弥漫大B细胞淋巴瘤治疗新进展PPT课件

.,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aprilzyz,.,2,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,.,3,概述,.,4,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%,.,5,HL及NHL的发病率,B-NHL6632,66%,UC378,4%,HL854,9%,T/NK-NHL2138,21%,病例总数：10002,.,6,SMZL,41,1%,B-LBL,172,3%,UC,387,6%,DLBCL,NOS,3328,48%,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,.,7,DLBCLFLMALTLMCLCLL/SLLBLSMZLNMZL,.,8,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)MichalletAS,etal.BloodRev.2009;23:11-23.,.,9,2010年NCCN指南:EssentialDiagnosticAssessmentsforDLBCL,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:(DLBCLtypicallyCD20+,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,kappa/lambdaNCCNPracticeGuidelinesinOncology.2010.,.,10,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2AnnArbor分期III/IV结外受累区1个*,Prognosticforpatientsolderthan60yrsofageonly.,InternationalNHLPrognosisFactorsProject.NEnglJMed.1993;329:987-994.,.,11,Yrs,PercentSurvival,Verygood,Good,Poor,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,SehnLH,etal.Blood.2007;109:1857-1861.,.,12,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%,AbramsonJS,etal.Blood.2005;106:1164-1174.,.,13,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,RosenwaldA,etal.JExpMed.2003;198:851-862.,.,14,RosenwaldA,etal.NEnglJMed.2002;346:1937-1947.Copyright2002MassachusettsMedicalSociety.Allrightsreserved.,0,0.2,0.4,0.6,0.8,1.0,0,4,8,ProbabilityofSurvival,6,10,2,P10yrs经过微阵列处理的相关性研究指标:比例风险模式(FFS,OS),WinterJN,etal.ASH2011.Abstract87.,.,18,基于基因表达的风险评分-预测DLBCL临床结果,N=183合格者,可评估案例6genesforR-CHOP5genesforCHOP(singlegeneoverlapLMO2)High-vslow-generiskscoressignificantlypredictedE4494clinicaloutcome(medianfollow-up:9.4yrs),WinterJN,etal.ASH2011.Abstract87.,.,19,基于基因表达的风险评分-预测DLBCL临床结果,CHOP,R-CHOP,WinterJN,etal.ASH2011.Abstract87.,Probability,MedianMedian,MedianMedian,1.0,0.8,0.6,0.4,0.2,0,12,0,2,4,6,8,10,Yrs,FFS,P=.001,.,20,基于基因表达的风险评分-预测DLBCL临床结果,High-vslow-generiskscoressignificantlypredictedOSCHOP(medianfollow-up:7.6yrs;P.0001)R-CHOP(medianfollow-up:2.8yrs;P=.0014)基因风险评分对调整后的IPI多元分析具有预测意义,WinterJN,etal.ASH2011.Abstract87.,.,21,基于基因表达的风险评分-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:significantdifferenceamongnongerminalcenterB-cell(GCB)cases(P=.0002)R-CHOP:significantdifferenceamongGCBcases(P=.03)MolecularpredictorslargelyindependentofIPIinbothCHOP,R-CHOPpatients,WinterJN,etal.ASH2011.Abstract87.,.,22,弥漫大B细胞淋巴瘤的治疗进展,.,23,初治DLBCL,.,24,CHOPRituximabinDLBCL:GELALNH-98.5PhaseIIIStudy,Primaryendpoint:EFSSecondaryendpoints:OS,RR,R-CHOPevery3wksfor8cycles(n=202),CHOPevery3wksfor8cycles(n=197),UntreatedelderlypatientswithstageII-IVDLBCL(N=399),Stratifiedbyriskfactors(0-1vs2-3),Assessment,CoiffierB,etal.NEnglJMed.2002;346:235-242.FeugierP,etal.JClinOncol.2005;23:4117-4126.,.,25,Maint.Ritux.AfterR-CHOPorCHOPinOlderDLBCL(E4494/C9793PhIIIStudy),Primaryendpoint:FFS,MorrisonVA,etal.ASCO2007.Abstract8011.HabermannTM,etal.JClinOncol.2006;24:3121-3127.,UntreatedpatientswithCD20+DLBCL,60yrsofageorolder,PS0-3(N=632),R-CHOPx6-8cycles(n=318),CHOPx6-8cycles(n=314),StratifiedbyIPIscore(0-1vs2-4),Responders(n=415),MaintenanceRituximabq6mosx2yrs,starting4wksafterlastcycle(n=207),Observation(n=208),StratifiedbyIPIscore,CR/PR,induction,.,26,CunninghamD,etal.ASCO2009.Abstract8506.,NewlydiagnosedCD20+DLBCLpatients(N=1080),R-CHOP-14x6cycles+Rituximabx8cycles+LenograstimonDays4-12(n=540),R-CHOP-21x8cycles+Rituximabx8cycles(n=540),StratifiedbyIPIscoreandage,R-CHOP-14vsR-CHOP-21inNewlyDiagnosedDLBCL(PhaseIIIStudy),Primaryendpoint:OSSecondaryendpoint:FFS,toxicity,responserates,.,27,CunninghamD,etal.ASCO2009.Abstract8506.,*249patientsnotevaluableordatamissing.,R-CHOP-14vsR-CHOP-21inNewlyDiagnosedDLBCL:Responses,.,28,LNH03-6BGELA:R-CHOP-14vsR-CHOP-21inElderlyDLBCLPatients,Primaryendpoint:EFSSecondaryendpoints:CRorCRu,ORR,PFS,DFS,OS,doseintensity,toxicity,DelarueR,etal.ASH2009.Abstract406.,R-CHOPevery14daysfor8cycles+ITMTXfor4cycles(n=103),R-CHOPevery21daysfor8cycles+ITMTXfor4cycles(n=99),DLBCLpatients60-80yrsofage(N=202),ProphylacticDarbepoetinalfa,Conventionaltreatmentforchemotherapy-inducedanemia,ProphylacticDarbepoetinalfa,Conventionaltreatmentforchemotherapy-inducedanemia,.,29,LNH03-6BGELATrial:Results,DelarueR,etal.ASH2009.Abstract406.,.,30,HematologictoxicitiesgreaterforR-CHOP-14PatientsonR-CHOP-14hadhigherratesoffebrileneutropenia,hospitalization,anddeathduetotoxicity,LNH03-6BGELATrial: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,Grade3/4Leukocytes,Grade3/4Neutrophils,Grade3/4Hemoglobin,RBCTransfusion,Grade3/4Platelets,PlateletTransfusion,DelarueR,etal.ASH2009.Abstract406.,PfreundschuhM,etal.LancetOncol.2006;7:379-391.,MInT:PhIIIStudyofCHOP-likeChemoRituximabinAdvDLBCL(YoungerPts),PatientswithuntreatedCD20+stageII-IVDLBCL(orbulkystageI),IPI0-1,18-60yrsofage(N=823),CHOP-likeregimen*+30-40Gyradiotherapy(n=410),CHOP-likeregimen*+Rituximab375mg/m2+30-40Gyradiotherapy(n=413),Cycle6,*CHOP-21,CHOEP-21,MACOP-B,orPMitCEBO.,Stratifiedbyage-adjustedIPIscore(0-1vs2-3),bulkydisease,treatmentcenter,andregimen,.,32,MInT:6-YrFollow-upData,Currentstudypresented6-yrfindings(N=823),MultivariateanalysisshowedEFSinfluencedbyRituximab(HR:0.49;P.001)Age-adjustedIPI(HR:1.73;P.001)Bulkydisease(HR:1.43;P=.004),PfreundshuhM,etal.ASH2010.Abstract111.,.,33,R-EPOCH方案,Givenevery21daysfor4-6cyclesRegimenconsistsofRituximab375mg/m2onDay1Etoposide65mg/m2continuousIVonDays2-4Prednisone60mg/m2POonDay1-14Vincristine0.5mgcontinuousIVonDay2-4Cyclophosphamide750mg/m2IVonDay5Doxorubicin15mg/m2continuousIVonDays2-4,.