外周T细胞淋巴瘤PPT课件.ppt

外周T细胞淋巴瘤治疗进展,外周T/NK细胞淋巴瘤定义,一组源于胸腺后成熟T淋巴细胞或自然杀伤(naturalkiller，NK)细胞的淋巴系统恶性肿瘤，其生物学行为及临床表现具有明显异质性。,WHO成熟T/NK细胞肿瘤分类(2008),T-cellprolymphocyticleukemiaT-celllargegranularlymphocyticleukemiaChroniclymphoproliferativeNKcellsAggressiveNK-cellleukemiaAdultT-celllymphoma/leukemiaSystemicEBV-positiveT-celllymphomaExtranodalNK/T-celllymphoma,nasaltypeEnteropathy-typeintestinalT-celllymphomaHepatosplenicT-celllymphomaAngioimmunoblasticT-celllymphomaAnaplasticlarge-celllymphoma,ALKpositiveAnaplasticlarge-celllymphoma,ALKnegativePeripheralT-celllymphoma,NOS,MycosisfungoidesSzarysyndromePrimarycutaneousCD30+lymphoproliferativePrimarycutaneousanaplasticlargecellLymphomatoidpapulosisBorderlinelesionsSubcutaneouspanniculitis-likeTcellPrimarycutaneousgamma-deltaTcellHydroavacciniformelymphomaPrimarycutaneousaggressiveepidermotropicCD8+cytotoxicTcellPrimarycutaneoussmall/mediumCD4+T-celllymphoma(provisional),SwerdlowSH,etal.WHOclassificationoftumoursofthehaematopoleticandlymphoidtissues.2008.,外周T细胞淋巴瘤各亚型分布,1314例T细胞淋巴瘤，各亚型分布,LosAngeles,CA.October4,2008,外周T细胞淋巴瘤各亚型生物学异质性,PTCL不同亚型疾病异质性,CHOP治疗PTCL不同亚型生存资料,如何改善PTCL预后？,传统治疗的探索剂量强度与密集方案高剂量化疗联合造血干细胞移植新药的开发与应用基于疾病异质性的特色治疗,PTCL生物学本质、疾病特点、以及各亚型异质性认识?!,开发应用于T细胞淋巴瘤的新药,开发应用于T细胞淋巴瘤的新药,吉西他滨治疗PTCL,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.,PhaseStudyofBendamustineinRelapsed/RefractoryT-CellLymphoma,PreliminaryResultsFromaMulticenter,PhaseIIStudyofBendamustineinRefactoryorRelapsedT-CellLymphomaTheBENTLYTrial,Adaptedfrom11-ICAM,PhaseStudyofBendamustineinRelapsed/RefractoryT-CellLymphoma,STUDYDESIGN,BENDAMUSTINE:120mg/m2,IV,day1and2Every3weeksfor3cycles(C1,C2,C3),CR,CRu,PR,SD,Progressive,BENDAMUSTINEC4,C5,C6,OffStudy,FinalEvaluation1monthaftertheendoftreatment,Adaptedfrom11-ICAM,PhaseStudyofBendamustineinRelapsed/RefractoryT-CellLymphoma,RESPONSEHISTOLOGICSUBTYPES,Adaptedfrom11-ICAM,PhaseStudyofBendamustineinRelapsed/RefractoryT-CellLymphoma,Adaptedfrom11-ICAM,PhaseStudyofBendamustineinRelapsed/RefractoryT-CellLymphoma:Conclusions,BendamustineisactiveinrefactoryandrelapsedT-celllymphomawithanacceptabletoxicityHighresponserateinhighlypretreatedpoorriskpatients(ORR42%;CR23%)Themedianresponsedurationtimeis5.5months.Nextstep:CombiningBendamustinewithotherdrugs,Adaptedfrom11-ICAM,普拉曲沙（Pralatrexate）治疗PTCL,HighaffinityforRFC-1(anactivetransportmechanismforreducedfolates)EffectivesubstrateforFPGS(catalyzestheformationofpolyglutamateswithimprovedintracellularretention)IsacompetitiveinhibitorofDHFR(premetrexedtargetsTS)15-25foldmorecytotoxicthanMTXinavarietyofhumantumorcelllines,PROPELTrial:PralatrexateinRelapsed/RefractoryPTCL,OConnorOA,etal.ASH2008.Abstract261.,Romidepsin治疗复发难治PTCLpivotalphaseIIstudy,Schedule:4-hourinfusion14mg/m2ondays1,8,103:2920-2924.2.KimJG,etal.CancerChemotherPharmacol.2007;60:129-134.,3.GallaminAi,etal.Blood.2007;110:2316-2323.4.WeidmannE,etal.LeukLymphoma.2010;51:447-455,PhaseCHOP+/-AinPTCL,PhaseIIStudyofDenileukinDiftitox+CHOPinPTCL:“CONCEPT”