本文關(guān)鍵詞： 慢性髓性白血病 伊馬替尼 干擾素 融合基因 Ph1染色體 早期慢性期 晚期慢性期　出處：《浙江大學(xué)》2015年碩士論文　論文類型：學(xué)位論文

【摘要】：研究背景 慢性髓性白血病(chronic myeloid leukemia,CML)是一種發(fā)生于造血干細胞水平的、常見的血液系統(tǒng)惡性克隆增生性疾病,其分為慢性期(chronic phase, CP)、加速期(accelerated phase, AP)、急變期(blastic phase, BP)三期。Phl染色體是CML的特征性細胞遺傳學(xué)改變,其是由t(9；22)(q34；q11)染色體易位形成的,即9號染色體的abl原癌基因移至22號染色體的bcr斷裂點形成bcr-abl融合基因并表達bcr-abl融合蛋白。該bcr-abl融合蛋白具有很強的酪氨酸激酶活性,能夠持續(xù)不斷的激活下游增殖信號轉(zhuǎn)導(dǎo)通路,促進細胞的增殖和存活,抑制細胞凋亡,并引起正常骨髓前體細胞的惡性轉(zhuǎn)化。伊馬替尼(Imatinib,IM)是第一代以bcr-abl融合蛋白為靶目標(biāo)的分子靶向藥物,它已成為治療CML的一線藥物。但在伊馬替尼(IM)時代之前,干擾素α是治療慢性髓性白血病慢性期(CML-CP)的一線藥物。國內(nèi)外均有文獻報道,應(yīng)用干擾素α治療CML-CP患者能讓少部分患者獲得細胞遺傳學(xué)及分子生物學(xué)緩解,改善長期生存,但是絕大部分患者不能獲益或者因不能耐受藥物毒副反應(yīng)而終止治療。目前,在我國CML患者發(fā)病率占總體白血病患者的20%左右,是一種很常見的惡性血液病,發(fā)病年齡在中老年人居多,IM時代之前多數(shù)患者中位生存期為3-4年,發(fā)生急變后預(yù)后極差。在一些偏遠山區(qū)或者低收入家庭中,由于經(jīng)濟條件等因素限制,國內(nèi)仍有部分患者選擇干擾素α作為一線治療；其中一些患者干擾素α治療失敗或者不耐受后再選擇伊馬替尼。有關(guān)伊馬替尼治療干擾素a失敗或者不耐受患者的療效如何,以及IM治療新診斷CML組與干擾素失敗組CML療效差異程度,國內(nèi)均無系統(tǒng)報道。本文回顧性分析和比較了伊馬替尼治療新診斷和干擾素α治療失敗的CML患者的療效差異情況以及毒副作用,以期為臨床治療策略的制定提供依據(jù)。 目的 1.比較伊馬替尼(IM)治療新診斷組和干擾素治療失敗或者不耐受組的慢性髓性白血病患者的療效差異,包括6個月時獲得部分細胞遺傳學(xué)緩解率、達到完全細胞遺傳學(xué)緩解的平均時間、獲得完全分子生物學(xué)反應(yīng)率。 2.比較伊馬替尼(M)治療新診斷組和干擾素治療失敗或者不耐受組的慢性髓性白血病患者的原發(fā)和繼發(fā)性細胞遺傳學(xué)耐藥差異。 3.比較在CML的早期慢性期(early chronic phase,ECP)、晚期慢性期(late chronic phase,LCP)接受IM治療的新診斷組和干擾素治療失敗或者不耐受組之間的療效差異,包括6個月時的部分細胞遺傳學(xué)緩解率、達到完全細胞遺傳學(xué)緩解的平均時間、獲得完全分子生物學(xué)反應(yīng)率。 4.比較伊馬替尼(IM)治療新診斷組和干擾素治療失敗或者不耐受組的慢性髓性白血病患者的毒副作用差異,包括血液學(xué)和非血液學(xué)毒副反應(yīng)。 方法 收集86例應(yīng)用400mg/天IM治療的CML-CP患者臨床資料,分為兩組,其中新診斷組患者61例,IFNa治療失敗或不耐受(統(tǒng)稱為干擾素α治療失敗組)組患者25例。采用R顯帶技術(shù)和定量實時PCR檢測細胞遺傳學(xué)和bcr-abl融合基因。對兩組患者應(yīng)用IM治療后療效差異、耐藥情況及藥物毒副反應(yīng)程度(包括血液學(xué)毒性和非血液學(xué)毒性)應(yīng)用統(tǒng)計學(xué)方法進行分析比較。 結(jié)果 1.新診斷組中,有50/61例(83%)患者IM治療6個月時就獲得部分細胞遺傳學(xué)緩解(PCyR),而干擾素α治療失敗組僅為9/25例(36%),兩組之間有顯著差異(P0.05)。24個月時獲得完全細胞遺傳學(xué)緩解(CCyR)的患者,新診斷組為53/61例(86.9%),干擾素α治療失敗組為17/25例(68%),兩組之間有顯著差異(P0.001)。達到CCyR的時間,新診斷組平均時間6.0個月(2.9-7.7個月),干擾素α治療失敗組平均時間15.1個月(5.5-28.8個月),兩組之間有顯著差異(P=0.002)。獲得主要分子生物學(xué)反應(yīng)者在新診斷組47/61(77%)中高于干擾素α治療失敗組14/25(58%),但兩組之間差異不顯著(P=0.062)。獲得完全分子生物學(xué)反應(yīng)兩組分別為43/61(70.4%)和10/25(40.0%),有顯著性差異(P=0.033)。 2.新診斷組和干擾素治療失敗組兩組患者中共有28例出現(xiàn)細胞遺傳學(xué)耐藥,新診斷組為14例(22.9%),其中原發(fā)性耐藥4例(6.6%)；干擾素α治療失敗組為14例(56.0%),均為原發(fā)性耐藥。干擾素α治療失敗組的患者對伊馬替尼的原發(fā)耐藥率顯著高于新診斷組(P=0.003)。 3.CML患者在ECP接受IM治療時,新診斷組患者24個月時獲得PCyR、 CCyR、MMR、CMR分別為6/7例、5/8例、6/7例、5/7例,干擾素α治療失敗組患者24個月時獲得PCyR、CCyR、MMR、CMR分別為7/7例、7/7例、6/7例、5/7例,兩組之間無顯著性差異(P0.05)。但新診斷組達到CCyR的中位時間為3.2個月(2.9-5.1個月)、干擾素α治療失敗組達到CcyR的中位時間為12.1個月(5.5-16.5個月),兩組之間有顯著差異(P0.05)。CML患者在LCP接受IM治療時,新診斷組的24個月時獲得PCyR、CCyR、MMR、CMR分別為51/54例、48/54例、41/54例、38/54例,干擾素α治療失敗組的24個月時獲得PCyR、CCyR、 MMR、CMR分別為16/18例,10/18例、8/18例、5/18例,兩組之間無顯著性差異(P0.05)。但新診斷組達到CCyR的中位時間為6.3個月(4.9-7.7個月)、干擾素α治療失敗組為17.0個月(5.9-28.8個月),兩組之間有顯著差異(P0.05)。 4.新診斷組和干擾素α治療失敗組兩組患者的血液學(xué)和非血液學(xué)毒性反應(yīng)相似。主要毒副作用是水鈉潴留,新診斷組和干擾素α治療失敗組分別為67.0%和68.7%；腹瀉分別為30.0%和28.3%；肌肉酸痛分別為22.2%和24.1%。但干擾素α治療失敗組患者出現(xiàn)3-4級的貧血和白細胞減少顯著高于新診斷組(P0.05)。 結(jié)論 1、與新診斷組相比,干擾素α治療失敗組的CML患者應(yīng)用伊馬替尼治療,其原發(fā)性耐藥發(fā)生率高、血液學(xué)毒副作用更大； 2、干擾素α治療失敗組患者應(yīng)用伊馬替尼治療早期反應(yīng)差,治療6個月獲得PCyR的患者比例顯著低于新診斷組； 3、伊馬替尼治療24個月時,干擾素α治療失敗組患者獲得CCyR和CMR的比例也顯著低于新診斷組患者； 4、干擾素α治療失敗組患者在CML的ECP和LCP接受伊馬替尼治療獲得CCyR中位時間均比新診斷組要延長； 5、研究結(jié)果提示CML-CP患者應(yīng)及早使用伊馬替尼治療,對干擾素α治療失敗或者不耐受者應(yīng)及時行bcr-abl激酶區(qū)突變檢測,適時更換第二代TKI治療。
