弥漫大B细胞淋巴瘤治疗新进展.ppt

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1、弥漫大B细胞淋巴瘤治疗新进展,张翼鷟天津医科大学附属肿瘤医院血液科天津市肿瘤防治重点实验室,概述 流行病学 基于分子生物学改变的预后评价 治疗进展 初治的DLBCL 难治复发的DLBCL 新药临床试验,概述,流行病学,弥漫大B细胞淋巴瘤:31%,滤泡性淋巴瘤:22%,边缘区淋巴瘤:8%,套细胞淋巴瘤:6%,小细胞淋巴瘤 7%,外周T细胞淋巴瘤:7%,HL及NHL的发病率,B-NHL 6632,66%,UC 378,4%,HL 854,9%,T/NK-NHL 2138,21%,病例总数：10002,SMZL,41,1%,B-LBL,172,3%,UC,387,6%,DLBCL,NOS,3328,

2、48%,MCL,307,5%,PCNs,221,3%,BL,107,2%,MMZL,99,1%,LPL,57,1%,DLBCL,SS,378,6%,MALTL,685,10%,FL,551,8%,CLL/SLL,424,6%,病例总数：6638,B-NHL亚型的发病率,DLBCL FL MALTL MCL CLL/SLL BL SMZL NMZL,弥漫大B细胞淋巴瘤,最常见的非霍奇金淋巴瘤:31%发病高峰:60岁临床表现及分子生物学特征:高度异质性 大细胞 无淋巴滤泡结构中位生存期:数周/月(若不治疗)30%到 40%伴有B 症状可能伴有结外病变(胃肠道,中枢神经系统,睾丸,皮肤)Michal

3、let AS,et al.Blood Rev.2009;23:11-23.,2010年NCCN指南:Essential Diagnostic Assessments for DLBCL,对所有切片进行血液病理学检查(至少1个为含有肿瘤组织的石蜡块)淋巴结切检当淋巴结难以切除或切取活检时,联合FNA和空心针活检并结合辅助检查时免疫表型:(DLBCL typically CD20+,CD45+,CD3-)免疫组化(石蜡切片):CD20,CD3,CD4,CD10,CD45,BCL2,BCL6,Ki-67,IRF-4/MUM1流式细胞学:CD45,CD3,CD5,CD19,CD10,CD20,kapp

4、a/lambdaNCCN Practice Guidelines in Oncology.2010.,弥漫大B细胞淋巴瘤的预后因素不良预后因素影响化疗效果与生存期年龄60岁LDH 正常值一般状态评分 2Ann Arbor 分期 III/IV结外受累区 1 个*,Prognostic for patients older than 60 yrs of age only.,International NHL Prognosis Factors Project.N Engl J Med.1993;329:987-994.,Yrs,Percent Survival,Very good,Good,Poo

5、r,P.0001,基于修正IPI评分的总生存率,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,0,1,2,3,4,5,Sehn LH,et al.Blood.2007;109:1857-1861.,与弥漫大B细胞淋巴瘤相关的分子遗传学改变,遗传学异常较常见染色体异位:50%DNA 失衡:高达67%,Abramson JS,et al.Blood.2005;106:1164-1174.,Yrs,OS,基因表达谱-分子水平将DLBCL分为不同的临床亚型,1.0,0.8,0.6,0.4,0.2,0,0,2,4,6,8,10,Rosenwald A,et al.J

6、 Exp Med.2003;198:851-862.,Rosenwald A,et al.N Engl J Med.2002;346:1937-1947.Copyright 2002 Massachusetts Medical Society.All rights reserved.,0,0.2,0.4,0.6,0.8,1.0,0,4,8,Probability of Survival,6,10,2,P.001,Yrs,不同亚型的DLBCL的生存期,Germinal-center B-cell like,Type 3,Activated B-cell like,基因表达谱-分子水平将DLBCL

7、分为不同的临床亚型,Bea S,et al.Blood.2005;106:3183-3190.,Lenz G,et al.N Engl J Med.2008;359:2313-2323.,CHOP-R治疗方案对DLBCL亚型的预后具有价值,CHOP-RituximabOS,1.0,0.8,0.6,0.4,0.2,0,Probability,0,1,2,3,4,5,6,Yrs,P=4 x 10-3,CHOP-RituximabPFS,CHOPOS,1.0,0.8,0.6,0.4,0.2,0,0,1,2,3,4,5,6,Yrs,P=1 x 10-4,1.0,0.8,0.6,0.4,0.2,0,0,

