發(fā)布時間：2018-06-19 05:30

  本文選題：多發(fā)性骨髓瘤 + 蛋白酶體抑制劑　； 參考：《甘肅中醫(yī)藥大學(原名：甘肅中醫(yī)學院)》2015年碩士論文

【摘要】：背景:多發(fā)性骨髓瘤(multiple myeloma,MM)起源于漿細胞,是一種血液系統(tǒng)惡性克隆增殖性疾病,以分泌單克隆免疫球蛋白或其片段(M蛋白)為特征,從而導致相關器官及組織受損。臨床的常見癥狀包括貧血、感染、腎功不全、骨骼破壞等。該病在血液腫瘤中發(fā)病概率約可占10%,中老年人好發(fā),在中國,平均發(fā)病年齡為56歲,自然病程約6~12個月,患者接受傳統(tǒng)化療后,中位生存期也僅提高到2.5~3年。上世紀末,造血干細胞移植在臨床廣泛應用,療效顯著,因而眾多國家指南推薦其為治療MM的一線方案。異基因造血干細胞移植(Allogeneic hematopoietic stem cell transplantation,allo-HSCT)雖有治愈MM的可能,但是Allo-HSCT僅適用于年齡55歲并有人類白細胞抗原(human leukocyte antigen,HLA)匹配的患者,而且由于移植相關死亡率(transplant related mortality,TRM)高、移植物抗宿主病(graft-versus-host disease,GVHD)等移植風險大,因而限制了allo-HSCT在臨床的廣泛應用。自體造血干細胞移植(Autologous hematopoietic stem cell transplantation,ASCT,auto-HSCT)能提高治療的反應率、完全緩解率、無事件存活率和總存活率,但移植后的遠期復發(fā)并不能避免,即不能徹底治愈疾病。近年隨著一些新藥的發(fā)現(xiàn)及老藥新用,如蛋白酶體抑制劑硼替佐米、卡非佐米,免疫調節(jié)劑沙利度胺、來那度胺等,MM治療的反應率和緩解率不斷被提高,取得了一定的研究進展,同時也對ASCT形成了挑戰(zhàn)。到目前為止,國內外已有多個隨機對照研究針對ASCT治療MM的療效與安全性進行了臨床試驗,并與傳統(tǒng)化療和新藥治療進行了比較。ASCT療效明顯高于傳統(tǒng)化療已經證實,但新藥(特別指蛋白酶體抑制劑和免疫調節(jié)劑)誘導后序貫鞏固及維持治療已成為新的趨勢,因此是否需要ASCT以及移植的時期已成為爭議的焦點�？紤]到單個研究可能存在統(tǒng)計學差異及臨床異質性,且樣本量小,缺乏有效的統(tǒng)計學效能,因此,我們運用系統(tǒng)評價中Meta分析的方法,閱讀和篩選出ASCT與靶向新藥治療MM的相關文獻7篇,累計自體造血干細胞移植的病例(ASCT組)達183例,靶向新藥治療的病例(新藥組)達208例,用定量合成的方法進行統(tǒng)計學處理,以期得到更加肯定、客觀及可靠的結論。目的:通過系統(tǒng)評價比較自體造血干細胞移植與新型藥物治療多發(fā)性骨髓瘤的療效及安全性。方法:通過計算機檢索以下中英文數(shù)據(jù)庫,即Pub Med、EMBase、中國生物醫(yī)學文摘(CBM)、中國知網(wǎng)(CNKI)、萬方醫(yī)學網(wǎng)、維普(VIP)、web of science等,全面收集自數(shù)據(jù)庫建立至2014年12月31日發(fā)表的關于ASCT與靶向新藥治療多發(fā)性骨髓瘤臨床病例對照研究的全部文獻,制定嚴格的納入/排除標準,搜索英文檢索詞:Multiple myeloma、Autologous hematopoietic stem cell transplantation、ASCT、proteasome inhibitor、protease inhibitor、immunomodulator、immunorugular、immunomodifier、Bortezomib、Tha Kdomide、Lenalidomide clinical trials;中文檢索詞:多發(fā)性骨髓瘤、自體造血干細胞移植、蛋白酶體抑制劑、免疫調節(jié)劑、硼替佐米、沙利度胺、來那度胺、臨床病例對照,最終篩選出符合納入標準的文獻共7篇,并應用Rev Man5.0軟件進行Meta分析,參與定量分析的結局指標包括完全緩解率/非常好地部分緩解率(complete response/very good partial response,CR/VGPR)、1年總生存率(overall survival,OS)、1年無進展生存率(progression free survival,PFS)、骨髓毒性反應率、III~IV級感染率、消化道反應率及周圍神經病變發(fā)生率。首先對納入的各研究效應量通過同質性檢驗(Qtest,Chi-square test),I2統(tǒng)計量定量,進行異質性分析,當存在低度異質性時,(即I250%),即各納入文獻無明顯統(tǒng)計學差異,則采用固定效應模型進行定量分析;反之,則采用隨機效應模型。通過漏斗圖檢測是否存在發(fā)表偏倚。用比值比(odds ratio,OR)和95%可信區(qū)間(confidence interval,CI)作為評價標準。結果:1.ASCT與新型藥物治療兩組間完全緩解/非常好地部分緩解(CR/VGPR)率的比較,結果顯示,兩組差異具有統(tǒng)計學意義[OR=2.30,95%CI(1.49,3.53),P=0.0002],且ASCT組治療MM的CR/VGPR率要高于新藥治療;2.ASCT與新型藥物治療兩組間1年無進展生存率(PFS)的比較,結果顯示,兩組差異無統(tǒng)計學意義[OR=2.00,95%CI(1.10,3.65),P=0.02];3.ASCT與新型藥物治療兩組間1年總生存率(OS)的比較,結果顯示,兩組差異無統(tǒng)計學意義[OR=2.24,95%CI(1.07,4.69),P=0.03];4.ASCT與新型藥物治療兩組間安全性的比較,結果顯示ASCT組與新型藥物治療組在治療MM的骨髓毒性反應率上,差異具有統(tǒng)計學意義[OR=3.02,95%CI(1.97,4.62),P0.00001],移植組的骨髓毒性反應要高于新藥治療;在III~IV級感染發(fā)生率上,差異具有統(tǒng)計學意義[OR=2.04,95%CI(1.24,3.35),P=0.005],移植組的III~IV級感染發(fā)生率要略高于新藥治療;兩組在消化道反應發(fā)生率上,差異具有統(tǒng)計學意義[OR=0.40,95%CI(0.22,0.72),P=0.002],且新藥組的消化道反應發(fā)生率略高于移植組;周圍神經病變發(fā)生率,差異具有明顯統(tǒng)計學意義[OR=0.14,95%CI(0.07,0.29),P0.00001],新藥組的周圍神經病變發(fā)生率明顯高于移植組。結論:1.經Meta分析檢驗提示,ASCT組治療MM的CR/VGPR率要高于新型藥物治療;2.經Meta分析檢驗提示,ASCT組與新型藥物治療MM的1年PFS率無明顯差異;3.經Meta分析檢驗提示,ASCT組與新型藥物治療MM的1年OS率無明顯差異;4.經Meta分析檢驗提示,ASCT組與新型藥物治療組在治療MM的安全性上,移植組的骨髓毒性反應及感染的發(fā)生率要高于新藥治療,但在消化道反應及周圍神經病變的發(fā)生率要低于新藥治療;5.自體造血干細胞移植治療多發(fā)性骨髓瘤的療效要略高于單純的新型藥物治療,但安全性并無顯著優(yōu)勢。
