纵隔大B淋巴瘤周生余.ppt

1、纵隔大B细胞淋巴瘤内科诊治策略,中国医学科学院肿瘤医院内科周 生 余,PMBL诊治策略,对PMBL认识DLBCL独特亚型；内科治疗策略第三代强烈化疗方案优于CHOP；联合利妥昔单抗优于单纯化疗；DA-EPOCH-R方案显示良好生存优势；中枢预防的应用。综合治疗探索标准治疗为化疗联合放疗；放疗临床获益待进一步明确；全身PET/CT指引下的临床治疗。,PMBL诊治策略,对PMBL认识DLBCL独特亚型；内科治疗策略第三代强烈化疗方案优于CHOP；联合利妥昔单抗优于单纯化疗；DA-EPOCH-R方案显示良好生存优势；中枢预防的应用。综合治疗探索标准治疗为化疗联合放疗；放疗临床获益待进一步明确；全身P

2、ET/CT指引下的临床治疗。,PMBL-概述,独立亚型：最早于1981年提出，1994年REAL，2008年WHO，DLBCL的独立亚型发病率：NHL 2-4%； DLBCL 6%-13%，纵膈最常见的NHL。发病年龄: 30-40岁青年，女男临床特征：前上纵膈大肿块，上腔静脉综合征，胸腔、心包积液I-II期，骨髓侵犯少见侵犯肺、胸壁、胸膜、心包复发时肝、肾、CNS可受累,DLBCL与PMBL临床特征,组织形态学：纤维组织增生，将肿瘤组织分隔形成结节；瘤细胞中等偏大，细胞质丰富，细胞核不规则，可见R-S样细胞。免疫组化表型：B细胞：CD19、CD20、 CD22、CD79a 核表达：PAX5、

3、BCL-6、IFRF4/mum-1，OCT2、BOB.1CD23+， CD30弱+，CD15-，CD10-遗传学改变：IGH基因克隆性重排；体细胞突变+9p24/JAK2（-75%）+2p25/REL（- 50%）+Xp11.4-21，+Xq24-26,PMBL-病理、分子遗传学特征,不同亚型DLBCL的致癌通路,NEJM, 2010,362;15,Oncogenic pathways for three subtypes of diffuse large B-cell lymphoma,Genetic alterations and deregulated signaling pathway

4、s,BLOOD, 8 SEPTEMBER 2011VOLUME 118, NUMBER 10,DLBCL基因表达谱与分子病理预后研究,46例诊断PMBL：35例（76%）PMBL；11例DLBCL-7例GCB、4例ABC DLBCL,纵隔淋巴瘤相关关系,Rosenwald A,et al. J Exp Med,2003,198:851,HL与PMBL基因表达谱高度重叠,低表达B细胞受体和细胞信号分子高表达细胞因子通路分子、细胞外基质成分高表达IL-13和NF-KB可以检测到下游的STATl和TRAFl表达不出现BCL2和BCL6重排,纵隔淋巴瘤的临床与生物学特征,PMBL诊治策略,对PMBL认

5、识DLBCL独特亚型；内科治疗策略第三代强烈化疗方案优于CHOP；联合利妥昔单抗优于单纯化疗；DA-EPOCH-R方案显示良好生存优势；中枢预防的应用。综合治疗探索标准治疗为化疗联合放疗；放疗临床获益待进一步明确；全身PET/CT指引下的临床治疗。,Overall survival by chemotherapy subtype in the IELSG study of 426 patients with primary mediastinal large B-cell lymphoma (PMBL).,Johnson P W , and Davies A J Hematology 2008

6、;2008:349-358,2008 by American Society of Hematology,Comparative outcomes of 76 patients with primary mediastinal large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with or without radiotherapy and 45 historical controls treated with

7、 cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without radiotherapy.,Vassilakopoulos T P et al. The Oncologist 2012;17:239-249,希腊 多中心回顾性分析,Vassilakopoulos T P et al. The Oncologist 2012;17:239-249,Baseline demographic, clinical, laboratory, and treatment characteristics o

8、f patients,Vassilakopoulos T P et al. The Oncologist 2012;17:239-249,Early failures, early deaths, and use of RT in patients,FFP,The Oncologist 2012;17:239 5-year FFP rates were 81% and 54% (p0.0006)249,无失败生存率（%）,时间（年）,方案,患者/进展,5年FFP,P值,无事件生存率（%）,时间（年）,方案,患者/进展,5年EFS,P值,R-CHOP优于CHOP,EFS,Vassilakopou

9、los T P et al. The Oncologist 2012;17:239-249,LSS,The Oncologist 2012;17:239249,淋巴瘤相关生存率（%）,总生存率（%）,时间（年）,时间（年）,方案,患者/进展,5年LSS,P值,方案,患者/死亡,5年OS,P值,OS,R-CHOP优于CHOP,Vassilakopoulos T P et al. The Oncologist 2012;17:239-249,MInT 研究 亚组分析,Rieger M,et al. Ann Oncol,2011,22:664,Distribution of the differen

10、t treatment regimens,Response after chemo(immuno)therapy and before intended radiotherapy,Response after treatment comparing PMBCL with DLBCL (assessable cases),Survival of all patients with PMBCL and with DLBCL,EFS, and OS of PMBCL and DLBCL assigned to CHOP-like regimens alone or CHOP-like regimen