8、1,2,3,4,5,Yrs,6,P=8 x 10-6,GCB DLBCL,ABC DLBCL,基于基因表达的风险评分-预测DLBCL临床结果,潜在的疾病生物学尚未确定研究目的:CHOP-及R-CHOP治疗后的DLBCL病人的基因表达特征III 期随机实验,E4494存档的组织,(N=632)CHOP vs R-CHOP rituximab 维持治疗老年DLBCL病人石蜡包埋组织储存 10 yrs 经过微阵列处理的相关性研究指标:比例风险模式(FFS,OS),Winter JN,et al.ASH 2011.Abstract 87.,基于基因表达的风险评分-预测DLBCL临床结果,N=183合格

9、者,可评估案例6 genes for R-CHOP5 genes for CHOP(single gene overlap LMO2)High-vs low-gene risk scores significantly predicted E4494 clinical outcome(median follow-up:9.4 yrs),Winter JN,et al.ASH 2011.Abstract 87.,基于基因表达的风险评分-预测DLBCL临床结果,CHOP,R-CHOP,Winter JN,et al.ASH 2011.Abstract 87.,Probability,Median

10、Median,Median Median,1.0,0.8,0.6,0.4,0.2,0,12,0,2,4,6,8,10,Yrs,FFS,P=.001,基于基因表达的风险评分-预测DLBCL临床结果,High-vs low-gene risk scores significantly predicted OSCHOP(median follow-up:7.6 yrs;P.0001)R-CHOP(median follow-up:2.8 yrs;P=.0014)基因风险评分对调整后的IPI多元分析具有预测意义,Winter JN,et al.ASH 2011.Abstract 87.,基于基因表达的

11、风险评分-预测DLBCL临床结果,该预测模型也可区分一些不同来源的细胞的差异CHOP:significant difference among nongerminal center B-cell(GCB)cases(P=.0002)R-CHOP:significant difference among GCB cases(P=.03)Molecular predictors largely independent of IPI in both CHOP,R-CHOP patients,Winter JN,et al.ASH 2011.Abstract 87.,弥漫大B细胞淋巴瘤的治疗进展,初治

12、DLBCL,CHOP Rituximab in DLBCL:GELA LNH-98.5 Phase III Study,Primary endpoint:EFSSecondary endpoints:OS,RR,R-CHOPevery 3 wks for 8 cycles(n=202),CHOPevery 3 wks for 8 cycles(n=197),Untreated elderly patients with stage II-IV DLBCL(N=399),Stratified by risk factors(0-1 vs 2-3),Assessment,Coiffier B,et

13、 al.N Engl J Med.2002;346:235-242.Feugier P,et al.J Clin Oncol.2005;23:4117-4126.,Maint.Ritux.After R-CHOP or CHOP in Older DLBCL(E4494/C9793 Ph III Study),Primary endpoint:FFS,Morrison VA,et al.ASCO 2007.Abstract 8011.Habermann TM,et al.J Clin Oncol.2006;24:3121-3127.,Untreated patients with CD20+D

14、LBCL,60 yrs of age or older,PS 0-3(N=632),R-CHOP x 6-8 cycles(n=318),CHOP x 6-8 cycles(n=314),Stratified by IPI score(0-1 vs 2-4),Responders(n=415),Maintenance Rituximabq6mos x 2 yrs,starting 4 wks after last cycle(n=207),Observation(n=208),Stratified by IPI score,CR/PR,induction,Cunningham D,et al.

15、ASCO 2009.Abstract 8506.,Newly diagnosed CD20+DLBCLpatients(N=1080),R-CHOP-14 x 6 cycles+Rituximab x 8 cycles+Lenograstim on Days 4-12(n=540),R-CHOP-21 x 8 cycles+Rituximab x 8 cycles(n=540),Stratified by IPI score and age,R-CHOP-14 vs R-CHOP-21 in Newly Diagnosed DLBCL(Phase III Study),Primary endp

16、oint:OSSecondary endpoint:FFS,toxicity,response rates,Cunningham D,et al.ASCO 2009.Abstract 8506.,*249 patients not evaluable or data missing.,R-CHOP-14 vs R-CHOP-21 in Newly Diagnosed DLBCL:Responses,LNH03-6B GELA:R-CHOP-14 vs R-CHOP-21 in Elderly DLBCL Patients,Primary endpoint:EFSSecondary endpoi