[Abstract]:Background: multiple myeloma (MM), which originated from plasma cells, is a malignant and proliferative disease of the blood system, which is characterized by secreting monoclonal immunoglobulin or its fragment (M protein), causing damage to related organs and tissues. The common clinical symptoms include anemia, infection, renal insufficiency, bone destruction, and so on. The incidence of the disease in the blood tumor is approximately 10%. The average age of the elderly is 56 years old in China. The course of natural disease is about 6~12 months. After the patients receive traditional chemotherapy, the median survival time is only increased to 2.5~3. Although Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has the potential to cure MM, Allo-HSCT only applies to patients aged 55 and 55 years old with human leukocyte antigen (human leukocyte antigen), and because of transplant related mortality Mortality, TRM), high risk of graft versus host disease (graft-versus-host disease, GVHD), and so on, limit the wide application of allo-HSCT in clinical practice. Autologous hematopoietic stem cell transplantation (Autologous hematopoietic stem cell transplantation, ASCT,) can improve the response rate, complete remission rate, non event survival rate, and no survival rate. The total survival rate, but the long-term recurrence after transplantation can not be avoided, that is, the disease can not be completely cured. In recent years, with the discovery of some new drugs and the new use of old drugs, such as the proteasome inhibitor bortezomib, camosomib, immunomodulator thalidomide, and amido, the reaction rate and remission rate of MM treatment have been continuously improved, and a certain study has been obtained. Progress has also been a challenge to ASCT. So far, a number of randomized controlled studies have conducted clinical trials on the efficacy and safety of ASCT for the treatment of MM, and compared with traditional chemotherapy and new drug treatment, the effect of.ASCT is obviously higher than that of traditional chemotherapy, but the new drugs (especially proteasome inhibitors and exemptions) The sequential consolidation and maintenance therapy after induction has become a new trend, so the need for ASCT and the period of transplantation has become the focus of controversy. Considering the possible existence of statistical and clinical heterogeneity in a single study, and the small sample size and lack of effective statistical effectiveness, we use Meta analysis in the system evaluation. Methods: reading and screening 7 articles related to ASCT and targeted new drugs for the treatment of MM, a total of 183 cases of autologous hematopoietic stem cell transplantation (group ASCT), and 208 cases (new drug groups) targeted to new drugs (new drug group), were statistically treated with quantitative synthetic methods to get more affirmative, objective and reliable conclusions. Objective: through system Evaluation and comparison of the efficacy and safety of autologous hematopoietic stem cell transplantation and new drug therapy for multiple myeloma. Methods: through the computer retrieval of the following Chinese and English databases, namely, Pub Med, EMBase, Chinese Biomedical Abstracts (CBM), Chinese knowledge network (CNKI), Wanfang medical network, VIP, web of science and so on. All literature on the clinical case control study of ASCT and targeted new drugs for multiple myeloma published in December 31, 2014, set strict inclusion / exclusion criteria, search English retrieval words: Multiple myeloma, Autologous hematopoietic stem cell transplantation, ASCT, proteasome inhibitor, protease consultants, R, immunorugular, immunomodifier, Bortezomib, Tha Kdomide, Lenalidomide clinical trials; Chinese retrieval words: multiple myeloma, autologous hematopoietic stem cell transplantation, proteasome inhibitor, immunomodulator, bortezomizomi, thalidomide, alidomide, in bed case control, and finally screened 7 documents conforming to the inclusion criteria, and should Rev Man5.0 software was used for Meta analysis, and the outcome indicators involved in quantitative analysis included complete remission rate / very good partial remission rate (complete response/very good partial response, CR/VGPR), 1 year total survival rate (overall survival, OS), 