自体造血干细胞移植与新药治疗多发性骨髓瘤疗效与安全性比较的Meta分析

发布时间：2018-06-19 05:30

本文选题：多发性骨髓瘤 + 蛋白酶体抑制剂　；参考：《甘肃中医药大学(原名：甘肃中医学院)》2015年硕士论文

【摘要】：背景:多发性骨髓瘤(multiple myeloma,MM)起源于浆细胞,是一种血液系统恶性克隆增殖性疾病,以分泌单克隆免疫球蛋白或其片段(M蛋白)为特征,从而导致相关器官及组织受损。临床的常见症状包括贫血、感染、肾功不全、骨骼破坏等。该病在血液肿瘤中发病概率约可占10%,中老年人好发,在中国,平均发病年龄为56岁,自然病程约6~12个月,患者接受传统化疗后,中位生存期也仅提高到2.5~3年。上世纪末,造血干细胞移植在临床广泛应用,疗效显著,因而众多国家指南推荐其为治疗MM的一线方案。异基因造血干细胞移植(Allogeneic hematopoietic stem cell transplantation,allo-HSCT)虽有治愈MM的可能,但是Allo-HSCT仅适用于年龄55岁并有人类白细胞抗原(human leukocyte antigen,HLA)匹配的患者,而且由于移植相关死亡率(transplant related mortality,TRM)高、移植物抗宿主病(graft-versus-host disease,GVHD)等移植风险大,因而限制了allo-HSCT在临床的广泛应用。自体造血干细胞移植(Autologous hematopoietic stem cell transplantation,ASCT,auto-HSCT)能提高治疗的反应率、完全缓解率、无事件存活率和总存活率,但移植后的远期复发并不能避免,即不能彻底治愈疾病。近年随着一些新药的发现及老药新用,如蛋白酶体抑制剂硼替佐米、卡非佐米,免疫调节剂沙利度胺、来那度胺等,MM治疗的反应率和缓解率不断被提高,取得了一定的研究进展,同时也对ASCT形成了挑战。到目前为止,国内外已有多个随机对照研究针对ASCT治疗MM的疗效与安全性进行了临床试验,并与传统化疗和新药治疗进行了比较。ASCT疗效明显高于传统化疗已经证实,但新药(特别指蛋白酶体抑制剂和免疫调节剂)诱导后序贯巩固及维持治疗已成为新的趋势,因此是否需要ASCT以及移植的时期已成为争议的焦点。考虑到单个研究可能存在统计学差异及临床异质性,且样本量小,缺乏有效的统计学效能,因此,我们运用系统评价中Meta分析的方法,阅读和筛选出ASCT与靶向新药治疗MM的相关文献7篇,累计自体造血干细胞移植的病例(ASCT组)达183例,靶向新药治疗的病例(新药组)达208例,用定量合成的方法进行统计学处理,以期得到更加肯定、客观及可靠的结论。目的:通过系统评价比较自体造血干细胞移植与新型药物治疗多发性骨髓瘤的疗效及安全性。方法:通过计算机检索以下中英文数据库,即Pub Med、EMBase、中国生物医学文摘(CBM)、中国知网(CNKI)、万方医学网、维普(VIP)、web of science等,全面收集自数据库建立至2014年12月31日发表的关于ASCT与靶向新药治疗多发性骨髓瘤临床病例对照研究的全部文献,制定严格的纳入/排除标准,搜索英文检索词:Multiple myeloma、Autologous hematopoietic stem cell transplantation、ASCT、proteasome inhibitor、protease inhibitor、immunomodulator、immunorugular、immunomodifier、Bortezomib、Tha Kdomide、Lenalidomide clinical trials;中文检索词:多发性骨髓瘤、自体造血干细胞移植、蛋白酶体抑制剂、免疫调节剂、硼替佐米、沙利度胺、来那度胺、临床病例对照,最终筛选出符合纳入标准的文献共7篇,并应用Rev Man5.0软件进行Meta分析,参与定量分析的结局指标包括完全缓解率/非常好地部分缓解率(complete response/very good partial response,CR/VGPR)、1年总生存率(overall survival,OS)、1年无进展生存率(progression free survival,PFS)、骨髓毒性反应率、III~IV级感染率、消化道反应率及周围神经病变发生率。首先对纳入的各研究效应量通过同质性检验(Qtest,Chi-square test),I2统计量定量,进行异质性分析,当存在低度异质性时,(即I250%),即各纳入文献无明显统计学差异,则采用固定效应模型进行定量分析;反之,则采用随机效应模型。通过漏斗图检测是否存在发表偏倚。用比值比(odds ratio,OR)和95%可信区间(confidence interval,CI)作为评价标准。结果:1.ASCT与新型药物治疗两组间完全缓解/非常好地部分缓解(CR/VGPR)率的比较,结果显示,两组差异具有统计学意义[OR=2.30,95%CI(1.49,3.53),P=0.0002],且ASCT组治疗MM的CR/VGPR率要高于新药治疗;2.ASCT与新型药物治疗两组间1年无进展生存率(PFS)的比较,结果显示,两组差异无统计学意义[OR=2.00,95%CI(1.10,3.65),P=0.02];3.ASCT与新型药物治疗两组间1年总生存率(OS)的比较,结果显示,两组差异无统计学意义[OR=2.24,95%CI(1.07,4.69),P=0.03];4.ASCT与新型药物治疗两组间安全性的比较,结果显示ASCT组与新型药物治疗组在治疗MM的骨髓毒性反应率上,差异具有统计学意义[OR=3.02,95%CI(1.97,4.62),P0.00001],移植组的骨髓毒性反应要高于新药治疗;在III~IV级感染发生率上,差异具有统计学意义[OR=2.04,95%CI(1.24,3.35),P=0.005],移植组的III~IV级感染发生率要略高于新药治疗;两组在消化道反应发生率上,差异具有统计学意义[OR=0.40,95%CI(0.22,0.72),P=0.002],且新药组的消化道反应发生率略高于移植组;周围神经病变发生率,差异具有明显统计学意义[OR=0.14,95%CI(0.07,0.29),P0.00001],新药组的周围神经病变发生率明显高于移植组。结论:1.经Meta分析检验提示,ASCT组治疗MM的CR/VGPR率要高于新型药物治疗;2.经Meta分析检验提示,ASCT组与新型药物治疗MM的1年PFS率无明显差异;3.经Meta分析检验提示,ASCT组与新型药物治疗MM的1年OS率无明显差异;4.经Meta分析检验提示,ASCT组与新型药物治疗组在治疗MM的安全性上,移植组的骨髓毒性反应及感染的发生率要高于新药治疗,但在消化道反应及周围神经病变的发生率要低于新药治疗;5.自体造血干细胞移植治疗多发性骨髓瘤的疗效要略高于单纯的新型药物治疗,但安全性并无显著优势。
[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.
【学位授予单位】：甘肃中医药大学(原名：甘肃中医学院)
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R733.3

【参考文献】