尼洛替尼治疗伊马替尼治疗6个月时BCR-ABL转录本水平未达到≤10%的CML-CP患者的临床观察
发布时间：2019-06-02 22:58
【摘要】：目的:应用酪氨酸激酶抑制剂(TKIs)治疗是慢性粒细胞白血病(CML)慢性期(CP)患者的标准治疗方案。甲磺酸伊马替尼由于相比于干扰素能够提高细胞遗传学及分子生物学缓解率,因此是第一个被批准作为一线治疗的酪氨酸激酶抑制剂。但是,近30%的CML-CP患者在伊马替尼治疗12个月时未达到完全细胞遗传学缓解。尼洛替尼和达沙替尼作为第二代酪氨酸激酶抑制剂(TKIs)已经显示出对伊马替尼耐药或者不耐受的CML-CP患者的益处。临床实验数据已经显示了伊马替尼治疗失败时换用二代TKI药物的优势,即换用二代TKI药物的患者相比于增加伊马替尼剂量的患者在12个月时有更高的CCy R获得率。早期分子生物学缓解(EMR)定义为伊马替尼或者达沙替尼治疗CML患者后3个月时BCR-ABL转录本水平≤10%,其判断预后的作用已得到认可。EMR已经被证实不仅与伊马替尼治疗后而且与伊马替尼治疗失败后二代酪氨酸激酶抑制剂治疗的长期生存包括无进展生存(PFS)和总生存(OS)密切相关。另外,有研究表明6个月时的BCR-ABL转录本水平与生存期也有关系。研究发现6个月时BCR-ABL转录本水平1%(89%)的患者的5年OS获得率较BCR-ABL转录本水平≤1%(97%)更低。最新出版的新ELN关于CML的治疗推荐规范将EMR的概念加入了临床决策系统。里程碑式地加入了3个月时BCR-ABL转录本水平≤10%以及6个月时BCR-ABL转录本水平≤1%这一测定结果。ELN指南考虑单一测定3个月时BCR-ABL转录本水平来定义治疗“失败”从而更改治疗方案理由并不充分,因此其建议6个月时复查BCR-ABL转录本水平。3个月BCR-ABL转录本水平10%被定义为治疗“预警”而非治疗“失败”,6个月时转录本水平大于10%被定义为治疗“失败”而6个月时转录本水平介于1-10%之间的也被归类为治疗“预警”。6个月转录本水平小于1%被认为是最理想的治疗反应。因此建议每3个月进行基因检测评估主要分子生物学缓解的获得,即利用定量多聚酶链式反应(q PCR)及国际标准(IS)测定BCR-ABL转录本水平≤0.1%。获得MMR已经被证明是延迟长期生存的一项重要指标。最近的研究都被批准利用分子检测研究更换二代TKI药物治疗的效果。ELN指南建议接受最初的TKI药物治疗后6个月BCR-ABL转录本水平未达到≤10%的CML-CP患者更换TKI药物治疗。因此,本研究旨在评估接受一线伊马替尼治疗后6个月BCR-ABL转录本水平未达到≤10%的CML-CP患者更换为尼洛替尼治疗后的临床疗效。方法:回顾性分析了81名自2007年1月至2015年1月河北医科大学第二医院收治的接受伊马替尼作为一线治疗但在治疗开始后6个月时未达到BCR-ABL转录本水平≤10%的CML-CP患者。所有的患者都满足以下条件:(1)以Ph(+)和/或BCR-ABL融合基因阳性的CML-CP患者;(2)初诊为CML时的年龄不得低于18岁;(3)在2001年1月至2015年1月之间接受伊马替尼作为一线治疗;(4)伊马替尼的治疗剂量至少为300mg/d且维持至少6个月,中途治疗中断时间不得多于30天;(5)每3个月测试分子生物学反应,并将治疗开始后6个月BCR-ABL转录本水平10%认定为治疗失败并且需要更换为二代TKI药物治疗。患者共分为两组。伊马替尼治疗开始6个月时BCR-ABL转录本水平未达到≤10%,但在此后更换为二代TKI药物治疗的患者为转换组。而在伊马替尼治疗开始6个月时BCR-ABL转录本水平未达到≤10%但在此后继续应用伊马替尼治疗超过3个月的患者为未转换组。其中转换组共22名患者,中位年龄37.5(18-67)岁,中位病程34.5(12-53)个月,伊马替尼中位治疗时间12.5(6-36)个月,尼洛替尼中位治疗时间17.5(8-36)个月,未转换组59名患者,中位年龄40(24-62)岁,中位病程48(15-72)个月,伊马替尼中位治疗时间43(15-72)个月。通过χ2检验比较两组患者在3、6、9、12个月时获得MMR的比例。同时比较伊马替尼以及尼洛替尼治疗过程中出现的不良反应情况。在治疗期间,患者规律复查血常规、血生化、骨髓象、BCR-ABL融合基因检测以评估疗效。结果:在治疗期间,与未转换组相比,转换组患者中大多数获得了MMR。转换组(n=17,77.3%),未转换组(n=25,42.4),P=0.005。另外,在每一个时间段,转换组MMR的获得率均较未转换组高。其中,3个月时,转换组(n=8,36.4%),未转换组(5,8.5%),P=0.007;6个月时,转换组(13,59.1%),未转换组(16,27.1%),P=0.008;9个月时,转换组(15,68.2%),未转换组(19,32.2%),P=0.004;12个月时,转换组(17,77.3%),未转换组(25,42.4%),P=0.005。结果显示转换组较未转换组获得MMR的时间更早且转换组较未转换组患者更容易获得MMR。统计结果显示,转换组患者在随访期间达到MMR的患者比例较未转换组大,且转换组患者较未转换组患者更易且更早达到MMR。而比较两组患者用药的不良反应结果发现,尼洛替尼较伊马替尼治疗不良反应少,患者耐受性更好。结论:1伊马替尼治疗后6个月时BCR-ABL转录本水平≤10%而及时转换为二代TKI药物尼洛替尼治疗后的CML-CP患者相比于没有转换继续应用伊马替尼治疗的患者更早且更容易获得MMR。2尼洛替尼较伊马替尼治疗不良反应少,患者耐受性更好。
[Abstract]:Objective: To treat chronic (CP) patients with chronic myelogenous leukemia (CML) with tyrosine kinase inhibitor (TKIs). Imatinib mesylate is the first tyrosine kinase inhibitor to be approved as a first line treatment due to the increased cytogenetic and molecular biological response rate compared to the interferon. However, nearly 30% of CML-CP patients did not achieve complete cytogenetic response at 12 months of imatinib treatment. Nilotinib and dasatinib as the second generation of tyrosine kinase inhibitors (TKIs) have shown the benefits of imatinib-resistant or intolerance-resistant CML-CP patients. Clinical trial data has shown the advantage of the replacement of the second-generation TKI drug at the time of failure of imatinib, i.e., a higher CCy R acquisition rate at 12 months for patients who use the second-generation TKI drug compared to patients who increased the imatinib dose. Early molecular biological response (EMR) was defined as 10% of the BCR-ABL transcript level after 3 months of treatment with imatinib or dasatinib for CML patients, and it was recognized that the effect of prognosis was recognized. EMR has been demonstrated to be closely related not only to the long-term survival of the second-generation tyrosine kinase inhibitor after treatment with imatinib and after treatment with imatinib, including progression-free survival (PFS) and overall survival (OS). In addition, the study showed that the level of BCR-ABL transcription at 6 months was also related to survival. The 5-year OS acquisition rate of BCR-ABL transcripts at 1% (89%) at 6 months was found to be lower than that of BCR-ABL transcripts (97%). The newly published new ELN's recommendations for treatment of CML incorporate the concept of EMR into the clinical decision-making system. The BCR-ABL transcript level was 10% at 3 months and