外周T細(xì)胞淋巴瘤診療進(jìn)展張智慧

外周T細(xì)胞淋巴瘤的治療進(jìn)展四川省腫瘤醫(yī)院腫瘤內(nèi)科張智慧主要內(nèi)容PTCL的分類(lèi)PTCL的流行病學(xué)PTCL的預(yù)后因子PTCL治療新藥物外周T淋巴瘤的分類(lèi)PTCLisaheterogeneousgroupofaggressivematureT-/NK-celllymphomasPTCLdoesnotrefertoanatomicsites,butrathertotheinvolvementofmoremature(postthymic)TcellsvsprethymicorimmatureTcellsAdaptedfromSwerdlowSH,etal.WHOClassificationofTumoursofHaematopoieticandLymphoidTissues.2008.Non-Hodgkin’slymphomaT-/NK-cellneoplasmsB-cellneoplasmsT-cellprolymphocyticLeukemiaPrecursorLymphoidNeoplasmsCutaneousExtranodalLeukemicMatureT-/NK-cellneoplasmsNodalNK/TCLnasaltypeAdultT-cellleukemia/lymphomaSubcutaneouspanniculitis-likeTCLEnteropathy-associatedTCLHepatosplenicTCLAggressiveNK-cellleukemiaTransformedMFPrimarycutaneousgamma/deltaTCLPeripheralTCL-NOSAngioimmunoblasticTCLAnaplasticlarge-celllymphoma(ALK+/-)AggressiveT-LymphoblasticLeukemia/LymphomaPrimarycutaneousCD30+T-celldisordersMFT-celllargegranularlymphocyticleukemiaSézarySyndromeIndolentInternationalT-CellLymphomaProject.JClinOncol.2008;26:4124-4130.1314例PTCL和NKTCL的分布25.9%18.5%10.4%9.6%6.6%5.5%4.7%12.2%2.5%0.9%1.4%1.7%PeripheralT-celllymphomaAngioimmunoblasticNaturalkiller/T-celllymphomaAdultT-cellleukemia/lymphomaAnaplasticlarge-celllymphoma,ALK+Anaplasticlarge-celllymphoma,ALK-Enteropathy-typeTcellPrimarycutaneousALCLHepatosplenicTcellSubcutaneouspanniculitis-likeUnclassifiablePTCLOtherdisorders四川省腫瘤醫(yī)院淋巴瘤病區(qū)截止2014年10月總數(shù)502例淋巴瘤患者T-NHL108例2012.4-2014.10四川省腫瘤醫(yī)院淋巴瘤數(shù)據(jù)四川省腫瘤醫(yī)院淋巴瘤病區(qū)截止2014年10月PTCL流行病學(xué)不同地域PTCL亞型相對(duì)發(fā)病率[1,2]總的發(fā)病率亞洲和加勒比地區(qū)更高1.SavageKJ.HematologyAmSocHematolEducProgram.2005;10:267-277.2.InternationalT-CellLymphomaProject.JClinOncol.2008;26:4124-4130.SubtypePercentage[2]NorthAmericaEuropeAsiaPTCL-NOS34.434.322.4Angioimmunoblastic16.028.717.9ALCL,ALK+16.06.43.2ALCL,ALK-NK/TCL5.14.322.4ATLL(HTLV-1+)2.01.025.0Enteropathy-typeHepatosplenic3.02.30.2PrimarycutaneousALCLSubcutaneouspanniculitis-likeUnclassifiableT-cellPTCL亞型及細(xì)胞來(lái)源PTCLSubtypeImmuneCellofOriginNK-celllymphomaNaturalkillercellsγδT-celllymphomaγδT-cellsALCLandPTCL/NOST-helperandT-cytotoxiccellsAITL/Tth-PTCL/NOST-follicularhelpercellsPiccalugaPP,etal.ExpertRevHematol.2011;4:415-425.PTCL的診斷10%PTCL診斷不正確大多數(shù)病人是III/IV期結(jié)外受累常見(jiàn):皮膚、肝臟、脾臟、骨髓、外周血PTCL的診斷：MIC（形態(tài)學(xué)、免疫學(xué)和細(xì)胞遺傳學(xué)）細(xì)針穿刺活檢不能作為診斷依據(jù)，必須進(jìn)行活檢切除術(shù)1.VoseJ,etal.JClinOncol.2008;26:4124-4130.2.WarnkeRA,etal.AmJClinPathol.2007;127:511-527.3.SwerdlowSH,etal.WHOClassificationofTumoursofHaematopoieticandLymphoidTissues.2008.

