高三尖杉酯碱治疗慢性粒细胞白血病

 　目的　研究高三尖杉酯碱（HHT）治疗慢性粒细胞白血病（CML）的疗效及安全性。方法　12例初诊CML患者,HHT 2.5 mg·m-2·d-1,静脉滴注维持6 h以上,持续14 ~ 21 d为 1个疗程。有效者每月HHT维持治疗,并以外周血中性粒细胞绝对值≥1.0×109／L、血小板≥40×109／L调整用药时间,一般用药5～14 d。每3个月或3个疗程后复查染色体。6个月后以羟基脲（Hu）维持治疗。结果　12例患者中,7例（58.3 %）获血液学完全缓解（CHR）,3个疗程后,总的细胞遗传学反应率50 %（3例CCR,3例MCR）;另5例（41.7 %）在治疗3个月内进入加速期或急变期（4例发生在HHT 1个疗程后）。12例患者中有6例出现严重骨髓抑制,均发生于CHR者。结论　HHT治疗CML-CP,可获得较高的血液学和细胞遗传学缓解率,但也可能早期进入加速期或急变期。     

酪氨酸激酶抑制剂联合高三尖杉酯碱对慢性粒细胞白血病细胞系K562的影响

目的:探索伊马替尼（IM）、尼罗替尼（NL）这两种药物分别与高三尖杉酯碱（HHT）联合应用对慢性粒细胞白血病（CML）细胞系K562增殖、凋亡以及BCR-ABL癌蛋白表达的影响。方法:实验分为十个组,分别为:不加药对照组、IM单药组、NL单药组、HHT单药组、先HHT后IM组(HHT-IM)、先IM后HHT组(IM-HHT)、先HHT后NL组(HHT-NL)、先NL后HHT组(NL-HHT)、IM与HHT共同作用组(IM+HHT)、NL与HHT共同作用组(NL+HHT)。应用CCK-8法检测各组K562细胞的增殖抑制率,Annexin V/PI双染流式细胞术检测各组细胞凋亡率,Western blot检测各组BCR-ABL癌蛋白表达。结果:各实验组凋亡率均较对照组升高。其中,IM+HHT组细胞凋亡率明显高于其他各组,HHT-IM组次之,而IM-HHT组凋亡率与单药组差别不大。进一步研究发现,IM+HHT组BCR-ABL蛋白的表达明显减少,HHT-IM次之,而HHT单药组、IM-HHT组BCR-ABL蛋白减少的并不明显。NL+HHT组趋势与之一致。结论:酪氨酸激酶抑制剂（TKI）与HHT多种联合用药方案可以促进CML细胞凋亡并下调BCR-ABL癌蛋白表达。其中TKI与HHT同时用药效果最佳,先HHT作用后TKI序贯治疗效果次之。     

伊马替尼治疗慢性粒细胞白血病的远期疗效观察

目的探讨伊马替尼治疗慢性粒细胞白血病(CML)的长期疗效及影响CML患者生存的因素。方法对66例CML患者应用伊马替尼治疗,检测血常规、染色体核型、bcr/abl转录本表达及不良反应情况。结果中位随访39(6～84)个月。CML慢性期患者完全血液学缓解(CHR)率为95.8%,主要细胞遗传学缓解(MCyR)率为75.0%,完全细胞遗传学缓解(CCyR)率为68.8%,完全分子学缓解(CM0R)率为41.7%,均显著高于加速期及急变期(P<0.01)。慢性期患者3、5和7年总生存(OS)率分别为95.3%、90.3%和87.5%,疾病无进展生存(PFS)率分别为91.6%、84.5%和81.3%;加速期患者1、2和3年OS率分别为90.5%、37.6%和37.6%;1、2和3年的预期PFS率分别为37.2%、28.4%和17.6%;急变期患者6、12、18个月的预期OS率分别为83.6%、32.3%和32.3%。慢性期患者与加速期、急变期患者OS及PFS比较差异有统计学意义(P<0.01);多因素分析结果显示,应用伊马替尼治疗前接受过其他治疗是影响PFS的不利因素。结论伊马替尼对CML慢性期疗效显著优于加速期及急变期;慢性期患者达到CCyR甚至CM0R,是获得长期生存的关键。     

