71.1 %。结论　CML患者服用伊马替尼治疗后药物血浆浓度与服用剂量有关,不同个体间差异较大,血浆谷浓度低于1050 ng／ml提示其临床疗效可能较差。     

bcr-abll激酶抑制剂耐药突变研究及治疗进展:第52届美国血液学年会的热点问题

伊马替尼（Imatinib）是人工设计的一种酪氨酸激酶抑制剂（tyrosine kinase inhibitor,TKI）,由于其出色的临床疗效,很快成为慢性粒细胞白血病（CML）的一线治疗药物。但伊马替尼仍不能很快根治CML,需要长期持续用药。不幸的是,许多患者应用不久后就出现了耐药现象。TKI耐药问题越来越被重视。在2010年12月在奥兰多召开的第52届美国血液学年会（Annual Meeting of American Society of Hematology,ASH）上,TKI耐药的研究是非常热门的话题。     

剂量爬坡法治疗酪氨酸激酶抑制剂不耐受慢性粒细胞白血病一例并文献复习

目的 探讨酪氨酸激酶抑制剂(TKI)治疗慢性粒细胞白血病(CML)不耐受患者的临床特征和治疗方案.方法 回顾性分析1例剂量爬坡法治疗TKI不耐受CML患者的临床资料,并复习相关文献.结果 TKI治疗CML不耐受患者,通过剂量爬坡法甲磺酸伊马替尼小剂量开始逐渐加量治疗可耐受.结论 剂量爬坡法治疗TKI不耐受CML患者有效且无明显血液学不良反应.     

Nilotinib as a second-line treatment for chronic myeloid leukemia

Chronic myeloid leukemia(CML)is a clonal disease of the hematopoietic stem cells that is characterized by excessive proliferation, but retains of the capacity for differentiation duringthe chronic phase of the disease. This phase is followed after 4-6 years by rapid progression, an accelerated phase, and consequently a fatal acute leukemia a blast crisis. The hallmark abnormality of CML is the Philadelphia chromosome that generates a BCR-ABL fusion gene, resulting in the expression of a leukemia-specific oncoprotein, Bcr-Abl. Bcr-Abl is a potent tyrosine kinase and plays a central role in CML pathogenesis. Recently, the treatment of CML has been revolutionized by the introduction of imatinib mesylate(IM). With daily IM treatment, more than 80% of chronic-phase CML patients achieve a complete cytogenetic response. Nevertheless, a small percentage of CML patients are primarily refractory or acquire secondary resistance against IM. Nilotinib is a highly selective Abl kinase inhibitor that possesses greater potency and selectivity for Abl kinase than IM. In addition to being more potent than IM against wild-type BCR-ABL, nilotinib is significantly active against many IM-resistant BCR-ABL mutants. In preclinical studies, nilotinib has produced hematologic and cytogenetic responses in CML patients, with either IM resistance or IM intolerance. As second-line treatment, both nilotinib and dasatinib may be used in case of suboptimal response or failure, which is defined in the efficacy criteria of the European Leukemia Net Consensus. The choice of second-generation tyrosine kinase inhibitors may be made after the mutation analyses of the kinase domain. It is recommended that nilotinib or dasatinib whichever was shown to be active against the specific mutation, should be chosen for treatment. For patients with no mutations or patients with IM intolerance, it is recommended that either second-generation tyrosine kinase inhibitor be chosen, based on the patient's disease history.     