4.KocjanG.JClinPathol.2005;58:561-567.主要的外周T細(xì)胞淋巴瘤的臨床和病理學(xué)特征ALCL,ALK+97%PTCL,unspecified75%ATLL93%Panniculitislike75%NasalNK/Tcell92%ALCL,ALK-74%Angioimmunoblastic81%Hepatosplenic72%Enteropathytype79%CutaneousALCL66%VoseJM,etal.JClinOncol.2008;26:4124-4130.專(zhuān)家診斷共識(shí)TheaggressiveperipheralT‐celllymphomas:2012updateondiagnosis,riskstratification,andmanagementAmericanJournalofHematology

Volume87,Issue5,pages511-519,17APR2012

PTCL的治療PTCL的臨床預(yù)后指數(shù)TheIPIforNHLiscommonlyusedinPTCL[1]1.InternationalNon-Hodgkin'sLymphomaPrognosticFactorsProject.NEnglJMed.1993;329:987-994.2.GallaminiA,etal.Blood.2004;103:2474-2479.InternationalPrognosticIndexAllpatientsAge(≤60yrsvs>60yrs)SerumLDH(≤1xULNvs>1xULN)Performancescore(0or1vs2-4)Stage(IorII[localized]vsIIIorIV[advanced])Extranodalinvolvement(≤1sitevs

>1site)Age-adjustedindex(age

≤60yrs)Stage(IorIIvsIIIorIV)SerumLDH(≤1xULNvs>1xULN)Performancescore(0or1vs2-4)ThePITisalsoinuse[2]PrognosticIndexforPTCL>60yrsofageECOGperformancescore(score≥2)ElevatedLDHBonemarrowinvolvementTheIPIiscalculatedbasedonthesumofthenumberofriskfactorspresentatdiagnosis:0-1Low2Low/intermediate3High/intermediate4-5HighThePITisbasedonnumberofriskfactorspresentatdiagnosis:Group1:0riskfactor(62%5-yrOS)Group2:1riskfactor(53%5-yrOS)Group3:2riskfactors(33%5-yrOS)Group4:3-4riskfactors(18%5-yrOS)PTCL的生物預(yù)后因素PTCLSubtypesALK+ALCLALK–ALCLPTCL-NOSAITLNK/TCLATLL5-yrOSrate,%704932323214Majorityofpatients(>85%)withmostcommondiseasesubtypesreceivedanthracycline-containingregimenInternationalT-CellLymphomaProject.JClinOncol.2008;26:4124-4130.OS(%)Yrs010203040506070809010002468101214161820ALCL,ALK+

ALCL,ALK-

AllNK/T-celllymphomas

PTCL-NOS

AITL

AdultT-cellleukemia/lymphoma含蒽環(huán)類(lèi)方案治療PTCL的療效有限TreatmentGuidelinesforPTCL:

StillCHOPBasedNCCN.Clinicalpracticeguidelinesinoncology:non-Hodgkin’slymphoma.v.3.2012.First-line

TherapyClinicaltrial(preferred)ALCL,ALK+histologyCHOP-21CHOEP-21Otherhistologies(ALCL,ALK-;PTCL-NOS;AITL;EATL),regimensthatcanbeusedinclude:CHOEPCHOP-14CHOP-21CHOPfollowedbyICECHOPfollowedbyIVE,alternatingwithintermediate-dosemethotrexate(Newcastleregimen)HyperCVAD,alternatingwithhigh-dosemethotrexateandcytarabine

