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。     

供体淋巴细胞输注联合伊马替尼治疗异基因造血干细胞移植后Ph+白血病复发的初步临床观察

 目的 观察供体淋巴细胞输注（DLI）联合伊马替尼治疗异基因移植后复发的Ph+白血病的疗效。方法 以实时定量聚合酶链反应（RQ-PCR）及荧光原位杂交（FISH）方法检测5例Ph+白血病患者移植后微小残留病灶（MRD）,在复发早期进行DLI联合伊马替尼治疗。伊马替尼初始剂量300～400 mg／d,DLI采用递增剂量方案,首次剂量为0.5×106／kg ~ 5×106／kg,间隔时间为1 ~ 4周。观察治疗反应及相关并发症。结果 5例患者中有2例慢性髓细胞白血病（CML）患者发生分子学反应,其中1例达分子学缓解;而2例高危Ph+急性淋巴细胞白血病（Ph+ ALL）患者及1例早期血液学复发的慢性髓细胞白血病第二次慢性期（CML-CP2）患者治疗无反应。复发后随访40 d～14个月,5例应用伊马替尼后均未发生严重并发症。DLI后1例发生Ⅳ度急性移植物抗宿主病（aGVHD）,2例发生Ⅰ～Ⅱ度aGVHD,1例发生肺部感染。结论 伊马替尼联合DLI可有效治疗移植后复发的CML慢性期患者,副作用可耐受,但对复发的Ph+ ALL及CML急变期患者疗效有限。     

国产甲磺酸伊马替尼治疗初诊慢性粒细胞白血病慢性期的临床观察

目的 观察国产甲磺酸伊马替尼治疗初诊慢性粒细胞白血病慢性期(CML-CP)的效果及安全性.方法 回顾性分析东莞市人民医院2014年10月至2016年10月收治的23例年龄＞18岁、初次确诊、除羟基脲外未接受其他任何抗CML治疗的CML-CP患者临床资料,所有患者均接受国产甲磺酸伊马替尼400 mg/次,1次/d口服治疗,评价3、6、12个月时的血液学、分子生物学反应及安全性.结果 23例患者治疗后均达到血液学完全缓解.在可评估的20例患者中,在3个月时15例bcr-abl国际标准化(IS)值＜10％;治疗6个月时16例达bcr-abl＜ 1％;治疗12个月时8例bcr-abl＜0.1％.不良反应均可耐受.结论 国产甲磺酸伊马替尼治疗初诊CML-CP疗效可靠,不良反应可耐受.     

干扰素联合化疗与伊马替尼治疗慢性粒细胞白血病的疗效比较分析

目的比较分析干扰素联合化疗与伊马替尼治疗慢性粒细胞白血病(CML)的临床疗效。方法 72例新诊断的Ph染色体阳性CML慢性期患者根据治疗方案的不同随机分为干扰素联合化疗组和伊马替尼组,并比较2组临床疗效。结果 2组总有效率比较差异无统计学意义(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 a总生存率均明显高于干扰素联合化疗组(P<0.05)。结论干扰素联合化疗和伊马替尼均可作为CML慢性期的有效治疗方法。     

伊马替尼联合HAG方案治疗慢性粒细胞白血病急变期临床观察

 目的　探讨使干扰素治疗失败的慢性粒细胞白血病（CML）急变期达完全缓解的有效方法。方法　CML急变期患者8例,Ph染色体、bcr-abl融合基因均阳性。2例出现附加染色体。每例患者急变前除应用羟基脲外,均应用过3个月以上干扰素,5例患者曾用含阿糖胞苷（Ara-C）的不同方案化疗,均未服用伊马替尼。8例急变期患者均服用伊马替尼600 mg／d,联合HAG方案[高三尖杉酯碱（HH）1～2 mg／d,Ara-C 15～25 mg每12 h 1次,粒细胞集落刺激因子（G-CSF）200 μg／m2]。根据患者年龄、血常规、骨髓象决定用药剂量及时间长短。结果　2例达血液学部分缓解,6例达血液学完全缓解,继续服用伊马替尼600 mg／d。6例血液学完全缓解者达遗传学缓解,生存时间6（3～9）个月,均未达分子生物学缓解。中位血液学复发时间10（3～26）个月,伊马替尼联合HAG方案治疗中位生存时间17（8～28）个月。结论　伊马替尼联合HAG方案治疗CML急变期患者安全有效。     