伊马替尼治疗慢性粒细胞白血病135例远期疗效观察

  目的　对伊马替尼治疗慢性粒细胞白血病（CML）的疗效及安全性进行分析,并初步探讨影响CML患者生存的因素。方法　135例CML患者应用伊马替尼治疗,监测其血常规、染色体核型、bcr-abl p210转录本表达及不良反应。结果　中位随访20（3～67）个月。慢性期患者累积获得的完全血液学缓解（CHR）率为97.9 ％,主要细胞遗传学缓解（MCyR）率为78.3 ％,完全细胞遗传学缓解（CCyR）率为72.2 ％,完全分子学缓解（CMoR）率为35.1 %,均显著高于加速期及急变期（P ＜0.001）。慢性期低危组与高危组之间CCyR率有差异（P＝0.048）。慢性期患者1、3和5年总生存（OS）率分别为：（97.8±1.5）%、（95.2±2.4）%、（91.9±3.2）%,疾病无进展生存（PFS）率分别为（92.6±2.7）%、（85.5±3.7）%、（81.3±4.3）%;加速期患者6个月、1、2年OS率分别为：（93.8±6.1）%、（72.5±11.8）%、（64.5±12.9）%,PFS率分别为：（92.3±7.4）%、（64.5±14.7）%、（53.7±15.7）%;急变期患者6、12、19个月OS率分别为：（86.4±7.3）%、（45.4±11.4）%、（19.4±9.8）%,PFS率分别为：（70.1±12.6）%、（37.6±15.6）%、（18.8±15.4）%。慢性期达到CMoR、CCyR的患者与仅达CHR者 PFS及OS比较差异均有统计学意义（P ≤0.001）;多因素分析显示：耐药是影响慢性期患者PFS（P＝0.000,RR＝46.744）及OS（P＝0.007,RR＝20.270）的因素。伊马替尼口服非血液学毒性较轻,患者多可耐受;血液学毒性是减量或停药的主要原因。结论　伊马替尼治疗CML慢性期疗效显著优于加速期及急变期;慢性期患者达到CCyR甚至CMoR是获得长期生存的关键,伊马替尼耐药是伊马替尼治疗CML面临的主要问题。     

高三尖杉酯碱联合干扰素治疗慢性粒细胞白血病疗效分析

ph+慢性粒细胞白血病(CML)目前无条件进行异基因骨髓移植者,治疗大多仅为完全血液学缓解(CHR),个别有细胞遗传学反应,如何提高CML的疗效,延长缓解期仍然是治疗的难点.我科从2000年3月以来,开始应用高三尖杉酯碱(HHT)联合干扰素(IFN-α2b),统计结果显示,二药联合使用有良好的细胞遗传学反应,毒副作用轻微,现报告如下.     

高三尖杉酯碱治疗慢性期慢性粒细胞白血病41例的长期疗效

目的 研究小剂量长疗程高三尖杉酯碱(LD-HHT),对慢性粒细胞白血病慢性期(CMI-CP)完全血液学缓解(CHR)及疾病无进展长期生存的影响.方法 对2002年5月前我院确诊的CML-CP患者41例,行肌肉注射或静脉滴注给药:HHT 1 mg/d持续8周,2 mg/d持续4周,间歇4～5周,再进行下1个疗程,并作为维持治疗方案.血象分类中有原粒、早幼粒细胞者:WBC升至4.0×109/L左右给药,降至1.2×109/L时停药,不受间歇期限制.结果 连续LD-HHT长疗程治疗4年,于2006年5月间统计时,39例无疾病进展生存5年(95%),2例急变(5%).其中27例达CHR(66%),12例仍在CMI-CP(29%).结论 LD-HHT长疗程治疗能显著延长CML的慢性期,提高患者血液学缓解率.     

达沙替尼与伊马替尼治疗慢性粒细胞白血病慢性期患者效果的Meta分析

目的 比较达沙替尼和伊马替尼治疗慢性粒细胞白血病慢性期(CML-CP)患者的效果.方法 通过计算机检索Cochrane图书馆、OVID数据库、Embase数据库、PubMed数据库、中国期刊全文数据库(CNKI)、Springer Link数据库、万方数据库、维普数据库,并进一步对纳入文献的参考文献扩大检索.对纳入的随机对照研究采用Cochrane风险偏倚评估工具进行质量评价.采用RevMan 5.1软件进行统计学分析.结果 共纳入5篇文献,CML-CP患者2 031例.Meta分析结果显示,达沙替尼组12个月完全细胞遗传学反应(CCyR)率高于伊马替尼组[83.6％(478/572)比70.6％(406/575),合并比值比(OR)=2.11,95％CI 1.59～2.80,P＜0.05];达沙替尼组12个月主要分子生物学反应(MMR)率高于伊马替尼组[49.3％(296/600)比30.6％(185/605),OR=2.22,95％CI 1.75 ～ 2.82,P＜0.05].结论 达沙替尼可以提高CML-CP患者12个月的CCyR率和MMR率.     

