AHS 淋巴瘤干细胞移植

自体造血干细胞移植治疗

恶性淋巴瘤应用进展IndicationsforHematopoieticStemCellTransplantsintheUnitedStates,2010

(Inflationfactor:Auto=1.25(80%),Allo=1.05(95%),AllTransplants)SUM12_28.pptSlide8NumberofTransplants1.HL,霍奇金淋巴瘤中山大学肿瘤医院SUNYAT-SENUNIVERSITYCANCERCENTERHL:ASCT综合治疗效果复发/耐药：CR34-80%长期生存率：25-50%

早期死亡率：4－21％复发/耐药：10年生存率：50%10yPFS：45%10yRFS：23%首次复发：5年PFS30–52%,5年生存率：34－60％

复发难治HL

PET/CT结果与自体移植的疗效关系中山大学肿瘤医院SUNYAT-SENUNIVERSITYCANCERCENTERHaematologica2012PET/CT-PET/CT+复发难治HD:不同预处理方案比较中山大学肿瘤医院SUNYAT-SENUNIVERSITYCANCERCENTER1998-2009100ptsBuMelTt(busulfan,melphalan,thiotepa):60ptsOthers:40ptsCBV(21)TBICyE(14)BEAM(4)Melphalan(1)5yr-OS73%VS.44%5yr-PFS66%VS.37%NodifferencesintoxicityandNRMImprovedoutcomewithbusulfan,melphalanandthiotepaconditioninginAHSCTforrelapsed/refractoryHLTarunpreetB.Leukemia&Lymphoma,2014;55(3):583–587PFSOSP=0.03P=0.052.NHL,DLBCL弥漫大B淋巴瘤中山大学肿瘤医院SUNYAT-SENUNIVERSITYCANCERCENTER复发NHL:自体移植是标准治疗手段

PARMA随机对照研究OSPFS美罗华治疗后复发：AHSCT价值，>2nd中山大学肿瘤医院SUNYAT-SENUNIVERSITYCANCERCENTERRituximab+DHAPandASCT

复发DLBCLEdoVellengaetal,blood,2008111:537-543DHAP 11273

40

19

9 R-DHAP 11376

55

31

14R-DHAPDHAPCumulativepercentageOverallsurvivalCORAL研究：

移植后疗效EFSFailurefromdiagnosis=>=12monthsFailurefromdiagnosis>12monthsFailurefromdiagnosis=<12monthsStandardsalvageregimendoesnotovercomepoorprognosisofearlyrelapseRituximab-化疗复发：自体移植的疗效BrJHaematol.

2014Mar;164(5):668-74.有研究提示，美罗华化疗后复发患者自体移植效果差？移植后5年

R+vsR-

PFS63%48%OS72%61%

美罗华治疗后不会影响移植效果中山大学肿瘤医院SUNYAT-SENUNIVERSITYCANCERCENTER弥漫大B淋巴瘤：一线中山大学肿瘤医院SUNYAT-SENUNIVERSITYCANCERCENTER美罗华之前：ASHCTDLBCL1st中山大学肿瘤医院SUNYAT-SENUNIVERSITYCANCERCENTERAdvancesinHematology,2012意大利DLBCL一线治疗:

HDCT试验的荟萃分析Grebetal.,2007,CancerTreatRev美罗华时代：自体移植疗效，1st中山大学肿瘤医院SUNYAT-SENUNIVERSITYCANCERCENTERAdvancesinHematology,2012意大利自体移植+/-rituximab治疗

初治高危弥漫大BNHL，III期随机对照OSEFSAnnalsofOncologyAdvanceAccesspublishedMay5,2010Dose-denseandhigh-dosechemotherapyplusrituximab+ASHSCT

forprimarytreatmentofDLBCL

withapoorprognosis:aphaseIImulticenterstudyR-HDCHDCR-HDCHDChaematologica|2009;94(9)R-HDCHDCHDCR-HDCSWOG-9704研究设计StiffP,etal.NEnglJMed2013;369(18):1681-1690.年龄:18-65岁aaIPI评分：2-3分主要终点：2年EFS，OS研究设计：253位患者接受5RCHOP21后随机接受原方案3个疗程的巩固治疗或者是自体移植做巩固治疗随机化(n=253)对照组(n=128)移植组(n=125)SWOG-9704显示：移植组较对照组

