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。     

尼洛替尼治疗慢性粒细胞白血病42例

目的探讨尼洛替尼(达希纳)治疗慢性粒细胞白血病的临床效果及安全性。方法选择2011年1月至2012年10月收治的慢性粒细胞白血病患者42例,均予口服尼洛替尼,每次400 mg,每天2次。结果完全血液学缓解率为慢性期为93.75%,加速期为66.67%,急变期为37.50%;完全遗传学缓解率分别为58.06%,33.33%,25.00%;部分遗传学缓解率分别为80.66%,66.67%,37.50%。血液学不良反应中Ⅲ级血小板减少9例,粒细胞减少和贫血各6例,程度轻微,无Ⅲ级及以上贫血发生。在血液学不良反应中大多数可通过调整剂量或加用粒细胞集落刺激因子控制。治疗过程中非血液学不良反应的发生率较高,如恶心、呕吐、头痛等,程度较为轻微,患者可耐受,不影响后期治疗。结论尼洛替尼(达希纳)治疗慢性粒细胞白血病疗效显著,无明显不良反应。     

慢性粒细胞白血病染色体核型分析及临床意义

目的探讨慢性粒细胞白血病患者染色体核型的临床特点及其意义。方法对靖江市人民医院2008年9月至2011年4月收治的37例慢性粒细胞白血病患者采用骨髓或外周血细胞培养G显带技术检测染色体情况,并进行核型分析。结果在37例患者中Ph(+)34例,占91.89%,且在慢性粒细胞白血病病程的慢性期、加速期及急变期均出现。在Ph(+)34例患者中30例Ph(+)细胞为100%,占88.24%,4例Ph(+)细胞为45%～96%,占11.76%。Ph(-)3例,占8.11%。结论染色体核型分析对于慢性粒细胞白血病患者的临床治疗、预后判断具有重要意义,尤其为预测急变、判断疗效和进行细胞遗传学分型提供帮助。     

Bcr-Abl激酶抑制剂尼罗替尼的药理与临床评价

慢性粒细胞性白血病(CML)和费城染色体阳性急性淋巴细胞白血病(Ph ALL),是由Bcr-Abl癌基因引起的.伊马替尼能抑制Bcr-Abl蛋白酪氨酸激酶活性,是一种有效的治疗慢性期CML的药物,但由于其耐药点突变,使加速期或急变期CML和Ph ALL患者常常复发.尼罗替尼是第2代Bcr-Abl激酶抑制剂,效果比伊马替尼强20倍,对伊马替尼耐药和不能耐受的患者(T3151除外)有广泛的活性.Ⅰ/Ⅱ期临床试验表明,尼罗替尼对伊马替尼耐药或不能耐受的CML患者仍能获得血液学和细胞遗传学的缓解.现对尼罗替尼的药理作用、药动学、药物相互作用、安全性进行综述.     

甲磺酸伊马替尼(格列卫)治疗晚期慢性粒细胞性白血病的临床疗效观察

目的:探讨甲磺酸伊马替尼(格列卫)治疗晚期慢性粒细胞白血病的临床疗效及不良反应情况。方法:对我院近年来应用甲磺酸伊马替尼治疗的29例晚期慢性粒细胞白血病患者的临床资料进行回顾性分析,并记录治疗过程中各时间点血常规、骨髓细胞形态学检查、细胞遗传学检查情况,对临床疗效及不良反应进行评价。结果:急变期CML患者血液学缓解率为28.6%,完全细胞遗传学缓解率为0,均明显低于加速期CML患者的73.3%和26.7%,差异均有统计学意义。治疗过程中血液学不良反应主要以白细胞,血小板减少多主,非血液学不良反应可有恶心、呕吐、水肿、骨骼肌酸痛、乏力、头昏、头痛、皮疹等。结论:甲磺酸伊马替尼治疗慢性粒细胞白血病加速期急变期患者疗效好,不良反应少,可耐受且加速期疗效优于急变期。     

