外周T細(xì)胞淋巴瘤治療進(jìn)展typhoonwho@2011.8.@CCMOBeijingCancerHospitalofCAMS&PUMC外周T/NK細(xì)胞淋巴瘤定義一組源于胸腺后成熟T淋巴細(xì)胞或自然殺傷(naturalkiller，NK)細(xì)胞的淋巴系統(tǒng)惡性腫瘤，其生物學(xué)行為及臨床表現(xiàn)具有明顯異質(zhì)性。WHO成熟T/NK細(xì)胞腫瘤分類(2008)T-cellprolymphocyticleukemiaT-celllargegranularlymphocyticleukemiaChroniclymphoproliferativeNKcellsAggressiveNK-cellleukemiaAdultT-celllymphoma/leukemiaSystemicEBV-positiveT-celllymphomaExtranodalNK/T-celllymphoma,nasaltypeEnteropathy-typeintestinalT-celllymphomaHepatosplenicT-celllymphomaAngioimmunoblasticT-celllymphomaAnaplasticlarge-celllymphoma,ALKpositiveAnaplasticlarge-celllymphoma,ALKnegativePeripheralT-celllymphoma,NOSMycosisfungoidesSézarysyndromePrimarycutaneousCD30+lymphoproliferativePrimarycutaneousanaplasticlargecellLymphomatoidpapulosisBorderlinelesionsSubcutaneouspanniculitis-likeTcellPrimarycutaneousgamma-deltaTcellHydroavacciniformelymphomaPrimarycutaneousaggressiveepidermotropicCD8+cytotoxicTcellPrimarycutaneoussmall/mediumCD4+T-celllymphoma(provisional)SwerdlowSH,etal.WHOclassificationoftumoursofthehaematopoleticandlymphoidtissues.2008.1314例T細(xì)胞淋巴瘤，各亞型分布LosAngeles,CA.October4,2008外周T細(xì)胞淋巴瘤各亞型分布外周T細(xì)胞淋巴瘤各亞型生物學(xué)異質(zhì)性PTCL不同亞型疾病異質(zhì)性CHOP治療PTCL不同亞型生存資料如何改善PTCL預(yù)后？傳統(tǒng)治療的探索劑量強度與密集方案高劑量化療聯(lián)合造血干細(xì)胞移植新藥的開發(fā)與應(yīng)用基于疾病異質(zhì)性的特色治療PTCL生物學(xué)本質(zhì)、疾病特點、以及各亞型異質(zhì)性認(rèn)識?!開發(fā)應(yīng)用于T細(xì)胞淋巴瘤的新藥開發(fā)應(yīng)用于T細(xì)胞淋巴瘤的新藥吉西他濱治療PTCLStudyRegimenNORRSallahetalGemcitabinemonotherapy1060%ZinzanietalPhaseIIGemcitabinemonotherapy1369%RoyalMarsdenPhaseIIGEM-P1669%SpenceretalPilotstudyVGF1070%KimetalPilotstudyCHOP-EG2677%CHOP-EG=CHOP-etoposide,gemcitabine;GEM-P=gemcitabine,cisplatin,methylprednisolone;VGF=vinorelbine,gemcitabine,filgrastim.Foss.2009ASCOEducationalBook.Alexandria,VA:AmericanSocietyofClinicalOncology.2009;480;Pro.2009ASCOEducationalBook.Alexandria,VA:AmericanSocietyofClinicalOncology.2009;486;Sallah.BrJHaematol.2001;113:185;Zinzani.AnnOncol.1998;9:1351;Arkenau.Haematologica.2007;92:271;Spencer.InternMedJ.2007;37:760;Kim.CancerChemotherPharmacol.2006;58:35.PhaseⅡStudyofBendamustineinRelapsed/RefractoryT-CellLymphomaPreliminaryResultsFromaMulticenter,PhaseIIStudyofBendamustineinRefactoryorRelapsedT-CellLymphoma《TheBENTLYTrial》Adaptedfrom11-ICAMPhaseⅡStudyofBendamustineinRelapsed/RefractoryT-CellLymphomaSTUDYDESIGNBENDAMUSTINE:120mg/m2,IV,day1and2Every3weeksfor3cycles(C1,C2,C3)CR,CRu,PR,SDProgressiveBENDAMUSTINEC4,C5,C6OffStudyFinalEvaluation1monthaftertheendoftreatmentAdaptedfrom11-ICAMPhaseⅡStudyofBendamustineinRelapsed/RefractoryT-CellLymphomaRESPONSEHISTOLOGICSUBTYPESNCR(%)PR(%)PD(%)ORR(%)ALLPatients4723195842AILT2425255050PTCLu1723126535Adaptedfrom11-ICAMPhaseⅡStudyofBendamustineinRelapsed/RefractoryT-CellLymphomaAdaptedfrom11-ICAMPhaseⅡStudyofBendamustineinRelapsed/RefractoryT-CellLymphoma:ConclusionsBendamustineisactiveinrefactoryandrelapsedT-celllymphomawithanacceptabletoxicityHighresponserateinhighlypretreatedpoorriskpatients(ORR42%;CR23%)Themedianresponsedurationtimeis5.5months.Nextstep:CombiningBendamustinewithotherdrugsAdaptedfrom11-ICAM普拉曲沙（Pralatrexate）治療PTCLHighaffinityforRFC-1(anactivetransportmechanismforreducedfolates)EffectivesubstrateforFPGS(catalyzestheformationofpolyglutamateswithimprovedintracellularretention)IsacompetitiveinhibitorofDHFR(premetrexedtargetsTS)15-25foldmorecytotoxicthanMTXinavarietyofhumantumorcelllinesPlasmamembraneLysosomecysteinecysteinecysteinecysteinePDXPDX(&NaturalFolates)PDXFPGSATP+MgCl2PDX(G)nPDXFPGH+SHGn?ATPADPRFC-1cMOAT/MRPATPasePDX(G)nTMTXPROPELTrial:PralatrexateinRelapsed/RefractoryPTCLEfficacy(n=109)ORR,n(%)AllpatientsNoresponsetorecenttherapy(n=69)Noresponsetoanytherapy(n=26)32(29%)17(25%)25(36%)Mediandurationofresponse,months10.1monthsMedianoverallsurvival,months14.5monthsGrade3/4AEs%ofPatients(n=111)Grade3Grade4Mucositis20(18%)4(4%)Fatigue6(5%)2(2%)Nausea4(4%)0(0%)Thrombocytopenia15(14%)21(19%)Anemia18(16%)2(2%)Neutropenia15(14%)9(8%)O’ConnorOA,etal.ASH2008.Abstract261.Romidepsin治療復(fù)發(fā)難治PTCL

