伊马替尼治疗常规化学治疗失败的进展期慢性粒细胞白血病21例

目的:观察伊马替尼治疗常规化学治疗(化疗)失败的进展期慢性粒细胞白血病(CML)的有效性及不良反应。方法:21例病人在常规化疗无效后服用伊马替尼,其中加速期4例,急变期17例,起始剂量400 mg·d~(-1),无明显不良反应后改为600 mg·d~(-1)。结果:所有病人服用伊马替尼后,白细胞、血小板及幼稚细胞均明显下降,与服药前比较差异非常显著(P<0.01)。除1例因败血症死亡,2例病人骨髓部分缓解外,其余病人服药后7～45d均达到血液学完全缓解。伊马替尼对白细胞影响较明显,部分病人出现恶心、呕吐等消化道症状及眼睑水肿、肌痛等不良反应。结论:伊马替尼治疗常规化疗失败的难治性CML有较高的血液学缓解率,服用方便,效果好,不良反应轻。     

伊马替尼治疗慢性粒细胞白血病期间血药浓度与临床疗效相关性分析

目的 探讨伊马替尼治疗慢性粒细胞白血病期间血药浓度与临床疗效相关性.方法 108例慢性粒细胞白血病患者均行伊马替尼治疗,观察患者的遗传学疗效及分子生物学疗效,并检测治疗期间患者的伊马替尼血药浓度,分析其与疗效之间的相关性.结果 获得遗传学缓解组患者伊马替尼的血浆谷浓度为( 1659.64±129.67) μg/L,显著高于未获得组的(794.51±93.62) μg/L(t =9.38,P＜0.05);获得分子生物学缓解组患者伊马替尼的血浆谷浓度为(1618.46±141.32)μg/L,显著高于未获得组的(904.78±80.77) μg/L(t=11.25,P＜0.05).治疗期间患者的伊马替尼血药浓度与遗传学疗效、分子生物学疗效之间的相关系数分别为0.235(P ＜0.05)及0.266(P ＜0.05).结论 伊马替尼治疗慢性粒细胞白血病期间血药浓度与临床疗效有一定相关性,监测伊马替尼血药浓度对判断患者病情及治疗效果有指导意义.     

伊马替尼治疗慢性粒细胞性白血病致严重皮肤损害一例

甲磺酸伊马替尼是一种酪氨酸激酶抑制剂,通过阻滞BCR-ABL磷酸化,选择性抑制其下游信号传导及BCR-ABL阳性细胞生长,从而诱导该类细胞凋亡[1].     

伊马替尼治疗慢性粒细胞性白血病致严重皮肤损害一例

甲磺酸伊马替尼是一种酪氨酸激酶抑制剂,通过阻滞BCR-ABL磷酸化,选择性抑制其下游信号传导及BCR-ABL阳性细胞生长,从而诱导该类细胞凋亡[1].     

伊马替尼治疗Ph染色体阳性慢性粒细胞白血病的临床观察

目的:评价酪氨酸激酶抑制剂伊马替尼治疗Ph染色体阳性慢性粒细胞白血病的有效性及安全性。方法:90例慢性粒细胞白血病患者,其中慢性期67例,非慢性期23例(加速期14例,急变期9例),每天应用剂量分别为400,600mg。每周复查血常规,每3个月进行骨髓象及细胞遗传学检查,根据血象和骨髓象调整剂量。结果:观察截止时,84例(93.3%)获得血液学完全缓解;68例可评价遗传学效应,35例(51.5%)发生主要遗传学效应(慢性期30例,加速期3例,急变期2例),其中31例(88.6%)为遗传学完全缓解(慢性期27例,加速期2例,急变期2例)。11例(12.2%)患者发生严重白细胞和/或血小板减少,但可通过调整剂量控制。严重非血液学不良反应发生较少。结论:伊马替尼治疗Ph染色体阳性慢性粒细胞白血病患者疗效较好,可获得较高的完全血液学缓解率和主要细胞遗传学缓解率,起效迅速,且不良反应较少,可耐受或自行消失。     

