弥漫大B细胞淋巴瘤课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,2021精选ppt,*,弥漫性大,B,细胞淋巴瘤临床治疗进展,2007,中华医学会恶性淋巴瘤,CME,1,2021精选ppt,弥漫性大B细胞淋巴瘤临床治疗进展2007中华医学会恶性淋巴,概述,弥漫性大,B,细胞淋巴瘤（,diffuse large B cell lymphoma, DLBCL,）,成人淋巴瘤中最常见的一种类型,欧美国家约占非霍奇金淋巴瘤（,NHL,）,30%,亚洲国家占,NHL,大于,40%,2,2021精选ppt,概述弥漫性大B细胞淋巴瘤（diffuse large B c,临床特点,可发生于任何年龄，老年人多见，中位发病年龄,60-64,岁,男性稍多于女性,典型临床表现：迅速增大的无痛性肿块,B,症状：,1/3,骨髓累及：,16%,肿瘤主要发生在淋巴结内，约,1/3,淋巴结外首发病灶,结外病灶常见于：胃肠道、骨和中枢神经系统,3,2021精选ppt,临床特点可发生于任何年龄，老年人多见，中位发病年龄60-64,形态学特点,具有形态学异质性的肿瘤,WHO,分类中,DLBCL,可包括,中心母细胞型,免疫母细胞型,富于,T,细胞,/,组织细胞型,间变细胞型,浆母细胞型,表达,ALK,全长型,亚型对临床治疗和预后没有明确的意义，,WHO,分类中将其归为一类,4,2021精选ppt,形态学特点具有形态学异质性的肿瘤 42021精选ppt,免疫组织化学,典型的免疫组化表达：,CD20+,、,CD45+,、,CD79a+,、,Ki67+,、,CD3-,分子遗传学检测抗原受体基因重排：,bcl-2,、,bcl-1,、,c-myc,5,2021精选ppt,免疫组织化学52021精选ppt,国际预后指数,IPI,年龄调整国际预后指数,aaIPI,所有患者： 年龄,60,LDH,正常值,PS 24,或,期,结外累及,1,个部位,IPI,评分： 低危,0-1,低中危,2,高中危,3,高危,4-5,60,患者：,或,期,LDH,正常值,PS 24,aaIPI,评分,:,低危,0,低中危,1,高中危,2,高危,3,IPI,International Prognostic Index,aaIPI,Age-Adjusted International Prognostic Index,6,2021精选ppt,国际预后指数 IPI,侵袭性,NHL,国际预后指数（,IPI,）,7,2021精选ppt,侵袭性NHL国际预后指数（IPI）72021精选ppt,侵袭性,NHL,国际预后指数（,IPI,）,各组化疗,CR,率和,5,年生存率分别为,低度组：,87%,和,73%,低到中度组：,67%,和,51%,中到高度组：,55%,和,43%,高度组：,44%,和,26%,8,2021精选ppt,侵袭性NHL国际预后指数（IPI）各组化疗CR率和5年生存,NCCN,指南,-2006,局限期（,I-II,期）治疗原则,9,2021精选ppt,NCCN指南-2006局限期（I-II期）治疗原则920,I-II,期：化疗,+,放疗,VS,单化疗,SWOG 8736,75%DLCL,I+IE,（大肿块）,II+IIE,（非大肿块）,随机分组,8,CHOP (201pts),3,CHOP+,RT,(200pts),Miller TP, et al. N Engl J Med, 1998, 339(1): 21-26.,10,2021精选ppt,I-II期：化疗+放疗 VS 单化疗SWOG 873675,5,年无进展生存率,CHOP: 64%,CHOP+RT: 77%,Miller TP, et al. N Engl J Med, 1998, 339(1): 21-26.,11,2021精选ppt,5年无进展生存率Miller TP, et al. N En,5,年生存率,CHOP: 72%,CHOP+RT: 82%,Miller TP, et al. N Engl J Med, 1998, 339(1): 21-26.,12,2021精选ppt,5年生存率Miller TP, et al. N Engl,Miller TP, et al. N Engl J Med, 1998, 339(1): 21-26.,13,2021精选ppt,Miller TP, et al. N Engl J Med,I-II,期：化疗,+,放疗,VS,单化疗,ECOG1484,I,（大肿块）,IE,II, IIE,352pts,Arm1,179pts,Arm2,173pts,Horning S, JCO Vol 22(15) ,2004: 3032-3038,14,2021精选ppt,I-II期：化疗+放疗 VS 单化疗I（大肿块）IEArm1,(A) Disease-free survival, (B) failure-free survival, and (C) time to progression for complete remission patients.,Horning S, JCO Vol 22(15) ,2004: 3032-3038,总生存率无差别,15,2021精选ppt,(A) Disease-free