伊马替尼治疗慢性粒细胞性白血病患者的临床疗效

目的观察应用伊马替尼治疗慢性粒细胞性白血病患者的临床疗效。方法选取2010年6月至2015年6月来本院治疗的86例粒细胞性白血病患者实施分析,所有患者均针对其分期类型给予伊马替尼治疗,观察不同分期患者在经伊马替尼治疗后的疗效评估。结果患者在慢性期、加速期及急变期的完全细胞遗传学缓解(CCy R)率、主要分子学缓解(MMo R)的结果有显著差异(P<0.05),慢性期患者59均实现完全血液学缓解(CHR),4例未实现;慢性期患者中,低危组血液学反应、细胞遗传学反应及分子学反应缓解率上均明显优于中、高危组。三组存在显著差异(P<0.05),统计学有意义。结论对慢性粒细胞性白血病患者实施伊马替尼治疗具有临床价值。     

FDA批准伯舒替尼治疗慢性髓性白血病

2012年9月,美国FDA批准了辉瑞公司的酪氨酸激酶抑制剂伯舒替尼（bosutinib,Bosulif）用于治疗慢性髓性白血病（CML）,该病是常见于老年人的血液骨髓系统疾病。本品适用于慢性期、加速期或急变期Ph染色体阳性的CML患者,这些患者对包括伊马替尼在内的其他治疗不耐受或有抵抗。     

酪氨酸激酶抑制剂治疗慢性粒细胞白血病的临床疗效分析

目的探讨慢性粒细胞白血病(CML)采用酪氨酸激酶抑制剂(TKI)治疗临床效果。方法 100例慢性粒细胞白血病患者,依据病程分为慢性期组(80例)、加速期组(10例)、急变期组(10例)。均采用TKI治疗。观察并比较三组疗效。结果全部患者完全血液学缓解(CHR)率为92.0%,细胞遗传学缓解(MCy R)率为76.0%,完全细胞遗传学缓解(CCy R)率为73.1%,分子学缓解(MMR)率为47.9%。慢性期组有效率为80.0%,加速期组有效率为60.0%,急变期组有效率为30.0%,三组比较差异有统计学意义(P<0.05)。慢性期组、加速期组、急变期组总生存率(OS)比较差异无统计学意义(P>0.05),但5年无事件生存(EFS)率慢性期组明显长于其他两组,差异有统计学意义(P<0.05)。结论针对慢性粒细胞白血病患者,采用酪氨酸激酶抑制剂治疗,可显著提高临床效果,延长患者生存时间。临床需重视病情的评估,对不同药物剂量进行选择,以最大程度改善预后。     

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。     

慢性粒细胞白血病60例临床诊治分析

目的探讨慢性粒细胞白血病的临床诊治特点。方法选择本院60例确诊为慢性粒细胞白血病患者,分析患者临床症状特点,并给予马利兰和羟基脲治疗。结果32例慢性期患者,30例达临床和血液学缓解,2例死于颅内出血;7例加速期患者,5例达血液学完全缓解,2例部分缓解。21例急变期患者,8例达完全缓解,6例达部分缓解,3例未缓解,2例死于颅内出血,2例合并中枢神经系统。结论慢性粒细胞白血病确诊比较容易,确诊后即可给予马利兰和（或）羟基脲治疗,但是要根据患者的外周血象和骨髓象的具体情况而定。     

Imatinib.