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。      

氟马替尼治疗伊马替尼耐药或不耐受慢性粒细胞白血病的效果及安全性

目的探讨氟马替尼治疗伊马替尼耐药或不耐受的慢性粒细胞白血病慢性期(CML-CP)患者的效果及安全性。方法回顾性分析2020年4月至2021年5月就诊于济宁市第一人民医院9例对一线伊马替尼耐药或不耐受而接受氟马替尼治疗的CML-CP患者的临床资料。评估患者血液学、细胞遗传学和分子学反应及无进展生存(PFS)、无事件生存(EFS)和不良反应发生情况。结果 9例CML-CP患者中, 包括4例伊马替尼耐药及5例伊马替尼不耐受患者。氟马替尼中位治疗时间为17个月(1～25个月)。除1例患者因4级血小板减少等不良反应早期停用氟马替尼外, 其余8例患者中7例在氟马替尼治疗3、6、12个月时获得最佳治疗反应。至2022年4月随访结束时, 获得完全细胞遗传学反应(CCyR)、主要分子学反应(MMR)和分子学反应4.5(MR4.5)分别有7、7、6例患者, 获得CCyR、MMR和MR4.5的中位时间分别为4.5个月(3～6个月)、12个月(3～12个月)和15个月(3～21个月)。中位随访17个月(11～25个月), 9例患者中7例EFS, 8例持续应用氟马替尼的患者均PFS。9例患者应用氟马替尼治疗后6...     

苹果酸舒尼替尼二线治疗国人晚期胃肠间质瘤的临床观察

的 探讨苹果酸舒尼替尼二线治疗甲磺酸伊马替尼治疗失败的国内胃肠间质瘤（GIST）患者的疗效和安全性,并初步分析后续治疗对生存的影响。方法 回顾性分析2008年11月至2009年12月应用舒尼替尼二线治疗伊马替尼失败的24例GIST患者资料,口服舒尼替尼50mg／日,连续4周,停药2周,6周为1周期。按照RECIST 1.1版进行疗效评价,根据NCI CTC 3.0版进行毒性评价。结果 24例患者共接受治疗232个周期,平均9.7个周期（2～29个周期）。获PR 6例,SD 12例,PD 6例,有效率为 25％,疾病控制率为75％。舒尼替尼二线治疗进展后有8例接受后续治疗。中位随访时间为378天（190～1554天）,中位无进展生存时间（PFS）为336天（95％CI：223.2～448.8天）,中位总生存时间（OS）为655天（95％CI：359.7～950.3天）。其中未接受后续治疗组的中位OS为392天（95％CI： 190.1～593.9天）,接受后续治疗组的中位OS为1303天（95％CI：661.2～1544.8天）,两组差异有统计学意义（P=0.000）。毒副反应多为1～2级,未发生治疗相关性死亡。结论 舒尼替尼二线治疗伊马替尼失败的国内GIST患者有效,不良反应轻微,安全可控;对于二线治疗失败的患者采取后续治疗可能有生存获益。     

