尼洛替尼治療伊馬替尼治療6個(gè)月時(shí)BCR-ABL轉(zhuǎn)錄本水平未達(dá)到≤10%的CML-CP患者的臨床觀察
發(fā)布時(shí)間：2019-06-02 22:58
【摘要】：目的:應(yīng)用酪氨酸激酶抑制劑(TKIs)治療是慢性粒細(xì)胞白血病(CML)慢性期(CP)患者的標(biāo)準(zhǔn)治療方案。甲磺酸伊馬替尼由于相比于干擾素能夠提高細(xì)胞遺傳學(xué)及分子生物學(xué)緩解率,因此是第一個(gè)被批準(zhǔn)作為一線治療的酪氨酸激酶抑制劑。但是,近30%的CML-CP患者在伊馬替尼治療12個(gè)月時(shí)未達(dá)到完全細(xì)胞遺傳學(xué)緩解。尼洛替尼和達(dá)沙替尼作為第二代酪氨酸激酶抑制劑(TKIs)已經(jīng)顯示出對(duì)伊馬替尼耐藥或者不耐受的CML-CP患者的益處。臨床實(shí)驗(yàn)數(shù)據(jù)已經(jīng)顯示了伊馬替尼治療失敗時(shí)換用二代TKI藥物的優(yōu)勢(shì),即換用二代TKI藥物的患者相比于增加伊馬替尼劑量的患者在12個(gè)月時(shí)有更高的CCy R獲得率。早期分子生物學(xué)緩解(EMR)定義為伊馬替尼或者達(dá)沙替尼治療CML患者后3個(gè)月時(shí)BCR-ABL轉(zhuǎn)錄本水平≤10%,其判斷預(yù)后的作用已得到認(rèn)可。EMR已經(jīng)被證實(shí)不僅與伊馬替尼治療后而且與伊馬替尼治療失敗后二代酪氨酸激酶抑制劑治療的長(zhǎng)期生存包括無進(jìn)展生存(PFS)和總生存(OS)密切相關(guān)。另外,有研究表明6個(gè)月時(shí)的BCR-ABL轉(zhuǎn)錄本水平與生存期也有關(guān)系。研究發(fā)現(xiàn)6個(gè)月時(shí)BCR-ABL轉(zhuǎn)錄本水平1%(89%)的患者的5年OS獲得率較BCR-ABL轉(zhuǎn)錄本水平≤1%(97%)更低。最新出版的新ELN關(guān)于CML的治療推薦規(guī)范將EMR的概念加入了臨床決策系統(tǒng)。里程碑式地加入了3個(gè)月時(shí)BCR-ABL轉(zhuǎn)錄本水平≤10%以及6個(gè)月時(shí)BCR-ABL轉(zhuǎn)錄本水平≤1%這一測(cè)定結(jié)果。ELN指南考慮單一測(cè)定3個(gè)月時(shí)BCR-ABL轉(zhuǎn)錄本水平來定義治療“失敗”從而更改治療方案理由并不充分,因此其建議6個(gè)月時(shí)復(fù)查BCR-ABL轉(zhuǎn)錄本水平。3個(gè)月BCR-ABL轉(zhuǎn)錄本水平10%被定義為治療“預(yù)警”而非治療“失敗”,6個(gè)月時(shí)轉(zhuǎn)錄本水平大于10%被定義為治療“失敗”而6個(gè)月時(shí)轉(zhuǎn)錄本水平介于1-10%之間的也被歸類為治療“預(yù)警”。6個(gè)月轉(zhuǎn)錄本水平小于1%被認(rèn)為是最理想的治療反應(yīng)。因此建議每3個(gè)月進(jìn)行基因檢測(cè)評(píng)估主要分子生物學(xué)緩解的獲得,即利用定量多聚酶鏈?zhǔn)椒磻?yīng)(q PCR)及國(guó)際標(biāo)準(zhǔn)(IS)測(cè)定BCR-ABL轉(zhuǎn)錄本水平≤0.1%。獲得MMR已經(jīng)被證明是延遲長(zhǎng)期生存的一項(xiàng)重要指標(biāo)。最近的研究都被批準(zhǔn)利用分子檢測(cè)研究更換二代TKI藥物治療的效果。ELN指南建議接受最初的TKI藥物治療后6個(gè)月BCR-ABL轉(zhuǎn)錄本水平未達(dá)到≤10%的CML-CP患者更換TKI藥物治療。因此,本研究旨在評(píng)估接受一線伊馬替尼治療后6個(gè)月BCR-ABL轉(zhuǎn)錄本水平未達(dá)到≤10%的CML-CP患者更換為尼洛替尼治療后的臨床療效。方法:回顧性分析了81名自2007年1月至2015年1月河北醫(yī)科大學(xué)第二醫(yī)院收治的接受伊馬替尼作為一線治療但在治療開始后6個(gè)月時(shí)未達(dá)到BCR-ABL轉(zhuǎn)錄本水平≤10%的CML-CP患者。