Imatinib inhibits the BCR-ABL tyrosine kinase created by the Philadelphia chromosome (Ph+) in chronic myeloid leukaemia (CML). Complete haematological responses were achieved in 88% of patients and major cytogenetic responses were detected in 49% of patients with chronic phase CML treated with oral imatinib 400 mg/day in a multicentre noncomparative study of 532 patients. Administration of oral imatinib 400 or 600 mg/day to 235 patients with accelerated phase CML in a multicentre noncomparative study resulted in haematological responses in 63% of patients and major cytogenetic responses in 21% of patients. 26% of the 260 patients with blast crisis CML receiving imatinib 400 or 600 mg/day in a multicentre noncomparative trial sustained a haematological response and 13.5% of patients had a major cytogenetic response. Imatinib 400 or 600 mg/day orally achieved ahaematological response in 19 of 32 patients with Ph+ acute lymphoblastic leukaemia in a pilot study. Clinical improvement was demonstrated in 89% of 36 patients with gastrointestinal stromal tumours unresponsive to standard chemotherapy during treatment with 400 or 600 mg/day oral imatinib in a noncomparative phase II trial. Adverse events were frequent in clinical trials of imatinib but most events were mild or moderate in severity. Serious adverse events reported include severe fluid retention, cytopenias and hepatotoxicity.     

The role of therapeutic drug monitoring of imatinib in patients with chronic myeloid leukemia and metastatic or unresectable gastrointestinal stromal tumors

Imatinib mesylate is a tyrosine kinase inhibitor used as first-line treatment in Philadelphia chromosome-positive chronic myeloid leukemia (Ph+ CML) and metastatic or unresectable gastrointestinal stromal tumors (GIST). Therapeutic drug monitoring (TDM) for imatinib has been suggested to improve efficacy, assess compliance, and evaluate drug-drug interactions. Imatinib has proven efficacy in improving treatment response and survival in patients with Ph+ CML and GIST. Several analytical methods are available to quantify total plasma imatinib concentrations. A good relationship exists between total imatinib plasma concentrations and pharmacologic response. Clinical evaluation of pharmacologic response to imatinib alone may be insufficient given the long duration of therapy before clinical response in patients with Ph+ CML and GIST. Thus, the authors have used a previously published 9-step decision-making algorithm to evaluate the utility of TDM for imatinib. The suggested trough concentrations for improved complete cytogenetic or major molecular response in patients with Ph+ CML and improved time to progression for patients with GIST are >1000 and >1100 ng/mL, respectively. Imatinib exhibits interindividual pharmacokinetic variability. Increased apparent clearance of imatinib has been observed in chronic phase chronic myeloid leukemia and increased body weight. Decreased apparent clearance has been observed in renal impairment and patients on concomitant medications with potent inhibition of cytochrome P450 3A4. Duration of therapy in patients with Ph+ CML and GIST is lifelong. Based on the available evidence, TDM for imatinib may provide additional information on efficacy, compliance, and safety than clinical evaluation alone. Patients with suboptimal response to treatment, treatment failure, rare adverse events, drug interactions, or suspected nonadherence will attain the greatest benefit from TDM.     

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。     

伊马替尼治疗慢性粒细胞性白血病的疗效观察

目的探讨伊马替尼治疗慢性粒细胞性白血病的近期疗效和安全性。方法应用伊马替尼400～600mg·d-1顿服治疗不同时期的慢性粒细胞性白血病患者18例,评价治疗后的临床疗效和不良反应的发生情况。结果 18例CML患者中11例患者达血液学完全缓解,占61.11%,2例患者血液学部分缓解,总体有效率达到72.22%,临床受益率达83.33%。所有患者均出现一种或多种不良反应,主要包括粒细胞及血小板减少(16.67%)、胃肠道反应(38.89%)、全身水肿(27.78%)、肌肉疼痛或痉挛(33.33%)、低热(16.67%)、皮疹(11.11%)。结论伊马替尼治疗CML患者的近期疗效好,且不良反应轻,可作为无法接受骨髓移植治疗的CML患者的首选化疗药物,但其远期临床疗效尚有待于进一步研究阐明。     