Trial,DD18mg/kg/dayondays1and2，CHOPstartingday3，G-CSFday4Every21days,for6-8cyclesN=49(ITT)，Medianage,52years(range,23-80years)PTCL,NOS,n=19；AITL,n=10；ALCL,n=8,Foss.ClinAdvHematolOncol.2009;7(suppl18):12.,第一代抗CD30单抗：毒性小，疗效有限,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.,MOAofBrentuximabVedotin(SGN-35),ReproducedwithpermissionfromSeattleGenetics,Inc.;Younes.EHA.2009(abstr0503).,ADC=antibody-drugconjugate;MMAE=monomethylauristatinE.,PhaseIStudy:BrentuximabVedotin(SGN-35)inRelapsed/RefractoryCD30+Lymphoma,Dosecohorts: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:safetyandMTD,Younes.EHA.2009(abstr0503).,Relapsed/refractoryCD30+lymphomaECOGPS2(N=45),SGN-35IVq21dfor2cyclesRestageaftercycle2;SDorbettermayreceiveadditionalcycles,1.2mg/kgMedianPFS=2.2mos,PhaseIStudy:BrentuximabVedotin(SGN-35)inRelapsed/RefractoryCD30+Lymphoma:Results,MTD=1.8mg/kgORR=41%DOR=7.3mo,AdaptedwithpermissionfromYounes.EHA.2009(abstr0503).,18,24,30,36,42,48,54,60,66,72,78,84,12,6,0,0,10,20,30,40,50,60,70,80,90,100,Time(Weeks),PatientsWithoutDiseaseProgression(%),1.2mg/kgMedianPFS=6.3mos,1.2mg/kg(N=16),1.2mg/kg(N=29),AllDoses,PhaseStudy:BrentuximabVedotin(SGN-35)inRelapsed/RefractoryALCL,DemographicsandBaselineCharacteristics,Adaptedfrom11-ICAM,PhaseStudy:BrentuximabVedotin(SGN-35)inRelapsed/RefractoryALCL,KeyResponseResultsSummary,Adaptedfrom11-ICAM,PhaseStudy:BrentuximabVedotin(SGN-35)inRelapsed/RefractoryALCL,PFSinPatientswithCRbySubsequentTransplant,Adaptedfrom11-ICAM,PhaseStudy:BrentuximabVedotin(SGN-35)inRelapsed/RefractoryALCL,Adaptedfrom11-ICAM,PhaseStudy:BrentuximabVedotin(SGN-35)inRelapsed/RefractoryALCL,Adaptedfrom11-ICAM,PhaseStudy:BrentuximabVedotin(SGN-35)inRelapsed/RefractoryALCL:Conclusions,DurablecompleteremissionsachievedwithbrentuximabvedotininhighlyrefactorysystemicALCLpatients,Adverseeventsweremanageable,includingperipheralneuropathy,Basedontheseencourangingtrialresulte,afrontlinestudyinsALCLisunderway(ClinicalT#NCT01309789),Adaptedfrom11-ICAM,Anti-CCR4（KW0761）治疗复发CCR4+ATLLorPTCL,TargetsCCR4(CCChemokinereceptortype4)Expressedonsub-populationofTregcells(Th2CD4+Tcells)88%ofpatientswithATLL38%ofpatientswithPTCLPhaseI/IIStudy16patientsreceivedantibodyqweekx4withescalatingdoses;1patientoffstudyearlysecondarytotreatmentrelatedsideeffectsNoMTDnoted;recommendeddosegoingforward1mg/kgRR31%,2CR3PRGrade3/4toxicitiesincludedlymphopenia(10),neutropenia(3),leukopenia(2),zoster(1),Anti-CCR4（KW0761）治疗复发CCR4+ATLL，Phase2Trial,Adaptedfrom11-ICML,Anti-CCR4（KW0761）治疗复发CCR4+ATLL，Phase2Trial,Adaptedfrom11-ICML,Anti-CCR4（KW0761）治疗复发CCR4+ATLL，Phase2Trial,Adaptedfrom11-ICML,SummeryofPhaseIIStudyofKW-0761,Adaptedfrom11-ICML,MostcommonAEs:infusionreactionandrashaswellashematologiconessuchaslymphopenia,thrombocytopeniaandneutropeniaGrade3rash:Observedin5pts,But,theydisappearedorimprovedbysteroidtreatmengsORR:50%(13/26;95%Cl.30-70%)MedianPFS,5.2months;medianOS,13.7months,Conclusion:KW-0761isaneffectiveagentwithacceptabletoxicit