the BCR-ABL transcript level was 1% at 6 months. The ELN guide defines the treatment "failure" for a single measurement of BCR-ABL at 3 months to change the rationale for the treatment regimen and is not sufficient, It is therefore recommended that the BCR-ABL transcript level be reviewed at 6 months. The 3-month BCR-ABL transcript level is defined as a therapeutic "early warning" rather than a therapeutic "failure", at 6 months the transcript level is defined as a therapeutic "failure" and the transcript level is between 1 and 10% at 6 months and is also classified as a treatment "early warning". The 6-month transcript level is less than 1% considered to be the most desirable therapeutic response. Therefore, the main molecular biological response of gene detection was suggested every 3 months, that is, the level of BCR-ABL transcription was 0.1% by quantitative polymerase chain reaction (q-PCR) and international standard (IS). The acquisition of MMR has proven to be an important indicator of the delay in long-term survival. Recent studies have been approved to use molecular detection to study the effect of replacing the second-generation TKI drug. The ELN guide recommended that patients with CML-CP who had not reached about 10% of the level of BCR-ABL at 6 months after the initial TKI medication were treated with TKI medication. Therefore, the purpose of this study was to assess the clinical efficacy of the replacement of patients with CML-CP at the level of BCR-ABL at 6 months after the treatment of the first-line imatinib to nilotinib. Methods:81 patients with CML-CP who received imatinib as first-line treatment and did not reach BCR-ABL at 6 months after the start of treatment were analyzed retrospectively. All patients met the following conditions: (1) CML-CP patients who were positive with Ph (+) and/ or BCR-ABL fusion genes; (2) the age at first diagnosis was not lower than 18 years; (3) imatinib was accepted as a first line treatment between January 2001 and January 2015; (4) the treatment dose of imatinib is at least 300 mg/ d and is maintained for at least 6 months, the interruption time in the middle is not more than 30 days, and (5) the molecular biological reaction is tested every three months, The BCR-ABL transcripts at 6 months after the start of treatment were identified as treatment failure and need to be replaced with the second generation of TKI drug therapy. The patient was divided into two groups. The BCR-ABL transcript was not up to 10% at 6 months from the start of the imatinib treatment, but the patient who was later replaced with the second-generation TKI drug was the conversion group. However, the BCR-ABL transcript was not up to 10% at 6 months from the start of the imatinib treatment, but the patient continued to apply imatinib for more than 3 months as an unswitched group. Of the 22 patients in the conversion group, the median age was 37.5 (18-67) years, the median course was 34.5 (12-53) months, the median duration of the imatinib was 12.5 (6-36) months, the median treatment time of nilotinib was 17.5 (8-36) months, the median age of 40 (24-62) years for the non-conversion group, and the median course of the course of 48 (15-72) months, The median treatment time in imatinib was 43 (15-72) months. The proportion of MMR was obtained in the two groups at 3,6,9, and 12 months by the second test. The adverse reactions that occurred during the treatment of imatinib and nilotinib were also compared. During the treatment period, the patient regularly reexamined the blood routine, the blood biochemistry, the bone marrow image, the BCR-ABL fusion gene detection to assess the efficacy. Results: Most of the patients in the conversion group received MMR during the treatment period as compared to the non-transformed group. Conversion group (n = 17, 77.3%), untransformed group (n = 25, 42.4), P = 0.005. In addition, at each time period, the acquisition rate of the conversion group MMR is higher than that of the non-conversion group. Of these, at 3 months, the conversion group (n = 8, 36.4%), the non-conversion group (5, 8.5%), P = 0.007,6 months, the conversion group (13, 59.1%), the non-conversion group (16, 27.1%), P = 0.008,9 months, the conversion