rituximabanddlbcl利妥昔单抗与弥漫大b细胞淋巴瘤.ppt

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,*,*,Rituximab,(,利妥昔单抗,),and DLBCL,(,弥漫大,B,细胞淋巴瘤,),报告人：,指导老师：,Outline:,Lymphoma,Non Hodgkins lymphoma,Diffuse large B cell lymphoma,Rituximab,-Mechnism,-Clinical trial,What is Lymphoma?,淋巴瘤（,lymphoma,）是起源于淋巴结和淋巴组织的免疫系统恶性肿瘤，其发生大多与免疫应答过程中淋巴细胞增殖分化产生的某种免疫细胞恶变有关。,淋巴瘤可发生在身体的任何部位，其中淋巴结、扁桃体、脾及骨髓是最易受到累及的部位。,按组织病理学可分为：霍奇金淋巴瘤和非霍奇金淋巴瘤,Aetiology of NHL,Viruses,EBV,Human T-cell leukaemia virus type I,Kaposi sarcoma-associated virus,Immunosuppression,Genetic and occupational factors,Clinical manifestation,Widespread painless lymphadenopathy(,无痛性淋巴结肿大,)is more common.Superior vena cava syndrome,（上腔静脉压迫综合征）,caused by a bulky mediastinal mass is also more frequent in.Hepatosplenomegaly,（肝脾肿大）,is frequent at diagnosis.,B symptoms(unexplained fever of 38C or higher,night sweats and loss of more than 10%of body weight in 6 months),What is Rituximab?,Rituximab:chimeric murine/human anti-human CD20(,人鼠嵌合抗,CD20),Rituximab destroys B cells,and is therefore used to treat diseases which are characterized by having too many B cells,overactive B cells or dysfunctional B cells.,This includes lymphomas,leukemias,transplant rejectionand someautoimmune disorders.,What is CD20?,CD20 is a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on pre-B and mature B lymphocytes,The antigen is expressed on most B-cell non-Hodgkins lymphomas but is not found on stem cells,pro-B cells,normal plasma cells or other normal tissues.,The mechanism of rituximab,1.Signaling induced cell death,2.CDC(,complement dependent cytotoxicity,),3.ADCC(,antibody dependent cytotoxicity,),4.Interacting mechanisms,Signaling induced cell death,CDC and ADCC,Therapeutic strategy,COP,：环磷酰胺，长春新碱，泼尼松,CHOP,：环磷酰胺，阿霉素，长春新碱，泼尼 松,m-BACOB,：博来霉素，阿霉素，环磷酰胺，长春新碱，地塞米松，甲氨蝶呤，四氢叶酸,Hyper CVAD,A,方案：环磷酰胺，美斯纳，长春新碱，阿霉素，地塞米松,B,方案：甲氨蝶呤，四氢叶酸，阿糖胞苷,14,临床试验,NHL,DLBCL,3741 GELA LNH98.5,研究,10,年,随访,406,R-CHOP14 vs R-CHOP21,治疗老年,DLBCL:LNH03-6B GELA,研究的中期分析,2316 309,例,年轻高危,DLBCL,长期随访,404 CHOEP-14+R,或,HDT(MegaCHOEP)+R,用于,年轻高危,侵袭性,B,细胞淋巴瘤,:,德国高度淋巴瘤研究组,(DSHNHL)MegaCHOEP,方案研究,3714 R-CHOP,治疗失败的老年,DLBCL,治疗结果,:R+HDT,二线治疗的作用,.,一项,RICOVER 60,试验回顾性分析,FL,CLL,Others:MCL,WM,PTLD,15,3741 GELA LNH98.5,研究,10,年随访,背景,:,LNH98.5,是第一个比较,R-CHOP vs CHOP,的随机研究。