,34,PhIIStudyofDose-AdjustedEPOCH-RinDLBCL(CALGB50103):PFSbyIPIScore,Medianpotentialfollow-up:54mos5-yrPFS:79%LowriskIPI:91%Low-intriskIPI:90%High-intriskIPI:67%HighriskIPI:47%IPIscoresignificantlyassociatedwithPFS(P=.007),WilsonWH,etal.JClinOncol.2008;26:2717-2724.,.,35,CALGB50303:R-CHOPvsR-EPOCHinNewlyDiagnosedDLBCL,Primaryendpoints:EFS,molecularpredictorsofoutcomeforeachregimenSecondaryendpoints:RR,OS,toxicity,useofmolecularprofilingforpathologicaldiagnosis,R-CHOPevery3wksfor6cycles,R-EPOCHDoxorubicin,etoposide,vincristineonDays1-4,cyclophosphamideonDay5,prednisoneonDays1-5,UntreatedpatientswithnewlydiagnosedDLBCL(N=478),ClinicalT.NCT00118209.,.,36,Primaryendpoints:OSandPFSClosed:12/15/07with276randomizedpatients,PatientswithbulkystageII-IV,high-intorhigh-riskCD20+NHL(N=276),CHOPorR-CHOPfor5cycles,PRorCR,CHOPorR-CHOPfor3coursesNoadditionaltherapyuntilprogression,CHOPorR-CHOPfor1course+ASCT,Stratifiedbydiseaserisk(int-highvshigh),OfftherapyifPR,ClinicalT.NCT00004031.,EarlyvsDelayedHDTinHigh-Int/High-RiskDLBCL:PhaseIIIS9704Study,.,37,复发难治DLBCL,.,38,NCCNGuidelineRecommendationsforTreatmentofRelapsedDLBCL,Second-linetherapyincandidatesforhigh-dosetherapy+ASCTDHAPrituximabESHAPrituximabGDPrituximabGemOxrituximabICErituximabminiBEAMrituximabMINErituximab,Second-linetherapyforpatientswhoarenotcandidatesforhigh-dosetherapyClinicaltrialRituximabCEPPrituximabPEPCEPOCHrituximab,NCCNPracticeGuidelinesinOncology.2010.,.,39,治疗DLBCL的新药临床试验,.,40,DLBCL研究中的药物(Off-LabelUse),Bevacizumab贝伐单抗recombinant,humanized,monoclonalVEGFantibodyBortezomib硼替佐米proteasomeinhibitorEnzastaurinPKC-selectiveinhibitorEpratuzumab依帕珠单抗recombinant,humanized,monoclonalCD22antibodyEverolimus依维莫司mTORinhibitorLenalidomide雷利度胺immunomodulator,antiangiogenicRadioimmunotherapyFostamatinibspecificinhibitorofSykinB-cellsignalingpathway,治疗DLBCL的研究中的药物:PhaseIIData,1.MicallefIN,etal.ASCO2008.Abstract8500.2.ZinzaniPL,etal.AnnOncol.2008;19:769-773.3.HaiounC,etal.ASCO2010.Abstract8069.4.FriedbergJW,etal.Blood.2010;115:2578-2585.5.WiernikPH,etal.JClinOncol.2008;26:4952-4957.,.,42,Bortezomib(硼替佐米)+CHOP-R作为DLBCL的一线治疗,PhaseI/IIN=40patientswithpreviouslyuntreatedDLBCLCHOP-21+rituximab375mg/m2eachcycleBortezomibgivenat3differentdosesArm0(n=4):0.7mg/m2Arm1(n=8):1.0mg/m2Arm2(n=28):1.3mg/m2,Medianfollow-up:21mos(range:9-35)ORRresultsITT(n=40):90%(CR/CRu:68%)Evaluable(n=36):100%(CR/CRu:75%)Estimated2-yrPFS:72%Treatmentgenerallywelltolerated4deathspriortofirstresponseassessment,LeonardJP,etal.ASCO2007.Abstract8031.,.,43,Bendamustine(苯达莫司汀)+RituximabforRel/RefDLBCL:PhaseIIStudy,Day1:bendamustine120mg/m2+rituximab375mg/m2;Day2:bendamustine120mg/m2ORRof60%requiredbystudydesign,Bendamustine+Rituximab28-daycyclesfor6cycles,Patientswithrelapsed/refractoryDLBCLwhofailedatleast1previoustherapy(N=2