显著延长2年PFS，但是OS上无差别StiffP,etal.NEnglJMed2013;369(18):1681-1690.PFS(%)时间(年)对照组(n=128)2年PFS=55%移植组(n=125)2年PFS=69%P=0.005036902040608010012对照组(n=128)2年OS=71%移植组(n=125)2年OS=74%P=0.30036902040608010012时间(年)OS(%)SWOG-9704亚组分析显示：移植组在aaIPI

为3分的患者中可以较对照组明显延长患者PFSStiffP,etal.NEnglJMed2013;369(18):1681-1690.aaIPI=2aaIPI=3中高危患者PFSPFS(%)时间(年)对照组2年PFS=63%移植组2年PFS=66%P=0.32高危患者PFS时间(年)对照组2年PFS=41%移植组2年PFS=75%P=0.001036912020406080100036912020406080100PFS(%)SWOG-9704亚组分析显示：移植组在aaIPI

为3分的患者中可以较对照组明显延长患者OSStiffP,etal.NEnglJMed2013;369(18):1681-1690.aaIPI=2aaIPI=3中高危患者OS时间(年)高危患者OSOS(%)对照组2年OS=75%移植组2年OS=70%P=0.48对照组2年OS=64%移植组2年OS=82%P=0.01036912020406080100036912020406080100时间(年)OS(%)

原发中枢淋巴瘤：自体移植价值

HDAraC+VP16(CYVE)+HDCT(TT-BU-CY)

assalvagefor

relapse/resistantPCNSL2011updateN=60,medianFU5yOSchemosensitive97mchemoresistant18m

ICML2011Abstr.035Resp+HDCTNoResp+HDCTRespnoHDCTNOrespnoHDCT中山大学肿瘤医院SUNYAT-SENUNIVERSITYCANCERCENTER继发中枢淋巴瘤移植效果好！

化疗敏感62%

vs不敏感36.2%Thiotepa,busulfanandcyclophosphamide+AHSCT，复发难治原发中枢淋巴瘤,5yOS

CR56.4%vs未CR31.1%Haematologica.

2012Nov;97(11):1751-6.AHSCT前CR/PR，移植后CR患者（5y-OS62%）AHSCT前SD/PD，移植后CR患者（5y-OS38.9%）移植后未获得CR患者（5y-OS31.1%）Thiotepa,busulfanandCTX+AHSCTforrelapsedorrefractoryPCNSL/PLOTHaematologica.

2012Nov;97(11):1751-6.2000至2010年27例中位年龄:59岁中位

ECOG评分:276%DLBCL中位OS7月1年OS：62%自体移植治疗淋巴瘤继发中枢侵犯anInternationalPrimaryCNSLStudyGroupprojectJacolineE.haematol.2012.070839ASCT：DLBCL临床资料70例，中山大学肿瘤医院2004.10-2013.3男性41例，女性29例中位年龄43岁（21-76岁）中位随访时间35.5月（0.4-94.2月）因肿瘤死亡29例,DLBCLOS生存曲线中山大学肿瘤医院1年OS91.0%,3年OS77.7%,5年OS56.9%AHSCT：复发难治老年DLBCL

-日本血液学协会回顾性研究，2013ASH1993-2010年484pts中位64岁（60-78）中位随访26.5月移植相关死亡-4.1%(100天)-5.9%（1年）-10.7%3年）2年

PFS48%，OS58%60-64,65-69，>70岁，移植相关死亡无差异OS预后因素：>70岁，PS2-4分，移植前未CRBiolBloodMarrowTransplant.

2014Jan31.100d:4.1%1yr:5.9%2yr:7.7%3yr:10.7%复发难治老年弥漫大B淋巴瘤DLBCL:ANationwideRetrospectiveStudyDaiChihara.BiolBMT.20(2014)684-6891993to2010yearJapanSocietyforHCTdatabase484patientsmedianage:≥60yearsThecumulativeriskofrelapse1-yr:38.8%2-yr:45.5%3-yr:47.7%Multivariateanalysis≥70yPS2to4atASCTnotinremissionatASCTHigh-DoseChemotherapywithASCTforElderlyPatientswithRelapsed/RefractoryDLBCL:ANationwideRetrospectiveStudyDaiChihara.BiolBMT.20(2014)684-6891-yr:55.9%2-yr:47.7%3-yr:40.6%1-yr:69.7%2-yr:57.9%3-yr:49.6%DaiChihara.BiolBMT.20(2014)684-689High-DoseChemotherapywithASCTforElderlyPatientswithRelapsed/RefractoryDLBCL:ANationwideRetrospectiveStudyHigh-DoseChemotherapywithASCTforElderlyPatientswithRelapsed/RefractoryDLBCL:ANationwideRetrospectiveStudy2-yrOS60~6464.6%65~6950.6%≥70y45.7%DaiChihara.BiolBMT.20(2014)684-689Zevaline+BEAM:DLBCL1stline