group (15, 68.2%), the non-conversion group (19, 32.2%), P = 0.004,12 months, the conversion group (17, 77.3%), the non-conversion group (25, 42.4%), P = 0.005. The results showed that the time of the MMR was more early in the conversion group than in the non-transformed group and the MMR was more easily obtained in the conversion group than in the non-transformed group. The results of the statistics show that the proportion of patients who have reached MMR at the follow-up period is greater than that of the non-transformed group, and the patients in the conversion group are more likely to reach the MMR at the time of the non-conversion group. The results of the adverse reactions of the two groups of patients found that the nilotinib was less adverse to the imatinib treatment and the patient was well-tolerated. Conclusion: BCR-ABL transcript levels of 10% at 6 months after imatinib treatment and the timely conversion to the second-generation TKI drug, nilotinib, is more early and easier to obtain MMR.2-nilotinib is less adverse reaction than imatinib. And the patient is well-tolerated.
【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R733.72
[Abstract]:Objective: To treat chronic (CP) patients with chronic myelogenous leukemia (CML) with tyrosine kinase inhibitor (TKIs). Imatinib mesylate is the first tyrosine kinase inhibitor to be approved as a first line treatment due to the increased cytogenetic and molecular biological response rate compared to the interferon. However, nearly 30% of CML-CP patients did not achieve complete cytogenetic response at 12 months of imatinib treatment. Nilotinib and dasatinib as the second generation of tyrosine kinase inhibitors (TKIs) have shown the benefits of imatinib-resistant or intolerance-resistant CML-CP patients. Clinical trial data has shown the advantage of the replacement of the second-generation TKI drug at the time of failure of imatinib, i.e., a higher CCy R acquisition rate at 12 months for patients who use the second-generation TKI drug compared to patients who increased the imatinib dose. Early molecular biological response (EMR) was defined as 10% of the BCR-ABL transcript level after 3 months of treatment with imatinib or dasatinib for CML patients, and it was recognized that the effect of prognosis was recognized. EMR has been demonstrated to be closely related not only to the long-term survival of the second-generation tyrosine kinase inhibitor after treatment with imatinib and after treatment with imatinib, including progression-free survival (PFS) and overall survival (OS). In addition, the study showed that the level of BCR-ABL transcription at 6 months was also related to survival. The 5-year OS acquisition rate of BCR-ABL transcripts at 1% (89%) at 6 months was found to be lower than that of BCR-ABL transcripts (97%). The newly published new ELN's recommendations for treatment of CML incorporate the concept of EMR into the clinical decision-making system. The BCR-ABL transcript level was 10% at 3 months and the BCR-ABL transcript level was 1% at 6 months. The ELN guide defines the treatment "failure" for a single measurement of BCR-ABL at 3 months to change the rationale for the treatment regimen and is not sufficient, It is therefore recommended that the BCR-ABL transcript level be reviewed at 6 months. The 3-month BCR-ABL transcript level is defined as a therapeutic "early warning" rather than a therapeutic "failure", at 6 months the transcript level is defined as a therapeutic "failure" and the transcript level is between 1 and 10% at 6 months and is also classified as a treatment "early warning". The 6-month transcript level is less than 1% considered to be the most desirable therapeutic response. Therefore, the main molecular biological response of gene detection was suggested every 3 months, that is, the level of BCR-ABL transcription was 0.1% by quantitative polymerase chain reaction (q-PCR) and international standard (IS). The acquisition of MMR has proven to be an important indicator of the delay in long-term survival. Recent studies have been approved to use molecular detection to study the effect of replacing the second-generation TKI drug. The ELN guide recommended that patients with CML-CP