伊马替尼一线治疗慢性粒细胞白血病慢性期患者- 单中心十年回顾性分析*

目的:总结以伊马替尼为一线治疗的慢性粒细胞白血病（chroni cmyeloid leukemia,CML ）初治患者的疗效和生存。方法:回顾性分析南昌大学第一附属医院2003年1 月至2013年12月间收治的295 例CML 初治患者的临床资料,其中185 例为入组格列卫全球患者援助项目（GIPAP）行伊马替尼治疗、30例为干扰素（IFN-α）治疗、50例为羟基脲单药治疗和30例为异基因外周血造血干细胞移植（allogeneic hematopoietic stem cell transplantation ,Allo-HSCT）治疗的患者,分析各组患者的治疗疗效和生存情况。结果:伊马替尼治疗组和Allo-HSCT 治疗组患者完全血液学缓解率（complete hematologic remission ,CHR ）均为96.7% ,完全细胞遗传学缓解率（complete cytogenetic remission,CCyR）为89.7% 和93.3% ,完全分子学缓解率（complete molecular remission ,CMoR）为49.7% 和83.3%（P = 0.001）;而干扰素和羟基脲治疗组CHR 、CCyR和CMoR 均明显低于伊马替尼治疗组和Allo-HSCT 治疗组。伊马替尼组患者的总生存时间（overall survival,OS）明显优于其他组（P < 0.001）,甚至优于Allo-HSCT 治疗组（10年OS为89.0% vs .67.0% ,P < 0.001）。 Cox 多因素分析显示接受伊马替尼治疗（HR= 5.267,95%CI 为1.054～1.940,P = 0.022）和获得CCyR（HR= 9.541,95%CI 为1.692～10.513,P = 0.002）是影响本组患者预后良好的独立因素。结论:CML 初治患者接受伊马替尼治疗可以获得更高的CHR 和CCyR,且OS更优,伊马替尼适合作为中国初治CML 患者的一线治疗。      

伊马替尼血药浓度检测的意义

 【摘要】伊马替尼已作为慢性粒细胞白血病（CML）的一线治疗,疗效令人鼓舞。伊马替尼的血药浓度与生存期及缓解率相关。其血浆浓度主要受α1-酸性糖蛋白（AGP）及改变细胞色素P450（CYP3A4）酶活性的药物影响。监测伊马替尼血药浓度有助于指导治疗。 【主题词】伊马替尼,血药浓度;意义     

国产甲磺酸伊马替尼治疗初诊慢性粒细胞白血病慢性期临床观察

目的 甲磺酸伊马替尼作为治疗慢性粒细胞白血病(chronic myelogenous leukemia,CML)-慢性期(chronic phase,CP)患者的一线治疗药物,国产药物应用的安全性和有效性尚缺乏系统评价参考.本研究探讨国产甲磺酸伊马替尼治疗初诊CML-CP患者的早期血液学、细胞遗传学、分子学反应与安全性.方法 收集2014-03-01-2015-10-31就诊于新疆自治区人民医院血液科的43例初诊CML-CP患者,给予国产甲磺酸伊马替尼(昕维?R)400 mg/d口服,治疗3、6、12个月时进行骨髓细胞学、染色体、FISH与骨髓BCR-ABL融合基因转录本水平评估,观察评估患者血液学反应、细胞遗传学反应和分子学反应及安全性.结果 43例患者治疗满3个月时,42例(97.7%)达完全血液学反应(complete hematologic response,CHR);35例(81.4%)达主要细胞遗传学反应(major cytogenetic response,MCyR),其中11例(25.6%)达完全细胞遗传学反应(complete cytogenetic response,CCyR);30例(69.8%)达国际标准化BCR-ABL转录本水平(BCR-ABLIS)≤10%,4例(9.3%)达BCR-ABLIS≤0.1%.17例患者治疗满6个月时,均达CHR(100.0%);11例(64.7%)达CCyR;12例(70.6%)达BCR-ABLIS≤1%,其中4例(23.5%)达BCR-ABLIS≤0.1%.5例患者治疗满12个月,4例达CCyR;2例BCR-ABLIS≤1%,2例BCR-ABLIS≤0.1%,1例BCR-ABLIS>10%.血液学不良反应:3/4级白细胞减少、血小板减少和贫血发生率分别为20.9%、23.3%和16.3%.非血液学不良反应发生率分别为水肿76.7%,恶心呕吐51.2%,骨关节肌肉酸痛39.5%),皮疹20.9%,发热11.6%,腹泻11.6%,肝功能损害2.3%.无4/4级血液学与非血液学不良反应.结论 国产甲磺酸伊马替尼治疗初诊CML-CP患者的近期疗效肯定,不良反应可耐受,但仍需长期观察研究.     