First-lineConsolidationAllpatientsexceptlowrisk(aaIPI)shouldbeconsideredforhigh-dosetherapyandstemcellrescue;ALCL,ALK+isasubtypewithgoodprognosisanddoesnotneedconsolidativetransplantifinremissionTheInternationalPTCLandNK/TCLStudy:AnalysisofTreatments多數(shù)PTCL或NK/TCL(除外ALK+ALCL)用含蒽環(huán)類(lèi)方案不能獲得生存受益InternationalT-CellLymphomaProject.JClinOncol.2008;26:4124-4130.PTCLAILTYrs018246810121416010080604020OS(%)Anthracyclineaspart

ofinitialtreatmentYes

NoP=.11Yrs018246810121416010080604020OS(%)Anthracyclineaspart

ofinitialtreatmentYes

NoP=.48傳統(tǒng)含阿霉素的方案對(duì)PTCL無(wú)效PTCL治療？采用新的誘導(dǎo)化療方案

CTOP，EPOCH,CEOP,CHOPE

noveldrugcombinationregimen?CONSOLIDATION?

Autologoustransplant?

Allogeneictransplant?MAINTENANCE???新藥、靶向藥物研發(fā)SurfaceAntigens/ReceptorsCD2CD4CD25CD30Chemokinereceptors...MicroenvironmentalFactorsAngiogenesisImmunomodulationViralpathogensCellularSurvivalMechanismsProteasomeinhibitionHDACinhibitionDeathreceptorsandligandsCell-cyclearrestSignaltransductioninhibitionPTCL治療可能的靶點(diǎn)化療方案的新嘗試改良CHOP方案（含蒽環(huán)類(lèi)藥物）--EPOCH--HyperCVAD--CHOP/ICE;CHOP/IVE--ACVBP新組合化療方案

--門(mén)冬酰胺酶為主方案聯(lián)合放療（NK/T細(xì)胞淋巴瘤鼻型）--IFO/VP-16/鉑類(lèi)/吉西他濱/MTX/Ara-C等新藥的使用

分子靶向藥物

單克隆抗體、小分子TKI

信號(hào)傳導(dǎo)

免疫調(diào)節(jié)劑

VoseJM,etal.JCO,2008;26:4124-30;NCCNguideline(2012);2012ASCO,abs8050SchmitzN,etal.Blood,2010;116:3418-25;DeardenCE,etal.Blood,2011;Sep26年輕PTCL患者：GHGNHLSG的研究SchmitzN,etal.Blood.2010;116:3418-3425.18-60yrsofage,LDH≤UNVOtherMajorSubtypesALCL,ALK+/-Months020010080604020EFS(%)p=0.0034060801006xCHOP-14/21(n=41)6xCHOEP-14/21(n=42)Months020010080604020EFS(%)p=0.012406080100nonEtoposide(n=12)Etoposide(n=32)Months020010080604020EFS(%)p=0.004406080100nonEtoposide(n=41)Etoposide(n=103)Months020010080604020EFS(%)p=0.057406080100nonEtoposide(n=29)Etoposide(n=69)PralatrexateisselectiveantifolatedesignedtopreferentiallyaccumulateincancercellsEntryPralatrexateisselectiveforcellsthatexpressRFC-1,whichisoverexpressedonsomecancercellsrelativetonormalcellsAccumulationOncetakenupbycancercells,pralatrexatebecomespolyglutamylated,resultinginhighintracellulardrugretentionInhibitionPralatrexateactsonfolatepathwaytointerferewithDNAsynthesisandelicitcancercelldeath