伊马替尼联合粒细胞集落刺激因子治疗慢性粒细胞白血病11例

 目的　研究伊马替尼（IM）联合粒细胞集落刺激因子（G-CSF）降低单药IM疗效欠佳的慢性粒细胞白血病（CML）残留病的疗效。方法　采用IM联合G-CSF治疗11例IM治疗后Ph染色体转阴率≥35 %的CML患者。起始治疗量为IM 400或600 mg／d,G-CSF 5 μg?kg-1?d-1,皮下注射。白细胞计数≥30×109／L者,延迟或间断使用G-CSF直至白细胞＜20×109／L。治疗过程中定期检测外周血bcr-abl转录水平,治疗6个月后转录水平降低未超过0.5个对数（log）者,停用G-CSF。bcr-abl转录水平持续下降但仍未获得完全分子生物学缓解者,继续使用该方案治疗1～6个月。结果　11例患者中9例出现bcr-abl转录水平的明显下降（包括7例下降＞1个对数和2例下降＞0.5个对数）,2例出现bcr-abl转录水平的下降小于0.5个对数。7例下降＞1个对数者,其中2例获得完全分子生物学缓解,5例原为部分细胞遗传学缓解的患者获得完全细胞遗传学缓解。所有患者均能耐受,未出现因不良反应中断治疗和治疗相关性死亡病例。结论　IM联合G-CSF方案治疗单药IM治疗反应欠佳的CML患者有效、安全。     

尼洛替尼与伊马替尼治疗初诊慢性髓性白血病慢性期的疗效对比

目的 研究比较临床上使用尼洛替尼与伊马替尼治疗初诊慢性髓性白血病慢性期的疗效.方法 回顾性选取初诊慢性髓性白血病慢性期患者60例,按给药方式分为对照组和观察组,各30例.观察组采用尼洛替尼治疗,1次/日,每次300 mg;对照组采用伊马替尼,1次/日,每次400 mg,连续治疗1年.比较观察组与对照组血液学缓解率、细胞...     

伊马替尼联合造血干细胞移植治疗慢性粒细胞白血病

 目的 研究伊马替尼（商品名：格列卫）对异基因造血干细胞移植（allo-HSCT）和自体外周血造血干细胞移植（APBSCT）的影响。方法 18例慢性粒细胞白血病（CML）分为2组：①al-lo-HSCT组14例,其中10例为CML加速期（AP）和急变期（BP）,4例为CML慢性期（CP）,移植之前格列卫疗程中位数为25（7～60）d,供受者HLA完全相合,亲缘相关供者9例、非亲缘供者5例,预处理方案为TBI+Cy+VP16或Bu／Cy±ATG,GVHD预防按常规方案进行;②APBSC动员4例,均为CML-CP患者,格列卫治疗的中位数疗程5.5（4～26）个月,动员前反复IFISH-bcr／abl阳性率0～2%,动员方案CAE+G-CSF,其中3例经TBI+Cy+VP16预处理后进行了APBSCT。结果 4例患者经G-CSF动员第5天分离自体外周血干细胞（APBSC）1次,得CD+34细胞的中位数6.8（3.9～9.6）×106／kg,动员产品中IFISH-bcr／abl阳性细胞比例高于动员前骨髓细胞（2.8 %∶0.8 %）,4例动员PBSC的患者中3例进行了APBSCT,移植后随访中位时间24（18～28）个月,2例复发,1例持续IFISH-bcr／abl阴性。14例allo-HSCT患者中位随访8（4～20）个月,造血重建需要8～21 d,发生GVHD 8例,白血病复发2例,移植相关并发症死亡2例,复发死亡1例,无病生存9例。结论 格列卫治疗后对CML患者造血干细胞的动员、移植结果无明显影响。     

