伊马替尼治疗新诊断和干扰素治疗失败的慢性髓性白血病疗效比较

发布时间：2018-02-22 22:52

  本文关键词： 慢性髓性白血病 伊马替尼 干扰素 融合基因 Ph1染色体 早期慢性期 晚期慢性期　出处：《浙江大学》2015年硕士论文　论文类型：学位论文

【摘要】：研究背景 慢性髓性白血病(chronic myeloid leukemia,CML)是一种发生于造血干细胞水平的、常见的血液系统恶性克隆增生性疾病,其分为慢性期(chronic phase, CP)、加速期(accelerated phase, AP)、急变期(blastic phase, BP)三期。Phl染色体是CML的特征性细胞遗传学改变,其是由t(9；22)(q34；q11)染色体易位形成的,即9号染色体的abl原癌基因移至22号染色体的bcr断裂点形成bcr-abl融合基因并表达bcr-abl融合蛋白。该bcr-abl融合蛋白具有很强的酪氨酸激酶活性,能够持续不断的激活下游增殖信号转导通路,促进细胞的增殖和存活,抑制细胞凋亡,并引起正常骨髓前体细胞的恶性转化。伊马替尼(Imatinib,IM)是第一代以bcr-abl融合蛋白为靶目标的分子靶向药物,它已成为治疗CML的一线药物。但在伊马替尼(IM)时代之前,干扰素α是治疗慢性髓性白血病慢性期(CML-CP)的一线药物。国内外均有文献报道,应用干扰素α治疗CML-CP患者能让少部分患者获得细胞遗传学及分子生物学缓解,改善长期生存,但是绝大部分患者不能获益或者因不能耐受药物毒副反应而终止治疗。目前,在我国CML患者发病率占总体白血病患者的20%左右,是一种很常见的恶性血液病,发病年龄在中老年人居多,IM时代之前多数患者中位生存期为3-4年,发生急变后预后极差。在一些偏远山区或者低收入家庭中,由于经济条件等因素限制,国内仍有部分患者选择干扰素α作为一线治疗；其中一些患者干扰素α治疗失败或者不耐受后再选择伊马替尼。有关伊马替尼治疗干扰素a失败或者不耐受患者的疗效如何,以及IM治疗新诊断CML组与干扰素失败组CML疗效差异程度,国内均无系统报道。本文回顾性分析和比较了伊马替尼治疗新诊断和干扰素α治疗失败的CML患者的疗效差异情况以及毒副作用,以期为临床治疗策略的制定提供依据。 目的 1.比较伊马替尼(IM)治疗新诊断组和干扰素治疗失败或者不耐受组的慢性髓性白血病患者的疗效差异,包括6个月时获得部分细胞遗传学缓解率、达到完全细胞遗传学缓解的平均时间、获得完全分子生物学反应率。 2.比较伊马替尼(M)治疗新诊断组和干扰素治疗失败或者不耐受组的慢性髓性白血病患者的原发和继发性细胞遗传学耐药差异。 3.比较在CML的早期慢性期(early chronic phase,ECP)、晚期慢性期(late chronic phase,LCP)接受IM治疗的新诊断组和干扰素治疗失败或者不耐受组之间的疗效差异,包括6个月时的部分细胞遗传学缓解率、达到完全细胞遗传学缓解的平均时间、获得完全分子生物学反应率。 4.比较伊马替尼(IM)治疗新诊断组和干扰素治疗失败或者不耐受组的慢性髓性白血病患者的毒副作用差异,包括血液学和非血液学毒副反应。 方法 收集86例应用400mg/天IM治疗的CML-CP患者临床资料,分为两组,其中新诊断组患者61例,IFNa治疗失败或不耐受(统称为干扰素α治疗失败组)组患者25例。采用R显带技术和定量实时PCR检测细胞遗传学和bcr-abl融合基因。对两组患者应用IM治疗后疗效差异、耐药情况及药物毒副反应程度(包括血液学毒性和非血液学毒性)应用统计学方法进行分析比较。 结果 1.新诊断组中,有50/61例(83%)患者IM治疗6个月时就获得部分细胞遗传学缓解(PCyR),而干扰素α治疗失败组仅为9/25例(36%),两组之间有显著差异(P0.05)。24个月时获得完全细胞遗传学缓解(CCyR)的患者,新诊断组为53/61例(86.9%),干扰素α治疗失败组为17/25例(68%),两组之间有显著差异(P0.001)。达到CCyR的时间,新诊断组平均时间6.0个月(2.9-7.7个月),干扰素α治疗失败组平均时间15.1个月(5.5-28.8个月),两组之间有显著差异(P=0.002)。获得主要分子生物学反应者在新诊断组47/61(77%)中高于干扰素α治疗失败组14/25(58%),但两组之间差异不显著(P=0.062)。获得完全分子生物学反应两组分别为43/61(70.4%)和10/25(40.0%),有显著性差异(P=0.033)。 2.新诊断组和干扰素治疗失败组两组患者中共有28例出现细胞遗传学耐药,新诊断组为14例(22.9%),其中原发性耐药4例(6.6%)；干扰素α治疗失败组为14例(56.0%),均为原发性耐药。干扰素α治疗失败组的患者对伊马替尼的原发耐药率显著高于新诊断组(P=0.003)。 3.CML患者在ECP接受IM治疗时,新诊断组患者24个月时获得PCyR、 CCyR、MMR、CMR分别为6/7例、5/8例、6/7例、5/7例,干扰素α治疗失败组患者24个月时获得PCyR、CCyR、MMR、CMR分别为7/7例、7/7例、6/7例、5/7例,两组之间无显著性差异(P0.05)。但新诊断组达到CCyR的中位时间为3.2个月(2.9-5.1个月)、干扰素α治疗失败组达到CcyR的中位时间为12.1个月(5.5-16.5个月),两组之间有显著差异(P0.05)。CML患者在LCP接受IM治疗时,新诊断组的24个月时获得PCyR、CCyR、MMR、CMR分别为51/54例、48/54例、41/54例、38/54例,干扰素α治疗失败组的24个月时获得PCyR、CCyR、 MMR、CMR分别为16/18例,10/18例、8/18例、5/18例,两组之间无显著性差异(P0.05)。但新诊断组达到CCyR的中位时间为6.3个月(4.9-7.7个月)、干扰素α治疗失败组为17.0个月(5.9-28.8个月),两组之间有显著差异(P0.05)。 4.新诊断组和干扰素α治疗失败组两组患者的血液学和非血液学毒性反应相似。主要毒副作用是水钠潴留,新诊断组和干扰素α治疗失败组分别为67.0%和68.7%；腹泻分别为30.0%和28.3%；肌肉酸痛分别为22.2%和24.1%。但干扰素α治疗失败组患者出现3-4级的贫血和白细胞减少显著高于新诊断组(P0.05)。 结论 1、与新诊断组相比,干扰素α治疗失败组的CML患者应用伊马替尼治疗,其原发性耐药发生率高、血液学毒副作用更大； 2、干扰素α治疗失败组患者应用伊马替尼治疗早期反应差,治疗6个月获得PCyR的患者比例显著低于新诊断组； 3、伊马替尼治疗24个月时,干扰素α治疗失败组患者获得CCyR和CMR的比例也显著低于新诊断组患者； 4、干扰素α治疗失败组患者在CML的ECP和LCP接受伊马替尼治疗获得CCyR中位时间均比新诊断组要延长； 5、研究结果提示CML-CP患者应及早使用伊马替尼治疗,对干扰素α治疗失败或者不耐受者应及时行bcr-abl激酶区突变检测,适时更换第二代TKI治疗。
[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).
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