SirotnakFM,etal.CancerChemotherPharmacol.1998;42:313-318.KrugLM,etal.ClinCancerRes.2000;6:3493-3498.WangES,etal.LeukLymphoma.2003;44:1027-1035.新藥Pralatrexate的作用機(jī)制PROPEL研究:PhaseIIPralatrexateinRelapsed/RefractoryPTCL111patientswithrelapsed/refractoryPTCLPralatrexate30mg/m2weeklyfor6wksin7-wkcyclesVitaminB12andfolicacidgiventodecreasemucositisORR:32/109(29%);CR:11%;PR:18%MedianPFS:3.5mosMedianOS:14.5mosGrade3/4toxicityThrombocytopenia:32%O’ConnorOA,etal.JClinOncol.2011;29:1182-1189.PROPEL研究:腫瘤體積、有效時(shí)間和生存O’ConnorOA,etal.JClinOncol.2011;29:1182-1189.Patients-1001007550-25-75ChangeinTumorVolumneFromBaseline(%)Months0301.00.2Progression-FreeSurvival(probability)9121821Pralatrexate30mg/m2(6/7weeks)

n=109;70events

Median(months)3.5;95%

CI,1.7to4.8Months03010080604020DurationofResponse(probability)9121824Months0301.00.2Overallsurvival(probability)9151824-5002515246Pralatrexate30mg/m2(6/7weeks)

n=109;62events

Median(months)14.5;95%CI,10.6to22.5

6-month,75%;95%CI,65.7%to82.1%Pralatrexate30mg/m2(6/7weeks)

n=32;16events

Median(months)10.1;95%

CI,3.4toNE6152121126Romidepsin:ANovel,PotentBicyclicHDACiGeneregulation[1]Histoneacetylation/transcriptioninduction[2]Proteinacetylation[3]Activationofapoptosis[4]Antiangiogenesis[5]Cell-cyclearrest[4]1.PeartMJ,etal.ProcNatAcadSciUSA.2005;102:3697-3702.2.BoldenJE,etal.NatRevDrugDiscov.2006;5:769-784.3.WangY,etal.BiochemBiophysResCommun.2007;356:998-1003.

4.SatoN,etal.IntJOncol.2004;24:679-685.5.KwonHJ,etal.IntJCancer.2002;97:290-296.Wk4Wk2Wk31221581Wk1Cycle1Wk1Cycle2Schedule:4-hrinfusion14mg/m2onDays1,8,and15every28daysCoiffierB,etal.JClinOncol.2012;30:631-636.RomidepsininRelapsed/RefractoryPTCL:TreatmentScheduleRomidepsinRomidepsinRomidepsinRomidepsinAPhaseII,Multicenter,Open-LabelTrialRomidepsininRel/RefPTCL:ORRsBestResponseCategory,n(%)IRC(N=130)Investigators(N=130)Objectiveresponse(CR/CRu+PR)33(25)38(29)Completeresponse(CR/CRu)19(15)21(16)CR13(10)19(15)CRu6(5)2(2)PR14(11)17(13)SD33(25)22(17)PD/notevaluable*64(49)70(54)CoiffierB,etal.JClinOncol.2012;30:631-636.*Insufficientefficacydatatodetermineresponseduetoearlytermination.RomidepsininRel/RefPTCL:DORandSafetyMedianDOR:17mosOf19patientsinCR/Cru,17(89%)hadnotprogressedatamedianfollow-upof13.4mosGrade≥3toxicitiesThrombocytopenia:24%Neutropenia:20%CoiffierB,etal.JClinOncol.2012;30:631-636.Romidepsinforthetreatmentofrelapsed/refractoryperipheralT-celllymphoma:(APhaseII,Multicenter,Open-LabelTrial)CoiffierB,etal.JClinOncol.2012;30:631-636.Anti-CD30ADC:BrentuximabVedotin(SGN-35)ADC:3partsChimericantibodySGN-30Syntheticanalogue(MMAE)oftheantitubulinagentdolastatin10StabledruglinkerProposedmechanismofactionBindstoCD30InternalizedintothetumorcellMMAEisreleasedTumorcellundergoesG2/Mphasecell-cyclearrestandapoptosisPreclinicalactivityobservedbothininvitroandinvivoFranciscoJA,etal.Blood.2003;102:1458-1465.BrentuximabVedotin+化療一線(xiàn)治療ALCLI期臨床試驗(yàn):39pts高危ALCL(IPI≥2)orCD30+成熟