17、nts:CR or CRu,ORR,PFS,DFS,OS,dose intensity,toxicity,Delarue R,et al.ASH 2009.Abstract 406.,R-CHOP every 14 days for 8 cycles+IT MTX for 4 cycles(n=103),R-CHOP every 21 days for 8 cycles+IT MTX for 4 cycles(n=99),DLBCL patients60-80 yrs of age(N=202),ProphylacticDarbepoetin alfa,Conventional treatme

18、ntfor chemotherapy-induced anemia,ProphylacticDarbepoetin alfa,Conventional treatmentfor chemotherapy-induced anemia,LNH03-6B GELA Trial:Results,Delarue R,et al.ASH 2009.Abstract 406.,Hematologic toxicities greater for R-CHOP-14Patients on R-CHOP-14 had higher rates of febrile neutropenia,hospitaliz

19、ation,and death due to toxicity,LNH03-6B GELA Trial:Toxicities,R-CHOP-14,R-CHOP-21,11,15,22,21,36,50,22,26,69,83,73,83,Patients(%),100,90,80,70,60,50,40,30,20,10,0,Grade 3/4Leukocytes,Grade 3/4Neutrophils,Grade 3/4Hemoglobin,RBCTransfusion,Grade 3/4Platelets,PlateletTransfusion,Delarue R,et al.ASH 2

20、009.Abstract 406.,Pfreundschuh M,et al.Lancet Oncol.2006;7:379-391.,MInT:Ph III Study of CHOP-like Chemo Rituximab in Adv DLBCL(Younger Pts),Patients with untreated CD20+stage II-IV DLBCL(or bulky stage I),IPI 0-1,18-60 yrs of age(N=823),CHOP-like regimen*+30-40 Gy radiotherapy(n=410),CHOP-like regi

21、men*+Rituximab 375 mg/m2+30-40 Gy radiotherapy(n=413),Cycle 6,*CHOP-21,CHOEP-21,MACOP-B,or PMitCEBO.,Stratified by age-adjusted IPI score(0-1 vs 2-3),bulky disease,treatment center,and regimen,MInT:6-Yr Follow-up Data,Current study presented 6-yr findings(N=823),Multivariate analysis showed EFS infl

22、uenced byRituximab(HR:0.49;P.001)Age-adjusted IPI(HR:1.73;P.001)Bulky disease(HR:1.43;P=.004),Pfreundshuh M,et al.ASH 2010.Abstract 111.,R-EPOCH 方案,Given every 21 days for 4-6 cyclesRegimen consists ofRituximab 375 mg/m2 on Day 1Etoposide 65 mg/m2 continuous IV on Days 2-4Prednisone 60 mg/m2 PO on D

23、ay 1-14Vincristine 0.5 mg continuous IV on Day 2-4Cyclophosphamide 750 mg/m2 IV on Day 5Doxorubicin 15 mg/m2 continuous IV on Days 2-4,Ph II Study of Dose-Adjusted EPOCH-R in DLBCL(CALGB 50103):PFS by IPI Score,Median potential follow-up:54 mos5-yr PFS:79%Low risk IPI:91%Low-int risk IPI:90%High-int

24、 risk IPI:67%High risk IPI:47%IPI score significantly associated with PFS(P=.007),Wilson WH,et al.J Clin Oncol.2008;26:2717-2724.,CALGB 50303:R-CHOP vs R-EPOCH in Newly Diagnosed DLBCL,Primary endpoints:EFS,molecular predictors of outcome for each regimenSecondary endpoints:RR,OS,toxicity,use of mol

25、ecular profiling for pathological diagnosis,R-CHOPevery 3 wks for 6 cycles,R-EPOCHDoxorubicin,etoposide,vincristine on Days 1-4,cyclophosphamide on Day 5,prednisone on Days 1-5,Untreated patients with newly diagnosedDLBCL(N=478),ClinicalTrials.gov.NCT00118209.,Primary endpoints:OS and PFSClosed:12/1

26、5/07 with 276 randomized patients,Patients with bulky stage II-IV,high-int or high-risk CD20+NHL(N=276),CHOP or R-CHOP for 5 cycles,PR or CR,CHOP or R-CHOP for 3 coursesNo additional therapy until progression,CHOP or R-CHOP for 1 course+ASCT,Stratified by disease risk(int-high vs high),Off therapy i

