1、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PET/CT指引下的临床治疗。PMBL-概述 独立亚型:最早于19
2、81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,骨髓侵犯少见骨髓侵犯少见 侵犯肺、胸壁、胸膜、心包侵犯肺、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:组织形态学:纤维组织增生,将肿瘤组织分隔形成纤维组织增生,将肿瘤组织分隔形成结节结节;瘤细胞中等偏大,细胞质丰;瘤细胞中等偏大,细胞质丰富,细胞核不规则,可见富,细胞核不规则,可见R-SR-S样细胞样细胞。免疫
3、组化表型:免疫组化表型:B B细胞:细胞:CD19CD19、CD20CD20、CD22CD22、CD79a CD79a 核表达:核表达:PAX5PAX5、BCL-6BCL-6、IFRF4/mum-1IFRF4/mum-1,OCT2OCT2、BOB.1BOB.1CD23+CD23+,CD30CD30弱弱+,CD15-CD15-,CD10-CD10-遗传学改变:遗传学改变:IGHIGH基因克隆性重排;体细胞突变基因克隆性重排;体细胞突变+9p24/+9p24/JAK2JAK2(-75%-75%)+2p25/+2p25/RELREL(-50%-50%)+Xp11.4-21+Xp11.4-21,+Xq
4、24-26+Xq24-26PMBL-病理、分子遗传学特征不同亚型不同亚型DLBCL的致癌通路的致癌通路NEJM,2010,362;15OncogenicpathwaysforthreesubtypesofdiffuselargeB-celllymphomaGenetic alterations and deregulated signaling pathwaysBLOOD,8SEPTEMBER2011 VOLUME118,NUMBER10DLBCL基因表达谱与分子病理预后研究ABCDLBCLGCBDLBCLPMBLGCBDLBCLABCDLBCLPMBL46例诊断PMBL:35例(76%)PM
5、BL;11例DLBCL-7例GCB、4例ABCDLBCL纵隔淋巴瘤相关关系RosenwaldA,etal.JExpMed,2003,198:851HL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
6、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;2008:349-3582008byAmericanSocietyofHematologyComparative outcomes of 76 patients with primary mediast
7、inal 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 cyclophosphamide,doxorubicin,vincristine,and prednisone(CHOP)with or without radiotherapy.Vassilakopoulos T P et
8、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;17:239-249Baseline demographic,clinical,laboratory,and treatment characteristics of patientsVassilakopoulos T P et al.The Oncologist 2012;17:239-249Early failures,early deaths,and use of RT in patientsFFPTheOnco
9、logist2012;17:2395-yearFFPrateswere81%and54%(p 0.0006)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优于优于CHOPEFSVassilakopoulos T P et al.The Oncologist 2012;17:239-249LSSTheOncologist2012;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LSSP值方案 患者/死亡 5年OS P值OSR-CHOP优于优于CHOPVa
10、ssilakopoulos T P et al.The Oncologist 2012;17:239-249MInT研究亚组分析RiegerM,etal.AnnOncol,2011,22:664Distribution of the different treatment regimensResponse after chemo(immuno)therapy and before intended radiotherapyResponse after treatment comparing PMBCL with DLBCL(assessable cases)Survival of all pa
11、tients with PMBCL and with DLBCLEFS,and OS of PMBCL and DLBCL assigned to CHOP-like regimens alone or CHOP-like regimens in combination with rituximabMultivariate analysis for CR(u)and PDMultivariate analysis for EFS,OSSavageKJetal.AnnOncol2006;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
12、R-CHOP不优于不优于MACOP-BMACOP-B/VACOP-BMACOP-B/VACOP-B CHOPCHOP R-CHOPR-CHOP MACOPB/VACOPB VS CHOP(P=.048)WilsonWH,etal.Blood,2002,99:2685EPOCH方案研究方案NEnglJMed2013;368:1408Baseline Characteristics of the Study PatientsNEnglJMed2013;368:1408EFS and OS in Prospective NCINEnglJMed2013;368:1408EFS and OS in R
13、etrospective StanfordBlood,2002,99:2685NEnglJMed2013;368:1408DA-EPOCH-R 较DA-EPOCH 显著改善患者的EFS 率(P=0.007)和 OS 率(P=0.01)Dose-Dense Therapy for PMBL(no R)MSKCCJClinOncol28:1896-1903,201017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
14、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.TillyH,etal.AnnalsofOncology.2012;23(Supplement7):vii78vii822.PeterW.M.JohnsonandAndrewJ.Davies.Hematology2008.PrimaryMediastinalB-CellLymphoma.PMBL具有具有CNS病变的高危因素病变的高危因素行中枢预防似乎是必要的行中枢预防似乎是必要的PMBL-中枢预防中枢预防Cumulative risk of CNS d
15、isease in patients with testes,bone marrow,or head involvement dependent on intrathecal prophylaxis and rituximab application.Boehme V et al.Blood 2009;113:3896-3902Central nervous system relapses in primary mediastinal large B-cell lymphoma:review of the literature comparing the pre-Rituximab and p
16、ost-Rituximab periodHematolOncol2013;31:1017PMBL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。Response after chemo(immuno)therapy and before intended radiotherapyhaematologicavol.87(12):december2002IELSG:426例初
17、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 1999NHL-15方案不含放
18、疗,中位随访10.9yearsBrJHaematol130:691-699,2005EFS:34%,60%and60%OS:51%,84%and78%Savage K J et al.Ann Oncol 2006;17:123-1302005EuropeanSocietyforMedicalOncologyPriortoJanuary1998(n=103)AfterJanuary1998(radiotherapyeran=50)5-yearOS(78%versus69%;P=0.1)Favorable outcome of primary mediastinal large B-cell ly
19、mphoma in a single institution:the British Columbia experienceEFS and OS in Prospective NCI(DA-EPOCH-R)NEnglJMed2013;368:14085.9,10.2,and14.5 FDG-PET-CT Findings after DA-EPOCH-R Therapy in the Prospective NCI CohortNEnglJMed2013;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SehnLH,etal.
20、12thICMLDLBCL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)JClinOncol2014;32:1769-1775.研究设计及方案overall survival(OS)and progression-free survival(PFS)CMRthemediastinalbloodpooluptakeasacutpoint(Deauvillescore3to5)theliveruptakeasacutpoint(Deauvillescore4to5)NPV and PPV谢谢!