縱隔大b淋巴瘤周生余

1、縱隔大B細(xì)胞淋巴瘤內(nèi)科診治策略,中國(guó)醫(yī)學(xué)科學(xué)院腫瘤醫(yī)院內(nèi)科周 生 余,,,,,PMBL診治策略,對(duì)PMBL認(rèn)識(shí)——DLBCL獨(dú)特亞型；內(nèi)科治療策略第三代強(qiáng)烈化療方案優(yōu)于 CHOP；聯(lián)合利妥昔單抗優(yōu)于單純化療；DA-EPOCH-R 方案顯示良好生存優(yōu)勢(shì)；中樞預(yù)防的應(yīng)用。綜合治療探索標(biāo)準(zhǔn)治療為化療聯(lián)合放療；放療臨床獲益待進(jìn)一步明確；全身PET/CT指引下的臨床治療。,PMBL診治策略,對(duì)PMBL

2、認(rèn)識(shí)——DLBCL獨(dú)特亞型；內(nèi)科治療策略第三代強(qiáng)烈化療方案優(yōu)于 CHOP；聯(lián)合利妥昔單抗優(yōu)于單純化療；DA-EPOCH-R 方案顯示良好生存優(yōu)勢(shì)；中樞預(yù)防的應(yīng)用。綜合治療探索標(biāo)準(zhǔn)治療為化療聯(lián)合放療；放療臨床獲益待進(jìn)一步明確；全身PET/CT指引下的臨床治療。。,PMBL---概述,獨(dú)立亞型：最早于1981年提出，1994年REAL，2008年WHO，DLBCL的獨(dú)立亞型發(fā)病率：NHL 2-4%；

3、 DLBCL 6%-13%，縱膈最常見(jiàn)的NHL。發(fā)病年齡: 30-40歲青年，女＞男臨床特征：前上縱膈大腫塊，上腔靜脈綜合征，胸腔、心包積液I-II期，骨髓侵犯少見(jiàn)侵犯肺、胸壁、胸膜、心包復(fù)發(fā)時(shí)肝、腎、CNS可受累,DLBCL與PMBL臨床特征,組織形態(tài)學(xué)：纖維組織增生，將腫瘤組織分隔形成結(jié)節(jié)；瘤細(xì)胞中等偏大，細(xì)胞質(zhì)豐富，細(xì)胞核不規(guī)則，可見(jiàn)R-S樣細(xì)胞。免疫組化表型：B細(xì)胞：CD19、CD20、 CD22、CD79a

4、核表達(dá)：PAX5、BCL-6、IFRF4/mum-1，OCT2、BOB.1CD23+， CD30弱+，CD15-，CD10-遺傳學(xué)改變：IGH基因克隆性重排；體細(xì)胞突變+9p24/JAK2（-75%）+2p25/REL（- 50%）+Xp11.4-21，+Xq24-26,PMBL---病理、分子遺傳學(xué)特征,不同亞型DLBCL的致癌通路,NEJM, 2010,362;15,Oncogenic pathways for thr

5、ee subtypes of diffuse large B-cell lymphoma,Genetic alterations and deregulated signaling pathways,BLOOD, 8 SEPTEMBER 2011
VOLUME 118, NUMBER 10,DLBCL基因表達(dá)譜與分子病理預(yù)后研究,,,46例診斷PMBL：35例（76%）PMBL；11例DLBCL-7例GCB、4例ABC DLBCL,,

6、,縱隔淋巴瘤相關(guān)關(guān)系,Rosenwald A,et al. J Exp Med,2003,198:851,HL與PMBL基因表達(dá)譜高度重疊,低表達(dá)B細(xì)胞受體和細(xì)胞信號(hào)分子高表達(dá)細(xì)胞因子通路分子、細(xì)胞外基質(zhì)成分高表達(dá)IL-13和NF-KB可以檢測(cè)到下游的STATl和TRAFl表達(dá)不出現(xiàn)BCL2和BCL6重排,縱隔淋巴瘤的臨床與生物學(xué)特征,PMBL診治策略,對(duì)PMBL認(rèn)識(shí)——DLBCL獨(dú)特亞型；內(nèi)科治療策略第三代強(qiáng)烈化療方

7、案優(yōu)于 CHOP；聯(lián)合利妥昔單抗優(yōu)于單純化療；DA-EPOCH-R 方案顯示良好生存優(yōu)勢(shì)；中樞預(yù)防的應(yīng)用。綜合治療探索標(biāo)準(zhǔn)治療為化療聯(lián)合放療；放療臨床獲益待進(jìn)一步明確；全身PET/CT指引下的臨床治療。。,Overall survival by chemotherapy subtype in the IELSG study of 426 patients with primary mediastina

8、l large B-cell lymphoma (PMBL).,Johnson P W , and Davies A J Hematology 2008;2008:349-358,©2008 by American Society of Hematology,Comparative outcomes of 76 patients with primary mediastinal large B-cell lymphoma tr

9、eated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with or without radiotherapy and 45 historical controls treated with cyclophosphamide, doxorubicin, vincristine, and prednison

10、e (CHOP) with or without radiotherapy.,Vassilakopoulos T P et al. The Oncologist 2012;17:239-249,希臘 多中心回顧性分析,Vassilakopoulos T P et al. The Oncologist 2012;17:239-249,Baseline demographic, clinical, laboratory, and tre

11、atment characteristics of 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% (p0.0