survival, (B),NCCN,指南,-2006,局限期（,I-II,期）治疗原则,16,2021精选ppt,NCCN指南-2006局限期（I-II期）治疗原则162,NCCN,指南,-2006,广泛期（,III-IV,期）治疗原则,17,2021精选ppt,NCCN指南-2006广泛期（III-IV期）治疗原则1,CHOP,对比各种方案治疗侵袭性淋巴瘤总生存率比较,Fisher et al.,N Engl J Med.,1993;328:1002.,年,患者 死亡,3,年生存预测,CHOP 226 88 54%,m-BACOD 223 93 52,ProMACE-CytaBOM 233 97 50%,MACOP-B 218 93 50%,100,80,60,40,20,0,0,1,2,3,4,5,6,CHOP,m-BACOD,ProMACE-CytaBOM,MACOP-B,生存率,(%),18,2021精选ppt,CHOP对比各种方案治疗侵袭性淋巴瘤总生存率比较Fishe,DLBCL,CD20,19,2021精选ppt,DLBCLCD20192021精选ppt,CHOP,利妥昔单抗,:,初治侵袭性淋巴瘤,(GELA,研究,),随,机,C,HOP,x,8,周期,(,每,3,周,),R,+,CHOP,x,8,周期,(,在,CHOP,疗程的第一天使用,),美罗华,375mg/m,2,i.v. day 1,环磷酰胺,750mg/m,2,i.v. day 1,长春新碱,1 .4mg/m,2,i.v. day 1,阿霉素,50mg/m,2,i.v. day 1,强的松,40mg/m,2,p.o. days 15,侵袭,性,NH,L (,85%,为,DLBCL),IIIV,期,60-80,岁,未接受过治疗,Coiffier et al.,N Engl J Med.,2002;346:235,Feugier et al.,JCO,2005 Vol.23;1-10,20,2021精选ppt,CHOP利妥昔单抗: 初治侵袭性淋巴瘤 (GELA研究)随,CHOP,R,+CHOP,患者数,202 199,年龄 平均,69 69,分期,III-IV 79% 80%,体力状况,1 22% 17%,LDH,升高,65% 67%,巨大肿块,30% 32%,骨髓受累,28% 28%,CHOP,利妥昔单抗,(GELA,研究,),21,2021精选ppt,CHOP R+CHOP,CR + CRu = 76%,CR + CRu = 63%,(%),ORR 83%,ORR 69%,CHOP,利妥昔单抗,(GELA,研究,),80,60,40,20,0,美罗华,-CHOP,CHOP,(n=202),(n=197),p=0.005,CR,CRu,PR,SD,PD,Death,NE,Coiffier et al.,N Engl J Med.,2002;346:235,Feugier et al.,JCO,2005 Vol.23;1-10,22,2021精选ppt,CR + CRu = 76%CR + CRu = 63%,5,年随访,58%,45%,年,0 1 2 3 4 5,59%,47%,62%,70%,51%,57%,83%,68%,0,2,0,4,0,6,0,8,0,10,0,CHOP,利妥昔单抗,(GELA,研究,),生存率,(%),Coiffier et al.,N Engl J Med.,2002;346:235,Feugier et al.,JCO,2005 Vol.23;1-10,R-CHOP,CHOP,23,2021精选ppt,5年随访58% 45% 年 0,3/4,度不良反应,R,+CHOP(%) CHOP(%),发热,2 5,感染,12 20,心脏,8 8,神经,5 9,肺,8 11,肝,3 5,CHOP,利妥昔单抗,(GELA,研究,),Coiffier et al.,N Engl J Med.,2002;346:235,Feugier et al.,JCO,2005 Vol.23;1-10,24,2021精选ppt,初治,DLBCL,18-60,岁,IPI 0,1,II-IV,期,I,期大包块,6 x,类,CHOP(CHEMO),+ 30-40 Gy (Bulk, E),6 x,类,CHOP (CHEMO),+ R,+ 30-40 Gy (Bulk, E),随机,类,CHOP,方案,利妥昔单抗治疗初治,DLBCL,(MInT,研究,),Pfreundschuh M, et al. Blood 2004;104:40a (Abstract 157),25,2021精选ppt,初治 DLBCL6 x 类CHOP(CHEMO)6 x 类C,平均年龄,47 47,组织分型,(%) DLBCL 87 86,其他,13 14,大包块,(%) 48 50,B,症状,(%) 26 24,结外病灶,(%) 35 33,Chemo n=410,R-Chemo n=413,Pfreundschuh M, et al. Blood 2004;104:40a (Abstract 157),类,CHOP,方案,利妥昔单抗,(MInT,研究,),26,2021精选ppt,平均年龄,CHOEP-21 44 % 44 % CHOP-21 48 % 48 % MACOP-B 4 % 4 % PMitCEBO 4 % 4 %,Chemo,(,n=410,),R-Chemo,(,n=413,),Pfreundschuh M, et al. Blood 2004;104:40a (Abstract 157),类,CHOP,方案,利妥昔单抗,(MInT,研究,),27,2021精选ppt,CHOEP-21 44 % 