pivotalphaseIIstudyWeek4Week2Week31221581Week1Cycle1Week1Cycle2Schedule:4-hourinfusion14mg/m2ondays1,8,&15every28daysCoiffierB,ProB,PrinceHM,etal.52ndASHAbstract114.Romidepsin治療復(fù)發(fā)難治PTCL

pivotalphaseIIstudyCoiffierB,ProB,PrinceHM,etal.52ndASHAbstract114.OutcomeIRCReview

(N=130)InvReview

(N=130)ORR(CR/CRu+PR)%2629CR+CRu,%1316PR,%1313SD,%2517MDR,mos(range)OR(CR/CRu+PR)12

(<1to26.0+)12

(<1to27.0+)CR+CRuNotreached

(<1.0to26.3+)14

(1.2to26.7+)MediantimetoOR,mos(range)2(2-6)2(1-4)MediantimetoCR,mos(range)4(2-9)2(2-10)MedianTTP,mos(range)6(<1to28+)3(<1to28)Romidepsin治療復(fù)發(fā)難治PTCL

pivotalphaseIIstudyConclusions:romidepsinshouldbefurtherinvestigatedincombinationwithchemotherapyinthefrontlinesettingOutcome,%PTCL-NOS(n=69)AITL(n=27)ALK-NegativeALCL

(n=21)Other

(n=13)ORR(CR/CRu+PR)2933240CR+CRu1315190Mostcommongrade≥3adverseevents,observedin≥10%Thrombocytopenia,Neutropenia,Infection,AnemiaCoiffierB,ProB,PrinceHM,etal.52ndASHAbstract114.單抗類藥物治療PTCLMoAbTargetNotesMDX-060CD30FullyhumanIgG1kSGN-30CD30Chimericmurine/humanantibodyBrentuximabvedotin(SGN-35)CD30SGN-30fusedwithantitubulinagentZanolimumabCD4IgG1k;targetsT-helpercellsDenileukinDiftitoxCD25interleukin-2fusedwithdiphtheriatoxinAlemtuzumabCD52IgG1;CD52highlyexpressedonmalignantTcellsKW-0761CCR4DefucosylatedhumanizedIgG1“Alemtuzumab+CHOP”inPTCLRegimenStatus(n)ResponseToxicityAlemtuzumabalone(pilotstudy)[1]Relapsed(14)StudyclosedearlyORR:36%CMVreactivation:43%TRM:36%Alemtuzumab+CHOP[2]Primary(20)55%stageI/IIStudyclosedearlyCR:65%1-yrEFS:43%Grade4neutropenia:90%Febrileneutropenia:55%CMVreactivation:25%TRM:10%Alemtuzumab+CHOP[3]Primary(24)CR:71%2-yrFFS:48%2-yrOS:53%Severeneutropenia:34%CMVreactivation:9%Infection:aspergillus,sepsis,