两种慢性髓系白血病细胞株对干扰素-α的敏感性

背景和目的：临床研究表明干扰素-α(interferon-alpha,IFN-α)是造血系统恶性肿瘤和淋巴瘤的有效治疗剂之一。然而,IFN-α仅可使约70％～80％的慢性髓系白血病(chronic myeloid leukemia,CML)患者获得血液学缓解。不同的CML患者对IFN-α反应性不同的机制尚未阐明。本研究旨在比较两种CML细胞株KA-1／A3、K562对IFN-α的不同敏感性。方法：(1)采用MTT、半固体集落形成和台盼蓝染色液体培养细胞检测,不同浓度IFN-α(100、500、1000、5000和10000u／ml)对KT-1／A3及K562细胞生长的影响;(2)IFN-α(1000u／ml)诱导KT-1／A3、K562细胞48h后,采用流式细胞分析(flow cytometry,FCM)、荧光染色和DNA片段检测细胞凋亡;(3)加入IFN-α(1000u／m1)培养KT-1／A3、K562细胞48h后采用相对定量RT-PCR分析细胞bcr／abl基因表达水平。结果：(1)IFN-α呈剂量依赖性(从100u／ml到10000u／ml)抑制KT-1／A3细胞生长;(2)IFN-α(1000u／m1)诱导48h后使KT-1／A3细胞凋亡率从3．3％升到11．8％,并使KT-1／A3细胞中bcr／abl嵌合基因的表达水平降至对照组的66．7％;(3)IFN-α对K562细胞的生长、凋亡及bcr／abl嵌合基因表达无明显调节效应。结论：不同类型的CML细胞对IFN-α的反应性不同。     

p53 in chronic myeloid leukemia cell lines.

Four human chronic myeloid leukemia (CML) cell lines, BV173, K562, KCL-22, and KYO-1, were studied for inactivation of human tumor suppressor gene p53. Southern blotting showed allele deletion in KCL-22 and cytogenetic studies showed a chromosome 17 deletion in KYO-1 but no gross structural abnormalities in the other two lines. Northern blotting showed increased amounts of normal size p53 mRNA in BV-173 and KYO-1, trace amounts in KCL-22, and none in K562. Direct sequencing of p53 cDNA revealed a missense point mutation in KYO-1 and a single base pair deletion consistent with a coding frame shift in KCL-22. Both abnormalities in these myeloid cell lines were located in the highly conserved region of p53. Studies with two monoclonal antibodies showed that the three cell lines with p53 mRNA had readily detectable p53 proteins. In KYO-1 and BV173 cells the p53 protein was located mainly in the nuclei but KCL-22 cells had weak staining in the cytoplasm. Our data support the assumption that inactivation of p53 tumor suppressor function in myeloid blast transformation of CML may result from point mutations or deletions that produce mutant proteins.     

Treatment of chronic myeloid leukemia with imatinib mesylate

Philadelphia (Ph) chromosome is the cytogenetic hallmark of chronic myeloid leukemia (CML). The translocation forms a chimeric gene, bcr-abl, which generates BCR-ABL. This fusion protein constitutively activate ABL tyrosine kinase and causes CML. Imatinib mesylate is a selective tyrosine kinase inhibitor on ABL, c-Kit and PGDF-receptor, and functions through competitive inhibition at the ATP-binding site of the enzyme, which leads to growth arrest or apoptosis in cells that express BCR-ABL. Imatinib has revolutionized the management of patients with CML, and at a dose of 400 mg daily has become the current standard therapy for newly diagnosed patients with CML even when they have HLA-matched family donors. Although imatinib therapy has only a 5-year history, it is hoped that CML will be cured with this drug and with forthcoming second-generation tyrosine kinase inhibitors as well as by allogeneic stem cell transplantation in patients who have become resistant to these drugs.     

Treatment selection after imatinib resistance in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a progressive and often fatal malignancy of the blood. The harbinger of CML is a chromosomal translocation that results in the synthesis of the BCR-ABL fusion protein, a constitutively active tyrosine kinase. The advent of imatinib, an inhibitor targeted specifically for BCR-ABL, represented a significant medical advance in CML therapy. However, patients with CML can exhibit varying responses to first-line treatment with imatinib. While most patients respond to treatment, some may experience a loss of response or require treatment discontinuation due to toxicity. Frequent monitoring for resistance or intolerance is a requirement for recognition of suboptimal response. Mutational analysis of the patient’s BCR-ABL alleles is also informative and may be predictive of a response to therapy. Published physician guidelines have highlighted these recommendations, but it is not clear if these guidelines are universally followed. One option in patients showing poor response to standard-dose imatinib of 400 mg is to escalate the dose. However, this option should be reserved for patients with minimal disease burden. Clinically available options mainly include second-generation tyrosine kinase inhibitors, such as dasatinib and nilotinib. Allogenic stem cell transplantations (for eligible patients) also should be considered. The disease and patient characteristics at the time of imatinib failure should be evaluated before choosing second-line therapy to optimize the therapeutic benefit without unnecessary delay.     