Beyond dose escalation: clinical options for relapse or resistance in chronic myelogenous leukemia

The development of imatinib has changed the management of chronic myeloid leukemia (CML), producing high response rates in most patients. However, most individuals treated with imatinib, 400 mg, have residual molecular disease, and both intrinsic and acquired resistance can occur. The newer tyrosine kinase inhibitors, dasatinib and nilotinib, are effective in patients with imatinib-resistant CML, In patients with relapse or resistance, current guidelines recommend escalating the dose of imatinib or switching to new tyrosine kinase inhibitors. Dasatinib has been investigated in patients who were resistant or intolerant to imatinib. Switching to dasatinib, 70 mg, twice daily has been shown to be more effective than high-dose imatinib. Another study found that dasatinib, 100 mg, once daily was just as effective as the twice-daily regimen but was better tolerated. Nilotinib is also effective in most patients with resistance or intolerance to imatinib and is associated with minimal toxicity. Other inhibitors, such as bosutinib and INNO-406, are being developed with favorable early results. New drugs are still needed, particularly for individuals who are resistant to tyrosine kinase inhibitors or those with the T3151 mutation. Emerging CML therapies, some of which have different mechanisms of action from those of tyrosine kinase inhibitors, have shown promising results and could offer an alternative to these patients as monotherapy or in combination.     

Nilotinib: a phenylamino-pyrimidine derivative with activity against BCR-ABL, KIT and PDGFR kinases

The BCR-ABL kinase inhibitor imatinib mesylate is currently the standard therapy for patients with chronic myeloid leukemia (CML). However, mutations within the ABL kinase domain interfering with drug binding have been identified as the main mechanism of resistance to imatinib. Multiple distinct BCR-ABL kinase mutant isoforms conferring varying degrees of resistance to tyrosine kinase inhibitors have been reported. Nilotinib is a tyrosine kinase inhibitor 30-fold more potent than imatinib against BCR-ABL kinase. Nilotinib is active against a wide range of imatinib-resistant BCR-ABL mutant isoforms, except for T315I. Results from Phase II studies of nilotinib for patients with CML after failure or intolerance to imatinib therapy have shown a favorable toxicity profile and confirmed the high efficacy of nilotinib in this setting. Studies addressing the activity of nilotinib in newly-diagnosed patients with CML are underway. Furthermore, nilotinib is a potent inhibitor of KIT and PDGFR kinases. Here, we review the preclinical development of nilotinib and the activity of this agent in patients with CML and in tumors driven by KIT and/or PDGFR mutant kinases, such as gastrointestinal stromal tumors and some forms of clonal hypereosinophilia.     

Phase 1 study of tipifarnib in combination with imatinib for patients with chronic myelogenous leukemia in chronic phase after imatinib failure

BACKGROUND: The tolerability and efficacy of the combination of tipifarnib, an orally bioavailable nonpeptidomimetic farnesyl transferase inhibitor, and imatinib was investigated in patients with chronic myelogenous leukemia in chronic phase who had failed imatinib. METHODS: Twenty-six patients (13 [50%] with Abl kinase domain mutations) were treated. The initial dose level was tipifarnib at a dose of 300 mg twice daily and imatinib at a dose of 300 mg daily. Therapy was escalated following a '3 + 3' phase 1 design and the maximum tolerated dose was defined as tipifarnib at a dose of 400 mg twice daily and imatinib at a dose of 400 mg daily. Therapy was administered for a median of 26 weeks (range, 3-150 weeks). RESULTS: Adverse events included diarrhea in 21 patients (81%) and nausea in 18 patients (69%), but were generally grade 2 or less (using the revised National Cancer Institute Common Toxicity Criteria). Grade 3-4 neutropenia and thrombocytopenia occurred in 11 patients (42%) and 8 patients (31%), respectively. Sixteen patients discontinued therapy (5 due to toxicity and 11 due to lack of response or disease progression). Hematologic responses were attained by 17 (68%) of 25 assessable patients. Nine patients (36%) also achieved a cytogenetic response (3 complete responses, 4 partial responses, and 2 minimal responses), including 4 patients harboring mutant Bcr-Abl tyrosine kinases. One patient bearing the highly imatinib-resistant T315I mutant achieved a partial cytogenetic response. The median response duration was 3 months (range, 2-30+ months). CONCLUSIONS: The combination of tipifarnib and imatinib is well tolerated and has activity against several Abl kinase domain mutants. Combinations of tipifarnib with more potent tyrosine kinase inhibitors warrant further investigation.     