,2,年，,5,年中位随访的缓解率和生存已有报告,(NEJM 2002;346:235 and JCO 2005;23:4117).,研究目的,:,本分析,报告了,10,年随访结果。,初治,DLBCL,6080,岁,IIIV,期,N=399,随访,CHOP,n=,197,R-CHOP,n=202,R,Coiffier,et al,.,Blood,2009 114:Abstract 3741.,16,研究结果：,中位随访,10,年。,Coiffier,et al,.,Blood,2009 114:Abstract 3741.,0,2,4,6,8,10,0.2,0.4,0.6,0.8,1.0,CHOP 28.0%,R-CHOP 43.5%,p,0.0001,0.0,年,OS,37,月,7,年,9,月,CHOP 19%,R-CHOP 34%,p,0.0001,0.2,0.4,0.6,0.8,1.0,0.0,0,2,4,6,8,10,年,EFS,0,2,4,6,8,10,0.2,0.4,0.6,0.8,1.0,CHOP 20.0%,R-CHOP 36.5%,p,0.0001,0.0,年,PFS,17,结论：,10,年随访表明：,R-CHOP,仍带来获益。,老年病人也可以长期生存,:40%,多的老年人,10,年后仍存活。,晚复发病人需要新的治疗策略,.,Comments,：,10,年随访仍证实,R-Chemo,的生存获益。,Coiffier,et al,.,Blood,2009 114:Abstract 3741.,18,406 R-CHOP14 vs R-CHOP21,治疗老年,DLBCL:LNH03-6B GELA,研究的中期分析,背景,:,Gela,证实,R-CHOP21,治疗老年,DLBCL,有生存获益。德国,2,项 研究提示,CHOP14,比,CHOP21,；,R-CHOP14,比,CHOP14,生存有改善。,LNH03-6B,中期分析,:,多中心,III,期开放性,随机试验，评估,R-CHOP14,和,R-CHOP21,的疗效,现已入组,202,例,中位随访,2,年,.,研究终点,:,主要终点：,EFS,次要终点：,OS,PFS,DFS,RR,，剂量密度分析和毒性,DLBCL,6080,岁,aaIPI 1,n=600,随访至少,1,年,R-CHOP14,q2w,8,R,R-CHOP,21,q3w,8,1:1,Delarue,et al,.,Blood,2009 114:Abstract 406.,19,研究结果：,202,例随机,201,例治疗,.,中位年龄,72,岁,.,中位随访,2y.,RCHOP21,N=98,RCHOP14,N=103,病人特征,aaIPI 2-3,B,症状,完成,8,疗程无进展,接受,G-CSF,59%,43%,76%,66%,67%,37%,71%,90%,疗效,RR,（,CR+CRu,）,2y EFS,2y PFS,2y DFS,2y OS,75%,61%,63%,70%,70%,67%,48%,49%,57%,67%,安全性,3-4,度毒性,血液,血液以外,RCHOP14组,更常见,如红血球和血小板输注，发热性中性粒减少,住院等,.,两组间无差异。,p=NS,p=NS,p=NS,p=NS,Delarue,et al,.,Blood,2009 114:Abstract 406.,20,LNH03-6B,试验中期分析更倾向用,R-CHOP21,治疗老年,DLBCL,。,和,R-CHOP14,比较，,R-CHOP21,疗效更好，副作用很少,.,计划,2010,年,602,例入组后做最终分析,.,Comments,：本研究和,D.Cunningham,et al,在,2009ASCO,上发表的研究都是双周比较,3,周方案。不同的是本研究入组老年患者，且双周化疗达,8,疗程。从中期分析来看，两组疗效和安全性基本相当。,结论：,Delarue,et al,.,Blood,2009 114:Abstract 406.,21,2316 309,例年轻高危,DLBCL,长期随访,:,一项,GIMURELL,和意大利淋巴瘤研究组,(IIL),研究的合并分析,背景,:,中高危和高危DLBCL预后很差.HDC/ASCT能有效挽救对化疗敏感的病人,但一线治疗的结论常自相矛盾.,R联合标准,化疗可显著改善预后，但年轻高危,DLBCL数据匮乏.,研究目的,:,本分析研究,了四种治疗变量的影响,:HDC/ASCT,R,MegaCEOP,或第,3代MACOP-B化疗,受累野放疗(IF-RT),。,初治,DLBCL,61,岁,中高危或高危,N=309,随访,2.,一项,II,期研究,MACOP-B,qw8/2,疗程高剂量,MAD(,米托蒽醌,阿糖胞苷,地塞米松,)+BEAM/ASCT,n=,40,3.,一项,III,期随机试验,一组,48,例高剂量交替,(HDS)/ASCT,，一组,59,例,MegaCEOP,qw,6,4.,一项,II,期试验，剂量密集,R-MegaCEOP,4/2,疗程高剂量,R-MAD+BEAM/ASCT,，,n=120,1.,一项,II,期研究,MACOP-B,qw,12,n=42,Chiappella,et al,.,Blood,2009 114:Abstract 2316,22,研究结果：,CR 69%,PR 7%,无缓解,18%,。