11、s in combination with rituximab,Multivariate analysis for CR(u) and PD,Multivariate analysis for EFS, OS,Savage K J et al. Ann Oncol 2006;17:123-130,英国一篇回顾性研究结果显示：R-CHOP相比于MACOPB /VACOPB OS无明显差异,R-CHOP不优于MACOP-B,MACOP-B/VACOP-B,CHOP,R-CHOP,MACOPB /VACOPB VS CHOP (P = .048),Wilson WH,et al. Blood,200

12、2,99:2685,EPOCH方案,研究方案,N Engl J Med 2013;368:1408,Baseline Characteristics of the Study Patients,N Engl J Med 2013;368:1408,EFS and OS in Prospective NCI,N Engl J Med 2013;368:1408,EFS and OS in Retrospective Stanford,Blood,2002,99:2685,N Engl J Med 2013;368:1408,DA-EPOCH-R较DA-EPOCH显著改善患者的EFS率（P=0.0

13、07）和OS率（P=0.01）,Dose-Dense Therapy for PMBL （no R）,MSKCC,J Clin Oncol 28:1896-1903, 2010,17例PET+BX-,ESMO指南2012对中枢预防的推荐1,IPI3分（尤其是）结外病变1处LDH高于正常睾丸淋巴瘤必须接受预防鼻旁窦、上颈部和骨髓浸润的淋巴瘤是否需要预防有待证实,PMBCL发生CNS病变的高危因素2,PMBCL常伴随LDH升高PMBCL常伴随其他结外病变如肾脏和肾上腺PMBCL初发时发生CNS病变较为罕见，但首次复发后，CNS病变发生率高达23%,1. Tilly H, et al. Annals

14、 of Oncology. 2012; 23 (Supplement 7): vii78vii822. Peter W.M. Johnson and Andrew J. Davies. Hematology 2008. Primary Mediastinal B-Cell Lymphoma.,PMBL具有CNS病变的高危因素行中枢预防似乎是必要的,PMBL-中枢预防,Cumulative risk of CNS disease in patients with testes, bone marrow, or head involvement dependent on intrathecal p

15、rophylaxis and rituximab application.,Boehme V et al. Blood 2009;113:3896-3902,Central nervous system relapses in primary mediastinal large B-cell lymphoma: review of the literature comparing the pre-Rituximab and post-Rituximab period,Hematol Oncol2013;31:1017,PMBL诊治策略,对PMBL认识DLBCL独特亚型；内科治疗策略第三代强烈化

16、疗方案优于CHOP；联合利妥昔单抗优于单纯化疗；DA-EPOCH-R方案显示良好生存优势；中枢预防的应用。综合治疗探索标准治疗为化疗联合放疗；放疗临床获益待进一步明确；全身PET/CT指引下的临床治疗。,Response after chemo(immuno)therapy and before intended radiotherapy,haematologicavol. 87(12):december 2002,IELSG：426例初治PMBL化疗联合放疗PR转化CR,放疗临床获益待进一步明确,PMBL放疗年代（1998-2005），常规联合放疗；第三代方案大剂量化疗、免疫化疗的应用，放疗

17、地位受到挑战？能否免予放疗带来的近远期毒性？大剂量免疫化疗？PET-CT引导下的治疗？,Primary mediastinal large B-cell lymphoma: optimal therapyand prognostic factor analysis in 141 consecutive patientstreated at Memorial Sloan Kettering from 1980 to 1999,NHL-15方案不含放疗，中位随访10.9 years,Br J Haematol 130:691-699, 2005,EFS：34%, 60% and 60%,OS：51

18、%, 84% and 78%,Savage K J et al. Ann Oncol 2006;17:123-130, 2005 European Society for Medical Oncology,Prior to January 1998 (n= 103),After January 1998(radiotherapy era n= 50）,5-year OS (78% versus 69%;P= 0.1）,Favorable outcome of primary mediastinal large B-cell lymphoma in a single institution: t

19、he British Columbia experience,EFS and OS in Prospective NCI（DA-EPOCH-R）,N Engl J Med 2013;368:1408,5.9, 10.2, and 14.5,FDG-PET-CT Findings after DA-EPOCH-R Therapy in the Prospective NCI Cohort,N Engl J Med 2013;368:1408,敏感性为100%，特异性为54%，阳性预测价值为17%，阴性预测价值为100%,PET引导下的巩固放疗,Sehn LH, et al. 12th ICML,

20、DLBCL患者：III/IV期，或者I/II期合并B症状或10cm巨块肿瘤,根据PET诊断状态及放疗与否对患者无进展生存期的分析(n=249),生存率,时间（年）,PET阳性+放疗,PET阳性-放疗,PET阴性,4年无进展生存率,根据肿瘤大小对PET诊断阴性患者无进展生存期的分析(n=148),生存率,时间（年）,4年无进展生存率,有巨大肿瘤(n=50),无巨大肿瘤(n=98),J Clin Oncol 2014；32:1769-1775.,研究设计及方案,overall survival (OS) and progression-free survival (PFS)CMR,the mediastinal blood pool uptake as a cut point (Deauville score 3 to 5),the liver uptake as a cut point (Deauville score 4 to 5),NPV and PPV,PMBL诊治策略,对PMBL认识DLBCL独特亚型；内科治疗策略第三代强烈化疗方案优于CHOP；联合利妥昔单抗优于单纯化疗；DA-EPOCH-R方案显示良好生存优势；中枢预防的应用。综合治疗探索标准治疗为化疗联合放疗；放疗临床获益待进一步明确；全身PET/CT指引下的临床治疗。,