A Critical Review of Trials of First-Line BCR-ABL Inhibitor Treatment in Patients With Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase

BackgroundThe characteristic expression of the constitutively active oncoprotein, BCR-ABL tyrosine kinase, in chronic myeloid leukemia (CML) was the basis for the development of BCR-ABL tyrosine kinase inhibitors for treatment. Three BCR-ABL inhibitors, imatinib, nilotinib, and dasatinib, have been approved by the US Food and Drug Administration for first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP).MethodsThis article reviews the key phase III clinical trials supporting the use of first-line imatinib, nilotinib, and dasatinib in patients with CML-CP, as well as findings of supportive phase II studies.ResultsAt the time of its approval in 2001, imatinib induced unprecedented response rates in patients with CML-CP; however, resistance and intolerance to imatinib prevent 20% to 30% of patients from deriving full therapeutic benefit. Nilotinib and dasatinib, both approved in 2010 for first-line CML-CP treatment, are more potent than imatinib and less susceptible to imatinib resistance mechanisms. Comparative clinical trials of each agent with imatinib have shown that they are associated with significantly deeper and more rapid responses than standard-dose imatinib, without compromising safety.ConclusionsGiven that evidence suggests achievement of an early response is predictive of improved long-term outcomes, earlier use of these compounds may lead to more rapid, deeper responses corresponding with improvements in patient outcome. Although future studies will benefit from more uniform definitions of end points and methods of analysis, data from published studies of first-line BCR-ABL inhibitor treatment for patients with newly diagnosed CML-CP support the use of dasatinib or nilotinib in place of imatinib.     

Bcr-Abl kinase domain mutations and the unsettled problem of Bcr-AblT315I: looking into the future of controlling drug resistance in chronic myeloid leukemia

In 2006, most newly diagnosed patients with chronic myeloid leukemia (CML) underwent first-line, molecular-targeted therapy with the Bcr-Abl tyrosine kinase inhibitor, imatinib. The expectation was that the vast majority of these patients would exhibit a complete cytogenetic response on imatinib alone. Studies of patients with acquired imatinib resistance revealed that Bcr-Abl signaling is reactivated at the time of resistance, predominantly because of mutations that interfere with drug binding in the kinase domain of Bcr-Abl. The knowledge that Bcr-Abl remains the optimal target for treating imatinib-refractory CML has driven an already highly successful search for alternative approaches to restore target inhibition. Here, we review the current state of affairs in the realm of controlling drug resistance in CML, including cutting-edge strategies to reign in Bcr-AblT315I, which is cross resistant to imatinib, as well as the "next generation" Bcr-Abl inhibitors, nilotinib and dasatinib. We also critically assess the role of combined Abl kinase inhibitor therapy in overcoming resistance and provide recommendations for monitoring patients for kinase domain mutations.     

Activity and tolerability of nilotinib

BACKGROUND:

Nilotinib is active in imatinib‐resistant and ‐intolerant chronic myeloid leukemia patients and was recently approved for these indications.

METHODS:

Data on the efficacy and safety of nilotinib treatment were collected from 2 phase 2 expanded access clinical trials with similar designs (CAMN107AIL01 and ENACT).

