弥漫大B细胞淋巴瘤免疫组化标记的预后意义及利妥昔单抗对其影响的临床研究
发布时间：2019-05-23 07:03
【摘要】：目的:DLBCL患者在治疗反应以及预后具有显著的生物学异质性,不同的免疫亚型及ki-67、bcl-2的表达与预后有着密切的关系。随着免疫治疗药物利妥昔单抗的应用DLBCL生存得到明显改善,因此上述基于传统化疗的预后指标有待重新评价研究。本文旨在探讨弥漫大B细胞淋巴瘤患者免疫学标记及免疫学亚型的预后价值,以及利妥昔单抗对免疫组化标记预后意义的影响。方法:回顾性分析新疆自治区人民医院2005年1月-2013年12月收治的186例临床资料和随访记录完整的初治DLBCL患者病例资料,重新进行国际预后指数评分,根据治疗方案分为化疗组(CHOP)及免疫化疗组(RCHOP),所有患者都应用免疫组织化学方法检测CD45RO,CD3,CD5,CD20,CD79a,bcl-2,ki-67,bcl-6,CD10,MUM-1的表达,并按hans分型方法将两组患者分别分为GCB、non-GCB亚型,采用Kaplan-Meier法和Cox回归模型,探讨并比较bcl-6,CD10,MUM-1的表达以及免疫学亚型、bcl-2、ki-67、国际预后指数等指标在两组DLBCL患者的预后意义。结果:1.186例DLBCL患者化疗组84例、免疫化疗组102例,5年OS分别为42.86%、65.69%,二者差异有统计学意义(?2=7.111,P=0.008)。2.化疗组中GCB型和non-GCB型的5年OS分别为58.82%和32.00%,差异有统计学意义(?2=8.482,P=0.004);免疫化疗组中GCB型和non-GCB型的5年OS分别为72.97%和61.54%,差异无统计学意义(?2=2.694,P=0.101);进一步分析显示,non-GCB亚型中免疫化疗组5年OS显著优于化疗组(?2=7.385,P=0.007),但GCB亚型中两种治疗组5年OS差异无统计学意义(?2=1.304,P=0.253)。3.低危组107例,其中化疗组47例,免疫化疗组60例,进一步分组,化疗组中GCB型(19例)和non-GCB型(28例)5年OS分别为63.16%和46.43%,差异无统计学意义(?2=1.531,P=0.216),免疫化疗组中GCB型(21例)和non-GCB型(39例)的5年OS分别为80.95%和74.36%,差异无统计学意义(?2=0.762,P=0.383);进一步分析显示,GCB及non-GCB亚型中化疗与免疫化疗组5年OS差异均无统计学意义(?2=0.867,P=0.352;?2=2.828,P=0.093)。高危组79例,其中化疗组37例,免疫化疗组42例,进一步分组,化疗组中GCB型(15例)和non-GCB型(22例)的5年OS分别为40.00%和22.72%,差异有统计学意义(?2=3.978,P=0.045),免疫化疗组中GCB型(16例)和non-GCB型(26例)的5年OS分别为62.50%和42.31%,差异无统计学意义(?2=2.072,P=0.150);进一步分析显示,GCB及non-GCB亚型中化疗组与免疫化疗组5年OS差异均无统计学意义(?2=1.336,P=0.248;?2=1.873,P=0.171)。4.Cox多因素分析结果显示,在化疗组,ki-67≥60%(HR=0.910,95%CI=1.334-4.623,P=0.004)、IPI高危组(HR=0.669,95%CI=1.059-3.599,P=0.032),在免疫化疗组,ki-67≥60%(HR=0.858,95%CI=1.078-4.521,P=0.030)、IPI高危组(HR=1.203,95%CI=1.609-6.889,P=0.001),两组ki-67、国际预后指数评分均是独立的预后因素。5.生存分析显示,化疗组non-GCB亚型中bcl-2阳性组较bcl-2阴性组预后差,差异有统计学意义(P=0.025),而其它各亚组bcl-2阳性组与bcl-2阴性组生存无差异。结论:1.免疫组化法将初治DLBCL分为两种免疫亚型,对于早期判断预后,指导治疗具有一定的指导意义,在利妥昔单抗时代,免疫组化分型预后预测意义可能较以往有所降低。2.利妥昔单抗可显著提高non-GCB型DLBCL患者的疗效,但是对GCB型患者生存期的影响还需进一步探讨。3.DLBCL患者免疫学标记具有一定的预后意义,无论在化疗组、免疫化疗组ki-67≥60%以及IPI高危组均是独立的不良预后因素。而bcl-2联合免疫学亚型对预后有一定提示意义。4.利妥昔单抗可改善DLBCL患者non-GCB亚型伴bcl-2阳性患者预后。在non-GCB亚型,利妥昔单抗显示出明显的治疗优势,可能与该亚型bcl-2过表达有关,进一步提示利妥昔单抗可能克服bcl-2过表达的不良影响。
[Abstract]:Objective: The patients with DLBCL have significant biological heterogeneity, different immune subtypes and ki-67, and the expression of bcl-2 is closely related to the prognosis. With the improvement of the survival of the DLBCL with the application of rituximab, the above-mentioned prognostic indicators based on conventional chemotherapy have yet to be re-evaluated. The purpose of this study is to study the prognostic value of immunological markers and immunological subtypes in patients with diffuse large B-cell lymphoma, as well as the effect of rituximab on the prognostic significance of immunohistochemistry. Methods:186 clinical data and follow-up records from January 2005 to December 2013 of the People's Hospital of Xinjiang Autonomous Region were analyzed retrospectively. The expressions of CD45RO, CD3, CD5, CD20, CD79a, bcl-2, ki-67, bcl-6, CD10 and MUM-1 were detected by immunohistochemistry in all patients. The expression of MUM-1, as well as the immunological subtype, bcl-2, ki-67, and international prognostic index in the prognosis of two groups of DLBCL patients. Results: 1.186 patients with DLBCL in the chemotherapy group,102 cases of the immune chemotherapy group and 42.86% and 65.69% of the 5-year OS, respectively. 2=7.111,P=0.008).2. The 5-year OS of GCB and non-GCB in the chemotherapy group was 58.82% and 32.00%, respectively. 