[Abstract]:Research background
Chronic myeloid leukemia (chronic myeloid, leukemia, CML) is a place in the level of hematopoietic stem cell, common hematological malignant clonal proliferative disease, divided into chronic phase (chronic, phase, CP), accelerated phase (accelerated, phase, AP) (blastic phase, BP blastic phase) three.Phl the chromosome is the characteristic changes of cell genetics of CML, which is composed of T (9; 22) (q34; Q11) translocation formation, namely BCR breaking point abl gene to chromosome 9 chromosome 22 formation of bcr-abl fusion gene and expression of bcr-abl fusion protein. The fusion protein of BCR-ABL with tyrosine kinase activity very strong, can continue to activate the proliferation signal transduction pathway, promote cell proliferation and survival, apoptosis, and cause the malignant transformation of normal bone marrow progenitor cells. Imatinib (Imatinib, IM) is the first generation of bcr-abl fusion Protein targeting molecular targeted drugs, it has become the first-line drug for the treatment of CML. But in imatinib (IM) before the time of interferon treatment of chronic myeloid leukemia in chronic phase (CML-CP) of the first-line drugs. At home and abroad have reported that application of interferon alpha therapy in patients with CML-CP can make a small part of the patients cytogenetic and molecular remission, improve long-term survival, but most patients do not benefit or due to toxicity of drug intolerance to terminate treatment. At present, in our country the incidence rate of patients with CML accounted for about 20% of overall leukemia patients, is a kind of malignant hematologic disease is very common, the age of onset in the elderly IM, before the age of majority of patients with a median survival of 3-4 years, poor prognosis after blast crisis. In some remote mountainous areas or in low-income families, due to the limited economic conditions and other factors, there are still some patients The choice of interferon alpha as first-line treatment; some patients with interferon alpha treatment failure or intolerance to imatinib. The imatinib treatment efficacy of interferon a failure or intolerance to patients, and IM in the treatment of newly diagnosed CML group and CML group the degree of failure of interferon efficacy, domestic no system. This paper reports review the difference analysis and comparison of the failure of imatinib treatment in newly diagnosed and interferon alpha therapy in CML patients the efficacy and side effects, in order to provide the basis for the development of clinical treatment strategies.
objective
1. compared with imatinib (IM) therapy in newly diagnosed group and the failure of interferon therapy or curative effect in chronic myeloid leukemia patients intolerant group, including 6 months to obtain partial cytogenetic remission rate, average time to complete cytogenetic remission, complete molecular response rate.