氟马替尼联合多药化疗治疗费城染色体阳性急性淋巴细胞白血病的疗效和安全性分析

  目的  评价氟马替尼联合多药化疗在费城染色体阳性急性淋巴细胞白血病（Philadelphia chromosome-positive acute lymphoblastic leukemia,Ph+ALL）患者中的疗效和安全性。  方法  回顾性分析南昌大学第一附属医院2019年12月至2022年2月收治的25例行氟马替尼联合CALLG-2008化疗方案治疗的成人Ph+ALL患者的临床资料,分析其疗效和安全性。  结果  25例患者中,21例（84%）患者于初次诱导期联合氟马替尼,4例（16%）患者于第1个疗程诱导结束后联合氟马替尼。患者化疗28天、3个月和6个月的完全缓解（complete response,CR）率分别为88%、91.67%和90.48%;主要分子学反应（major molecular response,MMR）率分别为68%、79.17%和80.95%;完全分子学反应（complete molecular response,CMR）率分别为60%、75%和80.95%。中位随访时间180（75.6～458.1）天,随访时总生存（overall survival,OS）率为82.61%,无复发生存（recurrence-free survival,RFS）率为73.91%。氟马替尼用药过程中,有22例（88%）患者出现Ⅳ度骨髓抑制,非血液学不良反应主要有腹泻、转氨酶升高、疲乏、恶心等,经对症治疗后均可好转。  结论  氟马替尼联合多药化疗治疗Ph+ALL患者安全有效。      

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.     

High imatinib dose overcomes insufficient response associated with ABCG2 haplotype in chronic myelogenous leukemia patients

Pharmacogenetic studies in chronic myelogenous leukemia (CML) typically use a candidate gene approach. In an alternative strategy, we analyzed the impact of single nucleotide polymorphisms (SNPs) in drug transporter genes on the molecular response to imatinib, using a DNA chip containing 857 SNPs covering 94 drug transporter genes. Two cohorts of CML patients treated with imatinib were evaluated: an exploratory cohort including 105 patients treated at 400 mg/d and a validation cohort including patients sampled from the 400 mg/d and 600 mg/d arms of the prospective SPIRIT trial (n=239). Twelve SNPs discriminating patients according to cumulative incidence of major molecular response (CI-MMR) were identified within the exploratory cohort. Three of them, all located within the ABCG2 gene, were validated in patients included in the 400 mg/d arm of the SPIRIT trial. We identified an ABCG2 haplotype (define as G-G, rs12505410 and rs2725252) as associated with significantly higher CI-MMR in patients treated at 400 mg/d. Interestingly, we found that patients carrying this ABCG2 “favorable” haplotype in the 400 mg arm reached similar CI-MMR rates that patients randomized in the imatinib 600 mg/d arm. Our results suggest that response to imatinib may be influenced by constitutive haplotypes in drug transporter genes. Lower response rates associated with “non-favorable” ABCG2 haplotypes may be overcome by increasing the imatinib daily dose up to 600 mg/d.     

伊马替尼联合造血干细胞移植或化疗治疗bcr-abl+急性淋巴细胞白血病

 目的　探讨伊马替尼联合异基因造血干细胞移植（allo-HSCT）或化疗治疗bcr-abl+融合基因成年人急性淋巴细胞白血病（ALL）（以下简称成年人ALL）的疗效。方法　12例成年人ALL经骨髓细胞学、细胞化学、免疫学表型、bcr-abl融合基因检测确诊为bcr-abl+ ALL（B细胞型）。初治时接受伊马替尼联合化疗诱导治疗,伊马替尼剂量为400 mg／d。完全缓解（CR）后8例接受allo-HSCT治疗,移植后bcr-abl融合基因转为阳性者给予伊马替尼（400～600 mg／d）治疗,3例接受伊马替尼与化疗交替巩固治疗。结果　11例获得CR,CR率91.7 %;诱导治疗2个疗程时bcr-abl融合基因转阴率为41.7 %;8例接受移植患者3例复发,3例化疗与伊马替尼交替巩固治疗的患者2例复发,伊马替尼联合造血干细胞移植组与伊马替尼联合化疗组患者的中位缓解期分别为16个月与10个月（P＜0.01）;中位生存期为18个月与12个月（P＜0.01）。结论　伊马替尼联合化疗诱导治疗bcr-abl+成年人ALL有较高的血液学和分子生物学缓解率,伊马替尼联合allo-HSCT的疗效优于伊马替尼联合化疗。     