12、006)–249,,,無(wú)失敗生存率（%）,時(shí)間（年）,方案,患者/進(jìn)展,5年FFP,P值,無(wú)事件生存率（%）,時(shí)間（年）,方案,患者/進(jìn)展,5年EFS,P值,R-CHOP優(yōu)于CHOP,EFS,Vassilakopoulos T P et al. The Oncologist 2012;17:239-249,LSS,The Oncologist 2012;17:239–249,,,淋巴瘤相關(guān)生存率（%）,總生存率（%）,時(shí)間（年）,時(shí)間（

13、年）,方案,患者/進(jìn)展,5年LSS,P值,方案,患者/死亡,5年OS,P值,OS,R-CHOP優(yōu)于CHOP,Vassilakopoulos T P et al. The Oncologist 2012;17:239-249,,MInT 研究 亞組分析,Rieger M,et al. Ann Oncol,2011,22:664,Distribution of the different treatment regimens,Resp

14、onse 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 a

15、ssigned to CHOP-like regimens alone or CHOP-like regimens 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,,英國(guó)一篇回顧性研究結(jié)果顯

16、示：R-CHOP相比于MACOPB /VACOPB OS無(wú)明顯差異,R-CHOP不優(yōu)于MACOP-B,MACOP-B/VACOP-B,CHOP,R-CHOP,MACOPB /VACOPB VS CHOP (P = .048),Wilson WH,et al. Blood,2002,99:2685,EPOCH方案,研究方案,N Engl J Med 2013;368:1408,Baseline Characteristics of

17、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 較DA-EPOCH&#

18、160;顯著改善患者的EFS 率（P=0.007） 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對(duì)中樞預(yù)防的推薦1,IPI≥3分（尤其是）結(jié)外病變＞1處LDH高于正常睪丸淋巴瘤必須接受預(yù)防鼻旁竇、上頸部和骨髓浸潤(rùn)的

19、淋巴瘤是否需要預(yù)防有待證實(shí),PMBCL發(fā)生CNS病變的高危因素2,PMBCL常伴隨LDH升高PMBCL常伴隨其他結(jié)外病變?nèi)缒I臟和腎上腺PMBCL初發(fā)時(shí)發(fā)生CNS病變較為罕見(jiàn)，但首次復(fù)發(fā)后，CNS病變發(fā)生率高達(dá)23%,1. Tilly H, et al. Annals of Oncology. 2012; 23 (Supplement 7): vii78–vii822. Peter W.M. Johnson and Andrew J

20、. Davies. Hematology 2008. Primary Mediastinal B-Cell Lymphoma.,PMBL具有CNS病變的高危因素行中樞預(yù)防似乎是必要的,PMBL---中樞預(yù)防,Cumulative risk of CNS disease in patients with testes, bone marrow, or head involvement dependent on intrathecal p

21、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

22、-Rituximab period,Hematol Oncol2013;31:10–17,PMBL診治策略,對(duì)PMBL認(rèn)識(shí)——DLBCL獨(dú)特亞型；內(nèi)科治療策略第三代強(qiáng)烈化療方案優(yōu)于 CHOP；聯(lián)合利妥昔單抗優(yōu)于單純化療；DA-EPOCH-R 方案顯示良好生存優(yōu)勢(shì)；中樞預(yù)防的應(yīng)用。綜合治療探索標(biāo)準(zhǔn)治療為化療聯(lián)合放療；放療臨床獲益待進(jìn)一步明確；全身PET/CT指引下的臨床治療。。,Response a

23、fter chemo(immuno)therapy and before intended radiotherapy,haematologicavol. 87(12):december 2002,IELSG：426例初治PMBL化療聯(lián)合放療PR轉(zhuǎn)化CR,放療臨床獲益待進(jìn)一步明確,PMBL放療年代（1998-2005），常規(guī)聯(lián)合放療；第三代方案大劑量化療、免疫化療的應(yīng)用，放療地位受到挑戰(zhàn)？能否免予放療帶來(lái)的近遠(yuǎn)期毒性？大劑量免疫化

24、療？PET-CT引導(dǎo)下的治療？,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方案不含放療，中位隨訪10.9 years,Br

25、J Haematol 130:691-699, 2005,EFS：34%, 60% and 60%,OS：51%, 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(radi

26、otherapy 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: the British Columbia experience,EFS and OS in Prospective

27、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,敏感性為 100%，特異性為54%，陽(yáng)性預(yù)測(cè)價(jià)值為 17%，陰性預(yù)測(cè)價(jià)值為

28、 100%,PET引導(dǎo)下的鞏固放療,Sehn LH, et al. 12th ICML,DLBCL患者：III/IV期，或者I/II期合并B癥狀或≥10cm巨塊腫瘤,根據(jù)PET診斷狀態(tài)及放療與否對(duì)患者無(wú)進(jìn)展生存期的分析(n=249),生存率,時(shí)間（年）,PET陽(yáng)性+放療,PET陽(yáng)性-放療,PET陰性,4年無(wú)進(jìn)展生存率,根據(jù)腫瘤大小對(duì)PET診斷陰性患者無(wú)進(jìn)展生存期的分析(n=148),生存率,時(shí)間（年）,4年無(wú)進(jìn)展生存率,有巨大

29、腫瘤(n=50),無(wú)巨大腫瘤(n=98),J Clin Oncol 2014；32:1769-1775.,研究設(shè)計(jì)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