2 = 8.482, P = 0.004); the 5-year OS of GCB and non-GCB in the immune chemotherapy group was 72.97% and 61.54%, respectively, with no statistical significance (? 2 = 2.694, P = 0.101); further analysis showed that the 5-year OS in the non-GCB subtype was significantly superior to the chemotherapy group (? 2 = 7.385, P = 0.007), but there was no statistical significance for the 5-year OS difference between the two treatment groups in the GCB subtype (? 2=1.304,P=0.253).3. There were 107 cases of low-risk group, including 47 cases of chemotherapy group,60 cases of immune chemotherapy group, further group, GCB-type (19 cases) and non-GCB-type (28 cases)5-year OS in the chemotherapy group were 63.16% and 46.43%, respectively, and the difference was not significant (? 2 = 1.531, P = 0.216), the 5-year OS of GCB-type (21 cases) and non-GCB-type (39 cases) in the immune-chemotherapy group were 80.95% and 74.36%, respectively. 2 = 0.762, P = 0.383); further analysis showed no statistical significance for the 5-year OS difference in the GCB and non-GCB subtypes (? 2=0.867,P=0.352;? 2=2.828,P=0.093). 79 of the high-risk group, including 37 of the chemotherapy group,42 in the immune-chemotherapy group, the further group, the 5-year OS of the GCB-type (15 cases) and the non-GCB-type (22 cases) in the chemotherapy group were 40.00% and 22.72%, respectively, and the difference was statistically significant (? 2 = 3.978, P = 0.045), the 5-year OS of GCB-type (16 cases) and non-GCB-type (26 cases) in the immune chemotherapy group was 62.50% and 42.31%, respectively. 2 = 2.072, P = 0.150); further analysis showed that there was no statistical significance for the 5-year OS difference between the chemotherapy group and the non-GCB subtype in the GCB and non-GCB subtypes (? 2=1.336,P=0.248;? 2 = 1.873, P = 0.171).4. Cox multi-factor analysis showed that in the chemotherapy group, ki-67-60% (HR = 0.910,95% CI = 1.334-4.623, P = 0.004), IPI high-risk group (HR = 0.669,95% CI = 1.059-3.599, P = 0.032), in the immune-chemotherapy group, ki-67-60% (HR = 0.858,95% CI = 1.078-4.521, P = 0.030), IPI high-risk group (HR = 1.203,95% CI = 1.609-6.889, P = 0.001), and the two groups of ki-67 and international prognostic index scores were independent prognostic factors. The survival analysis showed that the bcl-2 positive group and the bcl-2 negative group in the non-GCB subtype of the chemotherapy group had poor prognosis, and there was no difference in the survival of the bcl-2 positive group and the bcl-2 negative group in the other subgroups (P = 0.025). Conclusion:1. The first treatment of DLBCL was divided into two types of immunophenotyping. Rituximab can significantly improve the efficacy of non-GCB-type DLBCL patients, but it is necessary to further explore the effect of rituximab on the survival of patients with GCB type.3. The immunological markers of DLBCL patients have a certain prognostic significance, no matter in the chemotherapy group, The group of immunochemotherapy group ki-67-60% and the high-risk group of IPI were independent poor prognosis factors. The co-immunological subtype of bcl-2 has a certain significance for prognosis. Rituximab can improve the prognosis of non-GCB subtype with bcl-2 positive patients in the patients with DLBCL. In the non-GCB subtype, rituximab shows a significant therapeutic advantage and may be related to the overexpression of the subtype of bcl-2, further suggesting that rituximab may overcome the negative effects of the overexpression of bcl-2.