达沙替尼治疗伊马替尼耐药慢性粒细胞白血病效果

目的:探讨达沙替尼治疗伊马替尼耐药慢性粒细胞白血病效果.方法:选择2013年6月—2016年1月收治的伊马替尼耐药慢性粒细胞白血病患者40例,随机分为对照组和观察组各20例,对照组采用羟基脲和干扰素治疗,观察组采用达沙替尼治疗,对比分析两组疗效及不良反应.结果:观察组达到完全细胞遗传学反应时间为(4.1±1.4)个月,短于对照组的(5.9±2.2)个月,且持续时间为(16.7±1.9)个月,对照组为(14.4±2.1)个月,组间差异有统计学意义(P<0.05).观察组缓解率为80.0％(16/20),对照组为35.0％(7/20),组间差异有统计学意义(P<0.05).观察组不良反应发生率为20.0％(4/20),低于对照组的35.0％(7/20,P<0.05).结论:达沙替尼治疗伊马替尼耐药慢性粒细胞白血病效果显著,且起效快、不良反应少,值得推广.     

伊马替尼耐药慢性粒细胞白血病治疗进展

异基因造血干细胞移植目前尚不能在临床广泛应用.在过去的25年间,肿瘤治疗领域最具代表性的进展之一即为伊马替尼成为临床广泛使用的CML一线治疗药物.对伊马替尼耐药的CML者可考虑选择达沙替尼、高剂量伊马替尼、异基因造血干细胞移植、干扰素以及第二代酪氨酸激酶(ABL)抑制剂的联合治疗.     

伊马替尼联合三氧化二砷治疗进展期慢性粒细胞性白血病疗效观察

目的观察伊马替尼联合三氧化二砷治疗慢性粒细胞性白血病（CML）进展期的疗效和安全性。方法20例CML患者均予伊马替尼联合三氧化二砷治疗,常规体检,用药后血液学取得完全缓解后择期复查骨髓、Ph染色体和（或）bcr／abl基因。结果随访结束时,血液学完全缓解率20％（4／20）,部分缓解率25％（5／20）,总有效率45％,绝大多数为轻度不良反应,多可耐受。结论伊马替尼联合三氧化二砷治疗进展期CML有效、安全,但远期疗效需进一步观察。     

伊马替尼治疗不同时期慢性粒细胞白血病的疗效对比

目的 研究伊马替尼治疗不同时期慢性粒细胞白血病(CML)的临床疗效.方法 选取28例早期慢性粒细胞白血病患者作为观察组,另选取28例晚期慢性粒细胞白血病患者作为参照组.两组均采用伊马替尼治疗,观察比较两组患者的治疗效果及不良反应发生率.结果 观察组患者治疗总有效率96.43％ 高于参照组的75.00％,差异具有统计学意...     

伊马替尼治疗慢性粒细胞白血病急变期的疗效观察

目的 探讨伊马替尼治疗慢性粒细胞白血病急变期的疗效.方法 2005年2月至2010年2月收治慢性粒细胞白血病急变期患者148例,依据治疗方法不同分为伊马替尼组78例,常规治疗组70例,观察两组临床疗效.结果 伊马替尼组总有效率51.28 %,常规治疗组总有效率12.85%,两组总有效率比较P<0.01有显著差异性.结论 应用伊马替尼治疗慢性粒细胞白血病急变期能够取得近期良好的临床效果用药方便,毒性反应轻微,明显延长患者生命,改善患者生活质量.     

伊马替尼治疗慢性髓细胞白血病慢性期临床疗效观察

目的：分析甲磺酸伊马替尼（IM）治疗慢性髓系白血病（CML）慢性期的临床疗效及影响疗效的因素。方法随访观察74例 CML 慢性期患者,IM中位治疗剂量为400（200～600）mg·d －1,评估其临床疗效,总生存时间和疾病无进展生存时间,并对相关疗效影响因素进行分析。结果中位随访时间为20（6～72）个月,累积达到血液学缓解（CHR）为98．6％,血液学中位缓解时间1（1～3）月;63例（85．1％）达到主要细胞遗传学缓解（MCyR）,中位达 MCyR 时间为9（5～24）个月;53例（71．6％）达完全细胞遗传学缓解（CCyR）,41例（55．4％）达到主要分子生物学缓解（MMR）;6例（8．1％）达到完全分子生物学缓解（CMR）;初治组及复治组应用 IM治疗后 CHR 及 MCyR 差异无统计学意义,但 CCyR 及 MMR 差异均有统计学意义（P ＜0．016）;由 EUTOS 评分区分的低危组与高危组应用 IM治疗后 CHR 差异无统计学意义,但 MCyR、CCyR 及 MMR 差异均有统计学意义（P ＜0．020）;其中初治组与复治组及 EUTOS 评分低危组与高危组 OS 差异无统计学意义,但其 PFS 差异均有统计学意义（P 分别为0．021和0．004）。结论IM用于 CML 慢性期患者治疗可获得极高的血液学缓解率和较高细胞遗传学缓解率,不良反应少,提高了患者生存质量,延长患者的生存时间;在 CML 确诊早期应用可提高疗效,IM治疗前时间大于6个月或EUTOS 评分高危组可影响 IM疗效。     