Nilotinib

Nilotinib is an orally administered BCR-ABL tyrosine kinase inhibitor that has shown good clinical efficacy in imatinib-resistant or -intolerant, Philadelphia chromosome-positive, chronic myeloid leukaemia (CML) in a phase I/II trial. The phase I component of the trial established the dosage regimen used in the phase II part of the trial, which included several arms. Three of these arms, or phase II trials, evaluated nilotinib in each of the three phases of CML (chronic, accelerated or blast crisis).I n the phase II trial in patients with chronic-phase CML, major cytogenetic response (primary endpoint) was achieved in 48% of the 280 patients who received nilotinib and had a follow-up period of > or = 6 months. Major cytogenetic response rates did not differ between imatinib-resistant and -intolerant patients, and nilotinib was effective in patients with BCR-ABL mutations (except T315I). Haematologic response rate (primary endpoint) was 47% in the phase II trial with nilotinib in patients with accelerated-phase CML (n = 119). Complete haematologic response was achieved in 26% of patients and 21% had no evidence of leukaemia or returned to chronic-phase CML. Major cytogenetic response, an important secondary endpoint in the trial, occurred in 29% of patients. Data from the phase II trial in patients with CML in blast crisis (n = 135) also showed promising results, with 39% of patients achieving haematologic response with nilotinib. Adverse events reported with nilotinib have generally been of mild to moderate severity. Grade 3 or 4 neutropenia and thrombocytopenia were reported in 29% of patients each.     

新型抗肿瘤药物依曼替尼布

依曼替尼布是一种新型的 2 苯胺基嘧啶类酪氨酸激酶抑制药 ,用于α 干扰素治疗失败后的慢性髓样白血病 (CML)慢性期病人、加速期病人、急变期病人的治疗。临床研究表明该药对病人血液学缓解及主要细胞分化缓解显著     

Imatinib: in relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukaemia

* Imatinib inhibits the breakpoint cluster region-Abelson (BCR-ABL) tyrosine kinase, which is produced by the chromosomal abnormality known as the Philadelphia (Ph) chromosome in patients with Ph chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL). * The clinical efficacy and safety of oral imatinib in patients with relapsed or refractory Ph+ ALL has been demonstrated in a noncomparative, open-label phase II trial (n = 48) and an expanded-access study (n = 353). The majority of patients received imatinib 600mg once daily. * In the phase II trial, imatinib induced complete haematological responses in 19% of patients, marrow complete responses in 10% of patients and partial marrow responses in 31% of patients. These were sustained for at least 4 weeks in 27% of patients. * The estimated median times to progression were 2-3.1 months in the phase II trial, the expanded-access study and a population of 68 patients pooled from these studies, with estimated median overall survival rates of 4.9-9 months. * In 22 patients receiving imatinib prior to undergoing allogeneic stem cell tranplantation (SCT) in the phase II trial and expanded-access study, estimated disease-free survival and overall survival rates 12 months after SCT were 25.5% and 44.8%. * Although adverse events were frequent among relapsed or refractory Ph+ ALL patients treated with imatinib, the majority of non-haematological adverse events were mild or moderate in severity.     

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.     

Nilotinib: in the first-line treatment of newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase

Nilotinib is an effective first-line treatment for newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (CML) in chronic phase. It is an aminopyrimidine-based, high-affinity inhibitor of the tyrosine kinase activity of BCR-ABL. It thus decreases ABL-associated cell proliferation and kinase autophosphorylation. At 12 months, a significantly greater proportion of nilotinib 300?mg twice daily recipients experienced a major molecular response (primary endpoint) than those receiving imatinib 400?mg once daily, in the randomized, open-label, multicentre ENESTnd study in adults with newly diagnosed Philadelphia chromosome-positive CML in chronic phase. Moreover, a significantly greater proportion of nilotinib 300?mg twice daily than imatinib recipients had a complete molecular response at 12 months. Complete cytogenetic response rates were also significantly higher in the nilotinib 300?mg twice daily group than in the imatinib group at 12 months. Treatment differences in molecular response rates remained significant in an updated analysis, with data from a minimum follow-up of 24 months. Nilotinib 300?mg twice daily was generally well tolerated in the ENESTnd study. While nilotinib is associated with an increase in corrected QT interval (QTc), the incidence of cardiac-related adverse events in nilotinib recipients in the ENESTnd study was low.