Long-term outcome following imatinib therapy for chronic myelogenous leukemia, with assessment of dosage and blood levels: the JALSG CML202 study

A prospective multicenter Phase II study was performed to examine the efficacy and safety of imatinib therapy in newly diagnosed Japanese patients with chronic-phase CML. Patients were scheduled to receive imatinib 400 mg daily. Plasma imatinib concentrations were measured by liquid chromatography-tandem mass spectrometry. In 481 evaluable patients, estimated 7-year overall survival (OS) and event-free survival (EFS) at a median follow-up of 65 months were 93% and 87%, respectively. Because imatinib dosage was reduced in many patients due mainly to adverse events, subgroup analysis was performed according to the mean daily dose during the first 24 months of treatment: ≥360 mg (400-mg group; n = 294), 270-359 mg (300-mg group; n = 90) and <270 mg (200-mg group; n = 67). There were no significant differences in OS and EFS between the 300- and 400-mg groups; however, cumulative rates of complete cytogenetic and major molecular responses differed significantly between the two groups. There were no significant differences in mean imatinib trough levels between these two groups for the patients in whom trough levels had been measured. Survival and efficacy in the 200-mg group were markedly inferior to the former two groups. These results suggest that, although a daily dose of 400 mg imatinib is associated with better outcomes, 300 mg imatinib may be adequate for a considerable number of Japanese patients who are intolerant to 400 mg imatinib. Blood level monitoring would be useful to determine the optimal dose of imatinib.     

Update on practical aspects of the treatment of chronic myeloid leukemia with imatinib mesylate

Imatinib (imatinib mesylate, Gleevec® [formerly known as STI571], Novartis Pharmaceuticals, Basel, Switzerland) is a protein tyrosine kinase inhibitor that is approved by the US Food and Drug Administration for patients with all phases of chronic myeloid leukemia (CML). Imatinib is remarkably effective as treatment for CML in the chronic phase (at a dosage of 400 mg/d) and the accelerated phase (at 600 mg/d). At this time, it remains to be seen whether the chronic phase of CML can be extended sufficiently in some patients so that they are functionally "cured," and also whether the increased rate of major molecular response induced by doses of imatinib higher than 400 mg/d will further improve overall survival of patients with CML in the chronic phase. The value of molecular monitoring of response in patients with CML in the chronic phase is examined. Although imatinib 800 mg/d can induce dramatic responses in patients with myeloid blast crisis, lymphoid blast crisis, and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), the responses are usually incomplete and of short duration. We discuss the role of imatinib in relation to allogeneic stem cell transplantation (particularly in younger patients), recognizing that the data upon which any decisions can be made are relatively immature. Finally, recent data on new tyrosine kinase inhibitors capable of overcoming primary or acquired resistance to imatinib are reviewed.     

Clinical effect of imatinib added to intensive combination chemotherapy for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia.

Clinical impact of imatinib was evaluated in 20 patients (median age, 37 years; range, 15-67 years) with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), who were administered with induction chemotherapy of daunorubicin, vincristine, prednisolone, and L-asparaginase, along with imatinib 600 mg/day during remission induction and 400 mg/day during consolidation courses. One patient died on day 14 from septic shock, while the remaining 19 achieved complete remission (CR). In total, 15 patients underwent allogeneic hematopoietic cell transplantation (HCT) during first CR. After median follow-up period of 799 days, six patients experienced recurrence; two with early recurrence within 100 days, one with leptomeningeal recurrence at 11 month, and three with post-HCT recurrence. Eight patients died. Median CR duration (821 days) and median patient survival (894 days) in the study were significantly longer by 2.9- and 2.3-fold, respectively, when compared to those of 18 historical patients treated with same regimen of combination chemotherapy without imatinib. Toxicities of the combined treatment were manageable and included grade 4 myelosuppression (n = 20) and reversible > or = grade 3 hyperbilirubinemia (n = 4). Beneficial clinical effects were observed when imatinib was added to combination chemotherapy in patients with newly diagnosed Ph+ ALL. Further studies with larger number of patients are necessary.