,中位随访,10,年,10y OS,和,PFS,率分别为,:59%,和,48%.,Cox,s,多变量分析：,OS,R,治疗的病人显著改善,(HR=0.36,95%CI=0.21-0.63,p.0003),IF-RT,放疗显著改善,(HR=0.42,95%CI:0.27-0.66,p.0002),；,MegaCEOP vs MACOP-B,没有明显获益,(HR=0.86,95%CI:0.57-1.31,p.482),。,ASCT,无显著获益,(HR=0.94,95%CI:0.62-1.41,p.751).,IPI,分层后无明显差别,.,PFS,结果类似,Chiappella,et al,.,Blood,2009 114:Abstract 2316,23,结论：,免疫治疗,和受累野放疗在改善初治高危,DLBCL,病人长期生存中起主要作用,.,新型剂量密集型方案和,ASCT,可能有作用,.,正进行随机试验：评估,“,HDC/ASCT+R vs,标准免疫化疗方案,”,治疗高危,DLBCL,的效果,.,Comments,：,R,免疫治疗在改善初治高危,DLBCL,病人长期生存中起主要作用,.,Chiappella,et al,.,Blood,2009 114:Abstract 2316,24,404 CHOEP-14+R,或,HDT(MegaCHOEP)+R,用于年轻高危侵袭性,B,细胞淋巴瘤,:,德国高度淋巴瘤研究组,MegaCHOEP,方案研究,背景,:,传统化疗vs HDT/ASCT一线治疗年轻高危病人的结果常自相矛盾。R联合传统化疗或HDT的随机研究还没有。,一项随机,III,期研究的,中期分析,：,比较8CHOEP-14,+,6R,和 MegaCHOEP,+,6R,.,研究终点,:,主要终点：,EFS,次要终点：,PFS,，,OS,，安全性,初治侵袭性淋巴瘤,1860,岁,aaIPI,：,23,随访,CHOEP-14,8+6R,R,MegaCHOEP-21 4+6R,MegaCHOEP,-21 4,CHOEP,-14,Schmitz,et al,.,Blood,2009 114:Abstract 404.,25,8 x CHOEP-14+6 x R,治疗初治年轻高危侵袭性,B-NHL,效果很好,.,3,年,EFS,和,OS,是至今报告中最好的。,MegaCHOEP+6 x R,不优于传统方案,EFS,显著更差,.,毒性较大,R,联合传统化疗一线治疗高危侵袭性,B-NHL,即可，不需用,HDT/ASC,。,结论：,Comments,：,R-Chemo,为年轻高危患者带来生存获益。,Schmitz,et al,.,Blood,2009 114:Abstract 404.,26,3714 R-CHOP,治疗失败的老年,DLBCL,治疗结果,:R+HDT,二线治疗的作用,.,一项,RICOVER 60,试验回顾性分析,背景,:,R,一线治疗侵袭性,NHL,可显著改善治疗效果,.,但免疫化疗一线失败后的数据很少,.,特别,HDT/SCT,和美罗华挽救治疗的效果有待明确,.,研究目的,:,为了解,R-CHOP,治疗失败的病人,对,RICOVER-60,试验中二线治疗病人,的结果进行分析。,初治,DLBCL,6180,岁,N=1222,R,随访,CHOP-14,8+8 R,CHOP,-14 6+8 R,CHOP,-14 6,CHOP,-21 8,Glass,et al,.,Blood,2009 114:Abstract 3714.,27,研究结果：,301,例治疗失败,.4,例退出,.297,例入组分析,.,222(75%),例挽救,.70%PD,和,85%,复发病人经第二次强烈化疗诱导缓解。,59%,病人用,R+,方案挽救,.13%,病人用,HDT/ASCT,挽救,.,R+,挽救方案：,R+,挽救方案的生存远好于,R-,挽救方案,(3y OS,率,:39%vs 18%,p 0.001).,R-,初治的病人挽救效果更好,(3y OS,43%vs 24%,p 0.001),但,R-CHOP,初治的病人仍有效果,.,后面一组病人生存未出现平台期，不管挽救方案中是否有美罗华，但中位生存显著延长,(,中位生存,6 vs 15,月,3 y OS,率,12%vs 13%,p=0.011).,HDT/ASCT,：,R-,初治的病人,3y OS,：,66%vs 33%,p=0.019,R-CHOP,初治病人长期生存率不高于,10%.,Glass,et al,.,Blood,2009 114:Abstract 3714.,28,结论：,侵袭性,NHL,老年病人免疫化疗后二线治疗的预后很差，很少长期生存。,尽管很少病人获得长期生存,但美罗华可用于挽救治疗,延长生存。,化疗后,HDT+ASCT,是有效的,但,R-CHOP-14,治疗过的病人的长期生存率很低,.,新的二线治疗方案亟待建立,.,Glass,et al,.,Blood,2009 114:Abstract 3714.,DLBCL(NCCN2012)induction therapy,*,LDH elevated;stage;age,60y;performance status,2,Relapse/refractory disease,附：,