who had not reached about 10% of the level of BCR-ABL at 6 months after the initial TKI medication were treated with TKI medication. Therefore, the purpose of this study was to assess the clinical efficacy of the replacement of patients with CML-CP at the level of BCR-ABL at 6 months after the treatment of the first-line imatinib to nilotinib. Methods:81 patients with CML-CP who received imatinib as first-line treatment and did not reach BCR-ABL at 6 months after the start of treatment were analyzed retrospectively. All patients met the following conditions: (1) CML-CP patients who were positive with Ph (+) and/ or BCR-ABL fusion genes; (2) the age at first diagnosis was not lower than 18 years; (3) imatinib was accepted as a first line treatment between January 2001 and January 2015; (4) the treatment dose of imatinib is at least 300 mg/ d and is maintained for at least 6 months, the interruption time in the middle is not more than 30 days, and (5) the molecular biological reaction is tested every three months, The BCR-ABL transcripts at 6 months after the start of treatment were identified as treatment failure and need to be replaced with the second generation of TKI drug therapy. The patient was divided into two groups. The BCR-ABL transcript was not up to 10% at 6 months from the start of the imatinib treatment, but the patient who was later replaced with the second-generation TKI drug was the conversion group. However, the BCR-ABL transcript was not up to 10% at 6 months from the start of the imatinib treatment, but the patient continued to apply imatinib for more than 3 months as an unswitched group. Of the 22 patients in the conversion group, the median age was 37.5 (18-67) years, the median course was 34.5 (12-53) months, the median duration of the imatinib was 12.5 (6-36) months, the median treatment time of nilotinib was 17.5 (8-36) months, the median age of 40 (24-62) years for the non-conversion group, and the median course of the course of 48 (15-72) months, The median treatment time in imatinib was 43 (15-72) months. The proportion of MMR was obtained in the two groups at 3,6,9, and 12 months by the second test. The adverse reactions that occurred during the treatment of imatinib and nilotinib were also compared. During the treatment period, the patient regularly reexamined the blood routine, the blood biochemistry, the bone marrow image, the BCR-ABL fusion gene detection to assess the efficacy. Results: Most of the patients in the conversion group received MMR during the treatment period as compared to the non-transformed group. Conversion group (n = 17, 77.3%), untransformed group (n = 25, 42.4), P = 0.005. In addition, at each time period, the acquisition rate of the conversion group MMR is higher than that of the non-conversion group. Of these, at 3 months, the conversion group (n = 8, 36.4%), the non-conversion group (5, 8.5%), P = 0.007,6 months, the conversion group (13, 59.1%), the non-conversion group (16, 27.1%), P = 0.008,9 months, the conversion group (15, 68.2%), the non-conversion group (19, 32.2%), P = 0.004,12 months, the conversion group (17, 77.3%), the non-conversion group (25, 42.4%), P = 0.005. The results showed that the time of the MMR was more early in the conversion group than in the non-transformed group and the MMR was more easily obtained in the conversion group than in the non-transformed group. The results of the statistics show that the proportion of patients who have reached MMR at the follow-up period is greater than that of the non-transformed group, and the patients in the conversion group are more likely to reach the MMR at the time of the non-conversion group. The results of the adverse reactions of the two groups of patients found that the nilotinib was less adverse to the imatinib treatment and the patient was well-tolerated. Conclusion: BCR-ABL transcript levels of 10% at 6 months after imatinib treatment and the timely conversion to the second-generation TKI drug, nilotinib, is more early and easier to obtain MMR.2-nilotinib is less adverse reaction than imatinib. And the patient is well-tolerated.
【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R733.72
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