1 year progression free survival rate, bone marrow toxicity response rate, and sense of degree The rate of infection, the rate of digestive tract reaction and the incidence of peripheral neuropathy. First of all, the amount of study effects included by Qtest, Chi-square test, I2 statistics, and heterogeneity analysis. When there is low degree of heterogeneity, (i.e. I250%), that is, there is no significant statistical difference between the included articles, the fixed effect model is used for quantitative analysis. On the contrary, a random effect model was used. Whether there was a publication bias by the funnel plot. The ratio Ratio (odds ratio, OR) and 95% confidence interval (confidence interval, CI) were used as evaluation criteria. Results: the comparison of complete remission / non normally good partial remission (CR/VGPR) rate between the two groups of 1.ASCT and new drug treatment groups showed that two groups were found. The difference was statistically significant [OR=2.30,95%CI (1.49,3.53), P=0.0002], and the CR/VGPR rate of MM in group ASCT was higher than that of the new drug treatment. The comparison of the 1 year progression free survival rate (PFS) between the two groups of 2.ASCT and the new drug treatment group showed that the two groups had no statistically significant [OR= 2.00,95%CI (1.10,3.65), P=0.02], and new drug therapy two groups. The comparison of the total 1 year survival rate (OS) between the two groups showed that there was no significant difference between the two groups (1.07,4.69), P=0.03], and the comparison of the safety between the two groups of the new drug treatment groups, the results showed that the difference between the ASCT group and the new drug treatment group in the treatment of MM was statistically significant [OR=3.02,95%CI (1.97,4.62). P0.00001], the bone marrow toxicity of the transplanted group was higher than the new drug treatment, and the difference was statistically significant [OR=2.04,95%CI (1.24,3.35) in the incidence of III~IV infection, P=0.005], the incidence of III~IV grade infection in the transplantation group was slightly higher than that of the new drug treatment; the two groups had a statistically significant difference in the incidence of digestive tract reaction (0.2). (3) the difference of the two groups was statistically significant (0.2). 2,0.72), P=0.002], and the incidence of digestive tract reaction in the new drug group was slightly higher than that of the transplant group; the incidence of peripheral neuropathy was statistically significant [OR=0.14,95%CI (0.07,0.29). P0.00001], the incidence of peripheral neuropathy in the new drug group was significantly higher than that of the transplant group. Conclusion: 1. by Meta analysis, the CR/VGPR rate of MM in the ASCT group is required. Higher than new drug therapy; 2. Meta analysis showed no significant difference in the 1 year PFS rate between group ASCT and new drugs for MM. 3. Meta analysis showed no significant difference in the 1 year OS rate between the ASCT group and the new drug treatment MM; 4. the Meta analysis test suggested that the ASCT group and the new drug treatment group were safe for the MM treatment in the treatment group and the bone of the transplant group. The incidence of medullary toxicity and infection is higher than the new drug treatment, but the incidence of digestive tract reaction and peripheral neuropathy is lower than the new drug treatment. 5. autologous hematopoietic stem cell transplantation for multiple myeloma is slightly more effective than the simple new drug treatment, but there is no significant advantage in safety.
【學位授予單位】：甘肅中醫(yī)藥大學(原名：甘肅中醫(yī)學院)
【學位級別】：碩士
【學位授予年份】：2015
【分類號】：R733.3

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