27、f PR,ClinicalTrials.gov.NCT00004031.,Early vs Delayed HDT in High-Int/High-Risk DLBCL:Phase III S9704 Study,复发难治 DLBCL,NCCN Guideline Recommendations for Treatment of Relapsed DLBCL,Second-line therapy in candidates for high-dose therapy+ASCTDHAP rituximabESHAP rituximabGDP rituximabGemOx rituximabI

28、CE rituximabminiBEAM rituximabMINE rituximab,Second-line therapy for patients who are not candidates for high-dose therapyClinical trialRituximabCEPP rituximabPEPC EPOCH rituximab,NCCN Practice Guidelines in Oncology.2010.,治疗DLBCL的新药临床试验,DLBCL研究中的药物(Off-Label Use),Bevacizumab 贝伐单抗 recombinant,humani

29、zed,monoclonal VEGF antibodyBortezomib 硼替佐米proteasome inhibitorEnzastaurin PKC-selective inhibitorEpratuzumab 依帕珠单抗recombinant,humanized,monoclonal CD22 antibodyEverolimus 依维莫司mTOR inhibitorLenalidomide 雷利度胺immunomodulator,antiangiogenicRadioimmunotherapy Fostamatinib specific inhibitor of Syk in B-

30、cell signaling pathway,治疗DLBCL的研究中的药物:Phase II Data,1.Micallef IN,et al.ASCO 2008.Abstract 8500.2.Zinzani PL,et al.Ann Oncol.2008;19:769-773.3.Haioun C,et al.ASCO 2010.Abstract 8069.4.Friedberg JW,et al.Blood.2010;115:2578-2585.5.Wiernik PH,et al.J Clin Oncol.2008;26:4952-4957.,Bortezomib(硼替佐米)+CHOP

31、-R作为DLBCL的一线治疗,Phase I/IIN=40 patients with previously untreated DLBCLCHOP-21+rituximab 375 mg/m2 each cycle Bortezomib given at 3 different dosesArm 0(n=4):0.7 mg/m2Arm 1(n=8):1.0 mg/m2Arm 2(n=28):1.3 mg/m2,Median follow-up:21 mos(range:9-35)ORR resultsITT(n=40):90%(CR/CRu:68%)Evaluable(n=36):100%(

32、CR/CRu:75%)Estimated 2-yr PFS:72%Treatment generally well tolerated4 deaths prior to first response assessment,Leonard JP,et al.ASCO 2007.Abstract 8031.,Bendamustine(苯达莫司汀)+Rituximab for Rel/Ref DLBCL:Phase II Study,Day 1:bendamustine 120 mg/m2+rituximab 375 mg/m2;Day 2:bendamustine 120 mg/m2ORR of

33、60%required by study design,Bendamustine+Rituximab28-day cycles for 6 cycles,Patients with relapsed/refractory DLBCL whofailed at least 1 previous therapy(N=25,ITT),Vacirca JL,et al.ASCO 2010.Abstract 8041.,Bendamustine+Rituximab for Rel/Ref DLBCL:Preliminary Phase II Results,Vacirca JL,et al.ASCO 2

34、010.Abstract 8041.,Everolimus(依维莫司):Ongoing Phase II and III Studies in DLBCL,Phase IIEverolimus plus rituximab in relapsed/refractory DLBCL1Everolimus,panobinostat,or both in relapsed/refractory DLBCL2Everolimus in relapsed/refractory lymphoma3Phase IIIEverolimus as adjuvant therapy following CR to

35、 first-line rituximab-chemotherapy in patients with poor-risk DLBCL4,1.ClinicalTrials.gov.NCT00869999.2.ClinicalTrials.gov.NCT00978432.3.ClinicalTrials.gov.NCT00436618.4.ClinicalTrials.gov.NCT00790036.,Phase IIR-CHOP plus bevacizumab for first-line treatment of DLBCL1Bevacizumab plus R-CHOP for first-line treatment of stage II-IV DLBCL2Phase IIIR-CHOP vs R-CHOP plus bevacizumab for first-line treatment of DLBCL3,Bevacizumab(贝伐单抗):Ongoing Phase II and III Studies in DLBCL,ClinicalTrials.gov.NCT00788606.ClinicalTrials.gov.NCT00121199.3.ClinicalTrials.gov.NCT00486759,谢谢！,