2., we compared the difference between primary and secondary cytogenetic resistance in patients with chronic myelogenous leukemia treated by new diagnostic group and interferon treatment failure or intolerance group (M).
3. in the early chronic phase of CML (early chronic phase, ECP), the late chronic phase (late chronic phase, LCP) for the treatment of IM in newly diagnosed group and the failure of interferon therapy or curative effect between intolerance group, including some 6 months of cytogenetic remission rate, average time to complete remission cell genetics, complete molecular response rate.
4. to compare the side effects of imatinib (IM) in the treatment of chronic myelogenous leukemia in the new diagnostic group and the IFN treatment failure or intolerance group, including hematological and non hematologic side effects.
Method
86 cases were collected using 400mg/ days IM treatment of CML-CP clinical data were divided into two groups, including 61 cases of newly diagnosed patients with IFNa, treatment failure or intolerance (referred to as the failure group interferon therapy) 25 cases of patients. R banding technique and quantitative real-time PCR detection of cytogenetic and fusion gene by bcr-abl. The difference of curative effect of two groups of patients after treatment with IM, drug resistance and drug toxicity degree (including hematologic toxicity and non hematologic toxicity) were analyzed by statistical method.
Result
1. newly diagnosed group, 50/61 cases (83%) patients with IM for 6 months to get partial cytogenetic remission (PCyR), and interferon alpha treatment failure group was only 9/25 cases (36%), there are significant differences between the two groups (P0.05).24 months to obtain complete cytogenetic remission (CCyR) patients with newly diagnosed group 53/61 cases (86.9%), interferon alpha treatment failure group was 17/25 cases (68%), there are significant differences between the two groups (P0.001). At the time of CCyR, the newly diagnosed group the average time of 6 months (2.9-7.7 months), interferon failure group mean treatment time was 15.1 months (5.5-28.8 months), there were significant differences between the two groups (P=0.002). The main molecular response in newly diagnosed 47/61 group (77%) is higher than that of interferon alpha treatment failure group 14/25 (58%), but no significant difference between the two groups (P=0.062). The complete molecular reactions of the two groups respectively (43/61 70.4%) and 10/25 (40%), There were significant differences (P=0.033).
2. newly diagnosed group and the failure of interferon therapy group two patients with a total of 28 cases of cytogenetic resistance, newly diagnosed group was 14 cases (22.9%), the primary resistance in 4 cases (6.6%); interferon alpha for the treatment of 14 cases of failure group (56%), are the primary resistance to interferon treatment. Failure of treatment in patients with primary resistance to imatinib was significantly higher than the rate of newly diagnosed group (P=0.003).
3.CML鎮(zhèn)ｈ，

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