4,Chemo(n=346)*(%),R-Chemo(n=350)* (%),CR/CRu,68%,86%*,PR,15%,5%,NC,5%,3%,PD,11%,4%*,治疗期间死亡,1%,1%,*,p=0.001,*,p0.000 00005,Pfreundschuh M, et al. Blood 2004;104:40a (Abstract 157),*,可评估患者,类,CHOP,方案,利妥昔单抗,(MInT,研究,),28,2021精选ppt,Chemo(n=346)*(%)R-Chemo(n=35,p=0.0001,0,5,10,15,25,30,35,45,50,10,20,30,40,50,60,70,80,90,0,月,100,R-CHEMO,CHEMO,20,40,93%,84%,生存率,(%),Pfreundschuh M, et al. Lancet Oncol 2006;7:379-91,3,年总生存,类,CHOP,方案,利妥昔单抗,(MInT,研究,),29,2021精选ppt,p=0.00010510152530354550102030,p, 0.000,1,79%,59%,0,5,10,15,25,30,35,45,50,10,20,30,40,50,60,70,80,90,0,月,100,20,40,无事件生存率,(%),R-CHEMO,CHEMO,Pfreundschuh M, et al. Lancet Oncol 2006;7:379-91,3,年无事件生存,类,CHOP,方案,利妥昔单抗,(MInT,研究,),30,2021精选ppt,p 0.000179%59%05101525303545,Pfreundschuh M, et al. Blood 2004;104:40a (Abstract 157),类,CHOP,方案,利妥昔单抗,(MInT,研究,),不良反应,(%),31,2021精选ppt,Pfreundschuh M, et al. B,随机,2 x 2,析因设计,6,x CHOP-,21,+ 36 Gy (Bulk, E),6,x CHOP-,14+,G-CSF,+ 36 Gy (Bulk, E),6 x CHOEP-,21,+ 36 Gy (Bulk, E),6 x CHOEP-,14+,G-CSF,+ 36 Gy (Bulk, E),61-75,岁,初治,I-IV,期,侵袭性,NHL,剂量密度研究,NHL-B2,32,2021精选ppt,6 x CHOP-216 x CHOP-14+G-CSF6,剂量密度研究,NHL-B2,CHOP-21,CHOP-14,CHOEP-21,CHOEP-14,CR n(%),107(60.1),131(,71.6,),119(,70.0,),121(,71.6,),PR,5(2.8),11(6.4),10(5.9),11(6.5),SD,2(1.1),1(0.6),2(1.2),1(0.6),PD,52(29.2),20(11.6),25(14.7),16(9.5),治疗相关死亡,6(3.4),5(,2.9,),9(5.3),13(,7.7,),Pfreundschuh, M. et al. Blood 2004;104:634-641,33,2021精选ppt,剂量密度研究NHL-B2CHOP-21CHOP-14CHO,剂量密度研究,NHL-B2,CHOP-21,CHOP-14,CHOEP-21,CHOEP-14,P,3,年,EFS(%),41.3,54.2,45.5,46.0,0.003,5,年,EFS(%),32.5,43.8,41.1,40.2,3,年,OS(%),48.8,68.5,57.7,56.4,0.001,5,年,OS(%),40.6,53.3,45.8,49.8,Pfreundschuh, M. et al. Blood 2004;104:634-641,34,2021精选ppt,剂量密度研究NHL-B2CHOP-21CHOP-14CHO,Copyright 2004 American Society of Hematology. Copyright restrictions may apply.,Pfreundschuh, M. et al. Blood 2004;104:634-641,Figure 1. Event-free survival in the NHL-B2 trial,35,2021精选ppt,Copyright 2004 American Socie,Copyright 2004 American Society of Hematology. Copyright restrictions may apply.,Pfreundschuh, M. et al. Blood 2004;104:634-641,Figure 2. Overall survival in the NHL-B2 trial,36,2021精选ppt,Copyright 2004 American Socie,CHOP-21,CHOP-14,CHOEP-21,CHOEP-14,P,Leukocytopenia,72.1,70.1,94.4,92.4, .001,Thrombocytopenia,4.7,15.1,28.4,50.8, .001,Anemia,12.5,19.5,28.7,45.1, .001,Infection,8.0,10.6,13.2,24.1, .001,Mucositis,0.0,7.1,4.9,14.3, .001,Cardiac