伊马替尼与干扰素联合治疗慢性粒细胞白血病的疗效分析

目的:探讨伊马替尼与干扰素联合化疗治疗慢性粒细胞白血病(CM L)的疗效。方法:2004年6月—2009年7月新诊断的58例Ph染色体阳性CM L慢性期患者,随机分为伊马替尼组和干扰素联合化疗组,比较两组临床疗效。结果:两组总有效率差异无统计学意义(P>0.05);伊马替尼组完全血液学缓解率,完全细胞遗传学缓解率、完全分子学效应率、5年总生存率均明显高于干扰素联合化疗组(P<0.05)。结论:伊马替尼和干扰素联合化疗都可作为CM L慢性期的有效治疗方法,应依据不同情况实施个体化治疗。     

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。     

Some 2-[4-(1H-benzimidazol-1-yl) phenyl]-1H-benzimidazole derivatives overcome imatinib resistance by induction of apoptosis and reduction of P-glycoprotein activity

Imatinib (IMA) is a tyrosine kinase inhibitor (TKI) introduced for the chronic myeloid leukemia (CML) therapy. Emergence of IMA resistance leads to the relapse and failure in CML therapy. Benzimidazole is a heterocyclic organic compound which is widely investigated for the development of anticancer drugs. In this study, we aimed to explore the anticancer effects of some 2-[4-(1H-benzimidazol-1-yl) phenyl]-1H-benzimidazole derivatives on K562S (IMA-sensitive) and K562R (IMA-resistant) cells. To analyze the cytotoxic and apoptotic effects of the compounds, K562S, K562R, and L929 cells were exposed to increasing concentrations of the derivatives. Cytotoxic effects of compounds on cell viability were analyzed with MTT assay. Apoptosis induction, caspase3/7 activity were investigated with flow cytometry and BAX, BIM, and BAD genes expression levels were analyzed with qRT-PCR. Rhodamine123 (Rho-123) staining assays were carried out to evaluate the effect of compounds on P-glycoprotein (P-gp) activity. The hit compounds were screened using molecular docking, and the binding preference of each compounds to BCR-ABL protein was evaluated. Our results indicated that compounds triggered cytotoxicity, caspase3/7 activation in K562S and K562R cells. Rho-123 staining showed that compounds inhibited P-gp activity in K562R cells. Overall, our results reveal some benzimidazole derivatives as potential anticancer agents to overcome IMA resistance in CML.     

大剂量伊马替尼、达沙替尼和尼洛替尼治疗慢性髓性白血病的成本效用分析

目的：分析大剂量伊马替尼、达沙替尼和尼洛替尼治疗对标准剂量伊马替尼耐药的慢性髓性白血病患者的成本效用。方法：计算三种治疗方案下患者的效用和花费的成本,在马尔可夫模型（Markov）中以3个月为周期进行5年的模拟并对结果做成本效用比较。结果：尼洛替尼治疗方案累计成本为1 595 289.10元,健康效用为1.276 4质量调整生命年（QALYs）,相比于尼洛替尼,大剂量伊马替尼组的增量成本效用比（ICUR）为-22 759 433.08（￥/QALYs）,达沙替尼组为-30 960 469.51（￥/QALYs）。结论：尼洛替尼方案累计成本最低且获得最多的QALYs,为绝对优势方案。     

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。     

Dasatinib: the emerging evidence of its potential in the treatment of chronic myeloid leukemia