【学位授予单位】：安徽医科大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R733.1
本文编号：2483699
[Abstract]:Objective: The patients with DLBCL have significant biological heterogeneity, different immune subtypes and ki-67, and the expression of bcl-2 is closely related to the prognosis. With the improvement of the survival of the DLBCL with the application of rituximab, the above-mentioned prognostic indicators based on conventional chemotherapy have yet to be re-evaluated. The purpose of this study is to study the prognostic value of immunological markers and immunological subtypes in patients with diffuse large B-cell lymphoma, as well as the effect of rituximab on the prognostic significance of immunohistochemistry. Methods:186 clinical data and follow-up records from January 2005 to December 2013 of the People's Hospital of Xinjiang Autonomous Region were analyzed retrospectively. The expressions of CD45RO, CD3, CD5, CD20, CD79a, bcl-2, ki-67, bcl-6, CD10 and MUM-1 were detected by immunohistochemistry in all patients. The expression of MUM-1, as well as the immunological subtype, bcl-2, ki-67, and international prognostic index in the prognosis of two groups of DLBCL patients. Results: 1.186 patients with DLBCL in the chemotherapy group,102 cases of the immune chemotherapy group and 42.86% and 65.69% of the 5-year OS, respectively. 2=7.111,P=0.008).2. The 5-year OS of GCB and non-GCB in the chemotherapy group was 58.82% and 32.00%, respectively. 2 = 8.482, P = 0.004); the 5-year OS of GCB and non-GCB in the immune chemotherapy group was 72.97% and 61.54%, respectively, with no statistical significance (? 2 = 2.694, P = 0.101); further analysis showed that the 5-year OS in the non-GCB subtype was significantly superior to the chemotherapy group (? 2 = 7.385, P = 0.007), but there was no statistical significance for the 5-year OS difference between the two treatment groups in the GCB subtype (? 2=1.304,P=0.253).3. There were 107 cases of low-risk group, including 47 cases of chemotherapy group,60 cases of immune chemotherapy group, further group, GCB-type (19 cases) and non-GCB-type (28 cases)5-year OS in the chemotherapy group were 63.16% and 46.43%, respectively, and the difference was not significant (? 2 = 1.531, P = 0.216), the 5-year OS of GCB-type (21 cases) and non-GCB-type (39 cases) in the immune-chemotherapy group were 80.95% and 74.36%, respectively. 2 = 0.762, P = 0.383); further analysis showed no statistical significance for the 5-year OS difference in the GCB and non-GCB subtypes (? 2=0.867,P=0.352;? 2=2.828,P=0.093). 79 of the high-risk group, including 37 of the chemotherapy group,42 in the immune-chemotherapy group, the further group, the 5-year OS of the GCB-type (15 cases) and the non-GCB-type (22 cases) in the chemotherapy group were 40.00% and 22.72%, respectively, and the difference was statistically significant (? 2 = 3.978, P = 0.045), the 5-year OS of GCB-type (16 cases) and non-GCB-type (26 cases) in the immune chemotherapy group was 62.50% and 42.31%, respectively. 2 = 2.072, P = 0.150); further analysis showed that there was no statistical significance for the 5-year OS difference between the chemotherapy group and the non-GCB subtype in the GCB and non-GCB subtypes (? 2=1.336,P=0.248;? 2 = 1.873, P = 0.171).4. Cox multi-factor analysis showed that in the chemotherapy group, ki-67-60% (HR = 0.910,95% CI = 1.334-4.623, P = 0.004), IPI high-risk group (HR = 0.669,95% CI = 1.059-3.599, P = 0.032), in the immune-chemotherapy group, ki-67-60% (HR = 0.858,95% CI = 1.078-4.521, P = 0.030), IPI high-risk group (HR = 1.203,95% CI = 1.609-6.889, P = 0.001), and the two groups of ki-67 and international prognostic index scores were independent prognostic factors. The survival analysis showed that the bcl-2 positive group and the bcl-2 negative group in the non-GCB subtype of the chemotherapy group had poor prognosis, and there was no difference in the survival of the bcl-2 positive group and the bcl-2 negative group in the other subgroups (P = 0.025). Conclusion:1. The first treatment of DLBCL was divided into two types of immunophenotyping. Rituximab can significantly improve the efficacy of non-GCB-type DLBCL patients, but it is necessary to further explore the effect of rituximab on the survival of patients with GCB type.3. The immunological markers of DLBCL patients have a certain prognostic significance, no matter in the chemotherapy group, The group of immunochemotherapy group ki-67-60% and the high-risk group of IPI were independent poor prognosis factors. The co-immunological subtype of bcl-2 has a certain significance for prognosis. Rituximab can improve the prognosis of non-GCB subtype with bcl-2 positive patients in the patients with DLBCL. In the non-GCB subtype, rituximab shows a significant therapeutic advantage and may be related to the overexpression of the subtype of bcl-2, further suggesting that rituximab may overcome the negative effects of the overexpression of bcl-2.
【学位授予单位】：安徽医科大学
【学位级别】：硕士
【学位授予年份】：2015
【分类号】：R733.1
【参考文献】
相关期刊论文 前1条
1 周颖;赵瑜;薄剑;李艳芬;马超;石亚男;;Ki-67在弥漫大B细胞淋巴瘤中的表达及临床意义[J];中国实验血液学杂志;2013年05期
，本文编号：2483699
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