RESULTS:

Of 88 study patients (58 chronic, 11 accelerated, 19 blast crisis), the best responses to nilotinib were complete hematologic response (CHR) in 27%, partial cytogenetic response in 12%, complete cytogenetic response in 14%, and major molecular response in 19%. Patients achieving at least a CHR during imatinib therapy were more likely to respond to nilotinib, and failure to achieve at least a CHR on imatinib therapy was predictive of progression or lack of response to nilotinib (P = .0021). Responses were not statistically different in subgroup analysis, including that of imatinib intolerance compared with imatinib resistance, presence of ABL kinase domain mutations compared with absence of mutations, and previous treatment with another second‐generation tyrosine kinase inhibitor compared no prior treatment. The overall survival and progression‐free survival rates at 1 year were 83% and 48% for the entire cohort, 93% and 66% in chronic phase, and 64% and 19% in advanced phase. Adverse hematological events included thrombocytopenia (all events, 27%; grade 3‐4, 13%) and leukopenia (all events, 18%; grade 3‐4, 10%). The majority of the nonhematological events were mild, the most common being rash, infection, bone pain, headache, nausea, and vomiting.

CONCLUSIONS:

Nilotinib treatment is an efficient and safe therapy for imatinib‐resistant or ‐intolerant patients. Prior response to imatinib therapy is a predictor for the response to nilotinib. Cancer 2010. © 2010 American Cancer Society.     

Chronic Myeloid Leukemia in the Tyrosine Kinase Inhibitor Era: What Is the “Best” Therapy?

The introduction of imatinib mesylate, a Bcr-Abl1 tyrosine kinase inhibitor (TKI), has revolutionized the treatment of chronic myeloid leukemia (CML). By directly targeting the Bcr-Abl kinase, imatinib leads to durable cytogenetic remissions and in turn improved survival. However, many patients with CML develop resistance, fail to respond, or become intolerant to imatinib due to side effects. This has spurred interest in developing second-generation TKIs to overcome the mechanisms of resistance that lead to treatment failure, specifically Bcr-Abl1 kinase domain mutations. Two second-generation TKIs, nilotinib and dasatinib, are approved for the treatment of CML after imatinib failure or intolerance. Unfortunately, many patients fail subsequent treatment with these agents, as they can develop highly resistant mutations such as T315I. Various other strategies are now in use to optimize the treatment of CML, including dose optimization of imatinib, combination therapy, upfront use of second-generation TKIs, and use of maintenance therapy with interferon-α and vaccines. This review highlights progress made in the treatment of CML in the past year.     

Optimal management of patients with newly diagnosed chronic phase chronic myeloid leukemia in 2007

Chronic myeloid leukemia cells contain a Bcr-Abl oncoprotein with an enhanced tyrosine kinase activity, which is considered to be the principal cause of the leukemia. The use of the first-generation tyrosine kinase inhibitor imatinib to inhibit the dysregulated kinase activity has proved remarkably successful, and imatinib as a single-agent is now considered to be the best initial treatment for the majority of adult patients in chronic phase. For patients who develop resistance to imatinib, the Bcr-Abl signaling pathway is often re-activated, second generation tyrosine kinase inhibitors, such as dasatinib or nilotinib, might restore the kinase inhibition. Allogeneic stem cell transplantation is now generally offered to older patients in whom imatinib therapy, and perhaps dasatinib or nilotinib also, have failed; efforts to establish firm criteria for the selection of second-line therapies after imatinib failure continue. At this time, children and younger adults should probably be considered for transplantation as first-line treatment.     

Practical Management of Toxicities Associated with Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia

The tyrosine kinase inhibitor (TKI) imatinib constitutes the current first-line therapeutic approach for patients with chronic myeloid leukemia. The success of imatinib relies on its potent inhibitory activity against the Bcr-Abl kinase that drives the pathogenesis of this disorder. The vast majority of patients treated with imatinib as a single agent will achieve a complete cytogenetic response. However, a subset of patients will develop imatinib resistance, frequently associated with mutations within the Abl kinase domain. In this setting, treatment with the second-generation TKIs nilotinib and dasatinib has proved highly efficacious. While therapy with these Bcr-Abl TKIs is generally well tolerated, adverse events are common and can result in treatment interruptions that compromise clinical responses. Herein, we discuss some of the toxicities characteristically associated with TKI therapy and provide practical approaches to the clinical management of these adverse effects.