所有的患者都滿足以下條件:(1)以Ph(+)和/或BCR-ABL融合基因陽性的CML-CP患者;(2)初診為CML時(shí)的年齡不得低于18歲;(3)在2001年1月至2015年1月之間接受伊馬替尼作為一線治療;(4)伊馬替尼的治療劑量至少為300mg/d且維持至少6個(gè)月,中途治療中斷時(shí)間不得多于30天;(5)每3個(gè)月測(cè)試分子生物學(xué)反應(yīng),并將治療開始后6個(gè)月BCR-ABL轉(zhuǎn)錄本水平10%認(rèn)定為治療失敗并且需要更換為二代TKI藥物治療�；颊吖卜譃閮山M。伊馬替尼治療開始6個(gè)月時(shí)BCR-ABL轉(zhuǎn)錄本水平未達(dá)到≤10%,但在此后更換為二代TKI藥物治療的患者為轉(zhuǎn)換組。而在伊馬替尼治療開始6個(gè)月時(shí)BCR-ABL轉(zhuǎn)錄本水平未達(dá)到≤10%但在此后繼續(xù)應(yīng)用伊馬替尼治療超過3個(gè)月的患者為未轉(zhuǎn)換組。其中轉(zhuǎn)換組共22名患者,中位年齡37.5(18-67)歲,中位病程34.5(12-53)個(gè)月,伊馬替尼中位治療時(shí)間12.5(6-36)個(gè)月,尼洛替尼中位治療時(shí)間17.5(8-36)個(gè)月,未轉(zhuǎn)換組59名患者,中位年齡40(24-62)歲,中位病程48(15-72)個(gè)月,伊馬替尼中位治療時(shí)間43(15-72)個(gè)月。通過χ2檢驗(yàn)比較兩組患者在3、6、9、12個(gè)月時(shí)獲得MMR的比例。同時(shí)比較伊馬替尼以及尼洛替尼治療過程中出現(xiàn)的不良反應(yīng)情況。在治療期間,患者規(guī)律復(fù)查血常規(guī)、血生化、骨髓象、BCR-ABL融合基因檢測(cè)以評(píng)估療效。結(jié)果:在治療期間,與未轉(zhuǎn)換組相比,轉(zhuǎn)換組患者中大多數(shù)獲得了MMR。轉(zhuǎn)換組(n=17,77.3%),未轉(zhuǎn)換組(n=25,42.4),P=0.005。另外,在每一個(gè)時(shí)間段,轉(zhuǎn)換組MMR的獲得率均較未轉(zhuǎn)換組高。其中,3個(gè)月時(shí),轉(zhuǎn)換組(n=8,36.4%),未轉(zhuǎn)換組(5,8.5%),P=0.007;6個(gè)月時(shí),轉(zhuǎn)換組(13,59.1%),未轉(zhuǎn)換組(16,27.1%),P=0.008;9個(gè)月時(shí),轉(zhuǎn)換組(15,68.2%),未轉(zhuǎn)換組(19,32.2%),P=0.004;12個(gè)月時(shí),轉(zhuǎn)換組(17,77.3%),未轉(zhuǎn)換組(25,42.4%),P=0.005。結(jié)果顯示轉(zhuǎn)換組較未轉(zhuǎn)換組獲得MMR的時(shí)間更早且轉(zhuǎn)換組較未轉(zhuǎn)換組患者更容易獲得MMR。統(tǒng)計(jì)結(jié)果顯示,轉(zhuǎn)換組患者在隨訪期間達(dá)到MMR的患者比例較未轉(zhuǎn)換組大,且轉(zhuǎn)換組患者較未轉(zhuǎn)換組患者更易且更早達(dá)到MMR。而比較兩組患者用藥的不良反應(yīng)結(jié)果發(fā)現(xiàn),尼洛替尼較伊馬替尼治療不良反應(yīng)少,患者耐受性更好。結(jié)論:1伊馬替尼治療后6個(gè)月時(shí)BCR-ABL轉(zhuǎn)錄本水平≤10%而及時(shí)轉(zhuǎn)換為二代TKI藥物尼洛替尼治療后的CML-CP患者相比于沒有轉(zhuǎn)換繼續(xù)應(yīng)用伊馬替尼治療的患者更早且更容易獲得MMR。2尼洛替尼較伊馬替尼治療不良反應(yīng)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.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：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.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2015
【分類號(hào)】：R733.72
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