JCvirusreact,pneumoniaAlemtuzumab+FCD(fludarabine,cyclophosphamide,doxorubicin)[4]Primary(27)Rel/refr(11)StudyclosedearlyNewlydiagnosedORR:63%CR:44%MedOS:26mosMedPFS:12mosGrade3/4leucopenia:95%Febrileneutropenia:41%Severeinfections:37%CMVreactivation:32%TRM:22%(ofnewlydiagnosed)EBVLPD:5%1.EnbladG,etal.Blood.2004;103:2920-2924.2.KimJG,etal.CancerChemotherPharmacol.2007;60:129-134.3.GallaminAi,etal.Blood.2007;110:2316-2323.4.WeidmannE,etal.LeukLymphoma.2010;51:447-455PhaseⅢCHOP+/-AinPTCLPhaseIIStudyofDenileukinDiftitox+CHOPinPTCL:“CONCEPT”TrialDD18mg/kg/dayondays1and2，CHOPstartingday3，G-CSFday4Every21days,for6-8cyclesN=49(ITT)，Medianage,52years(range,23-80years)PTCL,NOS,n=19；AITL,n=10；ALCL,n=8n=49Median1-Year2-YearPFS12.4m50%41%OSNotyetreached79%63%ResponseITTn=49PTCLNOSAITLALCL

Overall32(65%)998

Complete(confirmed)25(51%)686Foss.ClinAdvHematolOncol.2009;7(suppl18):12.DrugPatientsDoseOutcomesAuthorSGN-30Chimericantibody24pts(3ALCL)PhaseI2-12mg/kgxwklyx61CRincALCLBartlett[1]

SGN-3079pts(41sALCL)PhaseII6-12mg/kgxwklyx6sALCLRR:17%(2CR,5PR)AllrespondersALK-Forero-Torres[2]

MDX-060Fullyhumanantibody72pts

(4ALCL)PhaseI/II1-15mg/kgwklyx4RR:8%

(2CRinALCL)Ansell[3]1.BartlettN,etal.Blood.2008;111:1848-1854.2.Forero-Torres,etal.BrJHaematol.2009;146:171-179.3.AnsellS,etal.JClinOncol.2007;25:2764-2769.第一代抗CD30單抗：毒性小，療效有限MOAofBrentuximabVedotin(SGN-35)ReproducedwithpermissionfromSeattleGenetics,Inc.;Younes.EHA.2009(abstr0503).ADC=antibody-drugconjugate;MMAE=monomethylauristatinE.PhaseIStudy:BrentuximabVedotin(SGN-35)inRelapsed/RefractoryCD30+LymphomaDosecohorts:0.1,0.2,0.4,0.6,0.8,1.2,1.8,2.7,and3.6mg/kgTumortypes(N)HL(42)SystemicALCL(2)AITL(1)Studyobjectives:safetyandMTDYounes.EHA.2009(abstr0503).Relapsed/refractoryCD30+lymphomaECOGPS≤2(N=45)SGN-35IVq21dfor2cyclesRestageaftercycle2;SDorbettermayreceiveadditionalcycles<1.2mg/kgMedianPFS=2.2mosPhaseIStudy:

BrentuximabVedotin(SGN-35)inRelapsed/RefractoryCD30+Lymphoma:ResultsMTD=1.8mg/kgORR=41%DOR=7.3moAdaptedwithpermissionfromYounes.EHA.2009(abstr0503).18243036424854606672788412600102030405060708090100Time(Weeks)PatientsWithoutDiseaseProgression(%)≥1.2mg/kgMedianPFS=6.3mos<1.2mg/kg(N=16)≥1.2mg/kg(N=29)AllDosesPhaseⅡStudy:BrentuximabVedotin(SGN-35)inRelapsed/RefractoryALCLN=58Age*52yr(14-76)Gender33M/25FECOGstatus033%166%22%ALCLconfirmedbycentralpathology97%ALK-negative72%Refractorytofrontlinetherapy62%Refractorytomostrecenttreatment50%Noresponsetoanypriortreatmeat22%Priorchemotherapyregimens*2(1-6)priorradiation45%priorASCT26%*Median(range)DemographicsandBaselineCharacteristicsAdaptedfrom11-ICAMPhaseⅡStudy:BrentuximabVedotin(SGN-35)inRelapsed/RefractoryALCLN=58Objectiveresponserate(95%Cl)86%(75,94)MediandurationofOR(95%Cl)12.6mo(5.7,-)CRrate(95%Cl)57%(43,70)MediandurationofresponseinpatientswithCR(95%Cl)13.2mo(10.8,-)MedianPFS(95%Cl)13.3mo(6.9,-)MedianOSNotreachedKeyResponseResultsSummaryAdaptedfrom11-ICAMPhaseⅡStudy:BrentuximabVedotin(SGN-35)inRelapsed/RefractoryALCLPFSinPatientswithCRbySubsequentTransplantPatientswhoachievedaCRNEventsMedianPFS(95%Cl)MediannumberofcyclesreceivedNosubsequenttransplant22714.3(13,-)12SubsequentSCTAllogenic6214.6(9.15)8Autologous51Notmet(8,-)8SubsequentSCTdidnotappeartomeaningfullyimpactPFSinthissmalldatasetAdaptedfrom11-ICAMPhaseⅡStudy:BrentuximabVedotin(SGN-35)inRelapsed/RefractoryALCLAdaptedfrom11-ICAMPhaseⅡStudy:BrentuximabVedotin(SGN-35)inRelapsed/RefractoryALCLAdaptedfrom11-ICAMPhaseⅡStudy:BrentuximabVedotin(SGN-35)inRelapsed/RefractoryALCL:ConclusionsCRORRate57%86%MedianDuration13.2mo12.6moDurablecompleteremissionsachievedwithbrentuximab

vedotininhighlyrefactorysystemicALCLpatientsAdverseeventsweremanageable,includingperipheralneuropathyBasedontheseencourangingtrialresulte,afrontlinestudyinsALCLisunderway(ClinicalT#NCT01309789)Adaptedfrom11-ICAMTargetsCCR4(CCChemokinereceptortype4)Expressedonsub-populationofTregcells(Th2CD4+Tcells)88%ofpatientswithATLL38%ofpatientswithPTCLPhaseI/IIStudy16patientsreceivedantibodyqweekx4withescalatingdoses;1patientoffstudyearlysecondarytotreatmentrelatedsideeffectsNoMTDnoted;recommendeddosegoingforward1mg/kgRR31%,2CR3PRGrade3/4toxicitiesincludedlymphopenia(10),neutropenia(3),leukopenia(2),zoster(1)Anti-CCR4（KW0761

）治療復(fù)發(fā)CCR4+ATLLorPTCLAnti-CCR4（KW0761）治療復(fù)發(fā)CCR4+ATLL，Phase2TrialAdaptedfrom11-ICMLAnti-CCR4（KW0761）治療復(fù)發(fā)CCR4+ATLL，Phase2TrialAdaptedfrom11-ICMLAnti-CCR4（KW0761）治療復(fù)發(fā)CCR4+ATLL，Phase2TrialAdaptedfrom11-ICMLSummeryofPhaseIIStudyofKW-0761Adaptedfrom11-ICMLMostcommonAEs:infusionreactionandrashaswellashematologiconessuchaslymphopenia,thrombocytopeniaandneutropenia

Grade3rash:Observedin5pts,But,theydisappearedorimprovedbysteroidtreatmengsORR:50%(13/26;95%Cl.30-70%)MedianPFS,5.2months;medianOS,13.7monthsConclusion:KW-0761isaneffectiveagentwithacceptabletoxicityprofilesforptswithrelapsedATL,inwhichnostandardtherapyexists.FurtherinvestigationarewarrantedSurfaceAntigens/ReceptorsCD2CD4CD25CD52CD30Chemokinereceptors….MicroenvironmentalFactorsAngiogenesisImmunomodulationViralPathogensCellularSurvivalMechanismsProteasomeInhibitionHDACinhibitionDeathReceptors&LigandsCellCycleArrestSignalTransductionInhibition基于疾病異質(zhì)性的特色治療CD30+T-celllymphomas:

ALCL,PTCL-nos初步研究顯示，第一代抗CD30單克隆抗體治療相關(guān)毒性小、臨床耐受性良好。SGN-35是第二代或改進(jìn)型抗CD30單抗，其治療復(fù)發(fā)耐藥ALCL的Ⅱ期臨床研究獲得了高CR率和持續(xù)性的緩解期。SGN-35與化療聯(lián)合的一線治療值得期待。CCR4+T-celllymphomas:ATLL，PTCLAngioimmunoblasticT-celllymphoma(AILT)SurfaceAntigens/ReceptorsCD4CD25CD52CD20MicroenvironmentalFactorsAngiogenesisImmunomodulationViralPathogensCellularSurvivalMechanismsProteasomeInhibitionHDACinhibitionDeathReceptors&LigandsCell