toxicity,3.4,4.7,3.7,5.0,.871,Neurologic toxicity,3.4,3.6,6.1,4.3,.617,Renal toxicity,1.1,0.0,0.6,0.6,.756,Lung toxicity,4.0,4.7,3.0,6.2,.560,Nausea or vomiting,8.0,13.5,9.7,15.4,.126,WHO grade 3 and grade 4 events observed in patients treated with CHOP-21, CHOP-14, CHOEP-21, and CHOEP-14,Pfreundschuh, M. et al. Blood 2004;104:634-641,37,2021精选ppt,CHOP-21CHOP,随机,2 x 2,析因设计,6,x CHOP-,21,+ 36 Gy (Bulk, E),6,x CHOP-,14,+G-CSF,+ 36 Gy (Bulk, E),6 x CHOEP-,21,+ 36 Gy (Bulk, E),6 x CHOEP-,14,+G-CSF,+ 36 Gy (Bulk, E),18-60,岁,侵袭性,NHL,LDH,正常,剂量密度研究,NHL-B1,Pfreundschuh, M. et al. Blood 2004;104:626-633,38,2021精选ppt,6 x CHOP-216 x CHOP-14+G-CSF6,Copyright 2004 American Society of Hematology. Copyright restrictions may apply.,Pfreundschuh, M. et al. Blood 2004;104:626-633,Overall survival of 710 patients treated according to the NHL-B1 protocol,39,2021精选ppt,Copyright 2004 American Socie,老年,DLBCL,随 机,CHOP,R-CHOP,有效患者,随 机,R,维持,观察,Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma,Habermann,，,J Clin Oncol. 2006 Jul 1;24(19):3121-7.,40,2021精选ppt,老年DLBCL 随,R,维持,vs,观察,3,年,FFS :,R-CHOP 53%,CHOP 46% p=0.04,2,次随机后的,2,年,FFS,R,维持,76%,观察,61% p=0.009,Habermann,，,J Clin Oncol. 2006 Jul 1;24(19):3121-7,41,2021精选ppt,R维持 vs 观察3年FFS :Habermann， J,FFS was prolonged with MR after CHOP (P = .0004) but not after R-CHOP (P = .81),2-year FFS,R-CHOP,：,77%,R-CHOP + MR,：,79%,CHOP + MR,：,74%,CHOP,：,45%,Habermann,，,J Clin Oncol. 2006 Jul 1;24(19):3121-7,42,2021精选ppt,FFS was prolonged with MR afte,预后研究,IPI,对侵袭性,NHL,的预后有很好的预测功能,但相同,IPI,分值,DLBCL,患者治疗后生存期情况并不一致,表明,DLBCL,是一种存在明显生物学异质性的疾病,从分子水平对,DLBCL,进行分类,基因表达的研究：,cDNA,微阵列技术,(microarray),43,2021精选ppt,预后研究 IPI对侵袭性NHL的预后有很好的预测功能4320,生发中心,B,细胞样（,GCB,）,vs,活化,B,细胞样（,ABC,）,所有患者,5,年生存率,52%,GCB,型患者,5,年生存率,76%,ABC,型患者,5,年生存率,16%,Alizadeh, Nature 403, 503-511 (2000),44,2021精选ppt,生发中心B细胞样（GCB）vs 活化B细胞样（ABC）Ali,DLBCL,的基因分型,Rosenwald A, et al. N Engl J Med. 2002,Germinal-centerB-celllike,Type 3,ActivatedB-celllike,GCB,型,ABC,型,OS,比较,5-year OS,GCB,non-GCB,76%,34%,45,2021精选ppt,DLBCL的基因分型 Rose,+,+,+,-,-,-,CD10,BCL-6,MUM1,GCB,GCB,Non-GCB,Non-GCB,GCB / non-GCB,判定方法,Hans CP,Blood, 2004, 103(1): 275-282,46,2021精选ppt,+-CD10BCL-6MUM1GCBGCBNon-G,利妥昔单抗对于,GCB,或,non-GCB,亚型生存期的影响,Farinha ASH 2006, Abst. 816,47,2021精选ppt,利妥昔单抗对于GCB或non-GCB亚型生存期的影响Far,谢 谢,48,2021精选ppt,谢 谢482021精选ppt,