INTRODUCTION: Current therapy options for chronic myeloid leukemia (CML) include conventional chemotherapy, allogeneic stem cell transplant, interferon-alfa, and imatinib mesylate, which has recently achieved gold standard status. Although the majority of patients initially respond well to treatment with imatinib, wider clinical experience with this drug has resulted in the development of imatinib resistance being increasingly documented. There is therefore an unmet medical need for novel therapies to override imatinib resistance in CML. AIMS: This review summarizes the emerging evidence for the potential use of dasatinib in the treatment of imatinib-resistant CML. DISEASE AND TREATMENT: Dasatinib is a novel small molecule that has shown potent antileukemic activity in imatinib-resistant cell lines, malignant marrow cells isolated from patients with imatinib-resistant CML, and in mouse xenograft models of imatinib-resistant CML. Preliminary data from an initial phase I dose escalation trial have been encouraging, indicating that dasatinib is generally well tolerated and produces hematologic and cytogenetic responses in patients with imatinib-resistant CML in all phases of the disease. The maximum tolerated dose (MTD) has not yet been reached, and dose escalation continues to determine the dose range that yields optimal results. PROFILE: Although dasatinib is still in the early stages of development, the potential impact of this molecule on the treatment of CML could be revolutionary, not only providing a much needed treatment option for patients with imatinib-resistant CML, but also, combined with imatinib, could possibly prove useful in delaying the onset of resistance to treatment. Furthermore, combined with other agents active in CML, dasatinib could have potential utility in purging residual leukemic cells in patients whose disease is controlled by imatinib.     

Nilotinib for the treatment of Philadelphia-chromosome-positive chronic myeloid leukemia

Importance of the field: Although the introduction of imatinib revolutionized the management of chronic myeloid leukemia (CML), some patients exhibit resistance or intolerance to the drug. Nilotinib induces high and rapid rates of cytogenetic and molecular responses. With recent approval for newly diagnosed patients with chronic phase CML, the current algorithm for treatment will probably be transformed.

Areas covered in this review: This review will describe evaluations of nilotinib in all phases of CML from 1995 to the present. Early preclinical data and Phase I, Phase II and Phase III evaluations will demonstrate the role of nilotinib in newly diagnosed CML, as well as in imatinib-resistant or imatinib-intolerant disease.

What the reader will gain: Mutations in the BCR-ABL kinase domain are responsible for the majority of resistance to imatinib. In comparison with imatinib, nilotinib displays increased selectivity and potency at inhibiting proliferation of BCR-ABL expressing cells. Although several mutations, including T315I, remain resistant to nilotinib, activity in all phases of CML has been reported.

Take home message: Nilotinib induces high and rapid rates of cytogenetic and molecular response, with less progression to advanced forms of disease compared with imatinib. Considering that the rapid achievement of these clinical milestones has been associated with positive long-term outcomes, nilotinib as initial therapy in patients with CML in chronic phase represents the future in CML treatment. Longer follow-up is necessary to recognize survival advantages.     

早幼粒细胞白血病蛋白在髓系白血病中的表达及其对慢性粒细胞白血病增殖的影响分析

目的 探讨早幼粒细胞白血病(PML)蛋白在髓系白血病中的表达情况及其对慢性粒细胞白血病细胞增殖的抑制作用.方法 收集髓系白血病患者(髓系白血病组)60例,非肿瘤性血液病患者(对照组)15例,患者骨髓制备石蜡切片,采用免疫荧光技术观察PML在细胞内的分布和表达;提取骨髓单核细胞总RNA,采用逆转录聚合酶链反应观察PML mRNA的表达情况;提取骨髓总蛋白,采用蛋白质印迹法(Western Blot)观察PML蛋白的表达情况;K562细胞分别转染空质粒(MSCV组)、截短失活PML(DN组)和野生型PML(Wt组),测定PML基因对K562细胞增殖和集落产生的影响.结果 非肿瘤性血液病患者的PML表达聚集在细胞核内,而髓系白血病患者的PML分散表达在细胞核和胞质内;髓系白血病组PML mRNA水平0.356±0.092显著低于对照组的表达0.536±0.066(t=7.11,P<0.01);髓系白血病组PML蛋白相对表达水平0.189±0.032显著低于对照组0.323±0.025(t=16.10,P<0.01);DN(转染截短失活PML)组,MSCV(转染空质粒)组和Wt(转染野生型PML)组在450 nm波长下吸光度值(Optical Density450,OD450)和集落生成单位(Colony-Forming Units,CFU)的数据均差异有统计学意义(F=34.28,25.39,P<0.05),q检验结果显示,均为Wt组的数值低于DN组和MSCV组.结论 髓系白血病患者中PML蛋白表达水平下降导致细胞异常增殖可能是其发病机制.