Homoharringtonine,omacetaxine mepesuccinate,and chronic myeloid leukemia circa 2009

Homoharringtonine (HHT) is a natural alkaloid that is obtained from various Cephalotaxus species. The mechanism of action by which HHT exerts its antitumor activity is through inhibition of protein synthesis and promotion of apoptosis. In the 1990s, HHT proved to be significantly active as salvage therapy for patients with chronic myeloid leukemia (CML) after failure on interferon?α therapy. However, the remarkable success of imatinib mesylate in the treatment of CML relegated HHT to oblivion. The development of omacetaxine mepesuccinate, a subcutaneously bioavailable semisynthetic form of HHT, and its activity in imatinib‐resistant CML has established this agent for the second time as a valuable option in the management of this disease. Preliminary results appear to support the use of this agent for patients who have imatinib‐resistant CML, including those who carry the tyrosine kinase inhibitor‐insensitive mutation that exchanges the amino acids threonine and isoleucine at position 315 (the T315I mutation). In this article, the authors discuss the current data on omacetaxine and the prospects of this agent to be integrated into the state‐of‐the‐art treatment algorithms for CML. Cancer 2009. © 2009 American Cancer Society.     

Strategies for overcoming imatinib resistance in chronic myeloid leukemia

Imatinib was the first treatment for chronic myeloid leukemia (CML) that specifically targeted the causative BCR-ABL oncoprotein, and represented a major therapeutic advance in this disease; however, some patients develop resistance or intolerance. Resistance can be classified as BCR-ABL-dependent (e.g., mutation in the BCR-ABL gene) or BCR-ABL-independent (alternative pathways of disease progression, e.g., SRC-family tyrosine kinases). The investigation of therapeutic options post-imatinib failure resulted in the development and regulatory approval of dasatinib, a BCR-ABL and SRC-family kinase inhibitor. Dasatinib is active across all phases of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia, and demonstrates activity in almost all imatinib-resistant mutations. Other therapeutic options are also under investigation, with nilotinib being the most clinically advanced. Nilotinib is an analog of imatinib with similar multiple kinase targets, but without inhibition of SRC, and reduced in vitro activity against BCR-ABL P-loop mutations compared with dasatinib. Similar to dasatinib, nilotinib has no activity against T315I mutations. The availability of dasatinib and development of other tyrosine kinase inhibitors provide positive prospects for patients with imatinib-resistant or -intolerant CML. Here, we discuss several of these new strategies for treating patients after imatinib failure.     

Acute renal failure secondary to imatinib mesylate treatment in chronic myeloid leukemia

A 58-year-old woman with chronic myeloid leukemia (CML), and previous intolerance to interferon was treated with the BCR-ABL tyrosine kinase protein inhibitor imatinib mesylate. Coincidentally, with the start of treatment, the patient developed acute renal failure, with acute tubular necrosis being observed on histopathology. Imatinib was stopped and three hemodialysis sessions were performed, which was followed by a progressive improvement of the renal function and normalization of the urine output. One year later the patient still has mild chronic renal failure and remains in chronic phase of CML on hydroxyurea treatment.     

p21 Confers resistance to imatinib in human chronic myeloid leukemia cells

Imatinib is a Bcr-Abl inhibitor used as first-line therapy of chronic myeloid leukemia (CML). p21^Cip1, initially described as a cell cycle inhibitor, also protects from apoptosis in some models. We describe that imatinib down-regulates p21^Cip1 expression in CML cells. Using K562 cells with inducible p21 expression and transient transfections we found that p21 confers partial resistance to imatinib-induced apoptosis. This protection is not related to the G2-arrest provoked by p21, a decrease in the imatinib activity against Bcr-Abl or a cytoplasmic localization of p21. The results suggest an involvement of p21^Cip1 in the response to imatinib in CML.