T-cell/NK-細(xì)胞淋巴瘤隨機(jī)分為3組1.8mg/kgbrentuximabvedotinq3wX2cycles,thenCHOPx6cycles1.8mg/kgbrentuximabvedotin+CHPq3wforupto6cyclesDetermineoptimaldoseofbrentuximabvedotintobeusedincombinationwithCHPinthirdarmRespondersreceiveadditionalcyclesofbrentuximabvedotinmonotherapyORR:100%(26/26);CR:88%(23/26)BrentuximabvedotinMTDnotexceededat1.8mg/kg1DLT:grade3rashin6pts治療相關(guān)并發(fā)癥:惡心(58%),疲乏(50%),腹瀉(50%),周?chē)窠?jīng)病變(38%),脫發(fā)(38%)FanaleMA,etal.ASH2012.Abstract60.ProB,etal.JClinOncol.2012;30:2190-2196.BrentuximabVedotininRel/RefSystemicALCL:MaximumTumorReduction(IRC)TumorSize(%change

frombaseline)-100-50050100IndividualPatients(n=57)BestclinicalresponseCompleteremissionPartialremission

Stabledisease

ProgressivediseaseHistologicallyineligibleDueckG,etal.Cancer.2010;116:4541-4548.來(lái)啦度胺II期臨床試驗(yàn)：24PTCLPts.（N=24）ORR:30%(7/23)AllPRs 所有亞型都有效MedianPFS:96days MedianOS:241days AEs:中性粒細(xì)胞減少、疼痛、血小板減少、皮疹I(lǐng)nterimreportofaphase2clinicaltrialoflenalidomideforT-cellnon-Hodgkinlymphoma

Relapsed/refractoryPTCLECOGPS0-2(N=24)Lenalidomide25mgPOqdon

Days1-21ofa28daycycleTheprimaryendpoint；ORR

Thesecondaryendpoints:OS,PFS,andsafety.open-label,single-arm,multicenterCanadianphase2clinicaltrial

September2006toNovember2008,CancerVolume116.Issue19.pages4541–4548,

1October2010PDorIntolerableInterimreportofaphase2clinicaltrialoflenalidomideforT-cellnon-Hodgkinlymphoma

CancerVolume116.Issue19.pages4541–4548,

1October2010Alisertib:InvestigationalAuroraAKinaseInhibitorResultsinmitoticdefectsAbnormalspindlesUnseparatedcentrosomesDelayedmitoticprogressionApoptosisorsenescenceUntreatedTreatedTreatedNCIOFNNHNOOHOFriedbergJ,etal.ASH2011.Abstract95.FriedbergJ,etal.ASH2011.Abstract95.Alisertib(MLN8237):AnAuroraAKinaseInhibitorII期進(jìn)展期B-cell和T-cellNHLN=48ORR:32%CR:12%病理學(xué)診斷PTCL:57%DLBCL:20%;MCL:23%;轉(zhuǎn)化FL:40%副作用:中性粒細(xì)胞減少,血小板減少,胃炎Alisertib的隨機(jī)臨床開(kāi)放III期臨床試驗(yàn)：復(fù)發(fā)難治PTCLPrimaryendpoint:ORR,PFSSecondaryendpoints:safety,CR,OS,TTPRelapsed/refractoryPTCLECOGPS0-2(N=354)*Choices:PralatrexateRomidepsinGemcitabineAlisertib5x10mgPOBIDon

Days1-7ofa21-daycycleInvestigator’schoice*ClinicalT.NCT01482962.PohlmanB,etal.ASH2009.Abstract920.Belinostat(PXD101):APan-HistoneDeacetylaseInhib