2011luganoabs256,GELA,法国

75DLBDL,R-CHOP/R-ABVCPIPI11;IPI227;IPI3-547F/U23m,2yEFS74%,2yOS80.5%PET+/-beforeAHSCT:same1toxicdeathpromisingwithacceptabletoxicity.Zevalin+BEAMvsBEAM→AHSCTfor

AggressiveLymphoma43CD20+pts

中位年龄55岁

病理类型-DLBCL-transformedFLZevalin+BEAMN=22BEAM

N=21RAHSCTZ-BEAM

-Rituximab250mg/m2-Zevalin0.4mCi/kgd-14-Carmustine300mg/m2d-6

-Etoposide200mg/m2d-5--2

-Cytarabine200mg/m2Q12hd-5--2

-Melphalan140mg/m2

d-1Cancer.

2012Oct1;118(19):4706-142y-OS:91%VS62%(P=0.05)Zevalin+BEAMvsBEAM→AHSCTfor

AggressiveLymphoma2y-PFS:59%VS37%(P=0.2)Cancer.

2012Oct1;118(19):4706-1423ptswithoutCRtosalvagechemotherapy6ptsRITcombinedwithHD-chemotherapy8ptsreceivedasequentialHD-chemotherapywithasecondASCTMyeloablativeAnti-CD20RIT±High-DoseChemotherapyFollowedbyASCTforRelapsed/RefractoryB-CellLymphomaResultsinExcellentLong-TermSurvivalWagnerJY.Oncotarget,June,Vol.4,No6TheORR87%CR:64%MedianPFS47.5mMedianOS101.5monthsMyeloablativeAnti-CD20RIT±High-DoseChemotherapyFollowedbyASCTforRelapsed/RefractoryB-CellLymphomaResultsinExcellentLong-TermSurvivalWagnerJY.Oncotarget,June,Vol.4,No6(A)OSaccordingtotreatmentmodality(B)PFSaccordingtotreatmentmodality(C)OSRITVS.RIT/HD-CTXorRIT/BEAM(D)PFSRITVS.RIT/HD-CTXorRIT/BEAMMyeloablativeAnti-CD20RIT±High-DoseChemotherapyFollowedbyASCTforRelapsed/RefractoryB-CellLymphomaResultsinExcellentLong-TermSurvivalWagnerJY.Oncotarget,June,Vol.4,No6PhilippeA.JClinOncol31:4199-4206.

PD-1BlockadePidilizumab+AHSCT

DLBCLanInternationalPhaseIITrial66例30centersinUSA化疗敏感复发，Chemotherapysensitive66pts

Pidilizumab(PD-1)1.5mg/kg×3,Q42d30to90dfromAHSCTAHSCTRestagedat30,44,and69wOS(16m):85%PFS(16m):72%DisablingImmuneTolerancebyPD-1BlockadeWithPidilizumabAfterAHSCTforDLBCL:ResultsofanInternationalPhaseIITrialPFSandOSofalleligiblepatientsPFSandOSofthe24eligiblepatientswhoPET(+)aftersalvagetherapyPFS(16m):70%(PET+)72%(PET-)PhilippeA.JClinOncol31:4199-4206.3.PTCL-U外周Ｔ非特异性中山大学肿瘤医院SUNYAT-SENUNIVERSITYCANCERCENTER复发耐药T-NHL长期随访结果，常规化疗

N=45,总生存曲线黄慧强等，2007《癌症》ASCT治疗外周T淋巴瘤：一线中山大学肿瘤医院SUNYAT-SENUNIVERSITYCANCERCENTERASCT外周T淋巴瘤：复发中山大学肿瘤医院SUNYAT-SENUNIVERSITYCANCERCENTERT-NHL自体干细胞移植随访结果35例,中位随访23个月，预计中位总生存54个月，PTCL-U17.1%，LBL42.9%，ALCL20%，NK/T14.33%，皮下脂膜炎样T5.7%1，3，5年OS为71%，59%，46%中山大学肿瘤医院内科ASHCT治疗T-NHL(一线/复发)

2011luganoICML,abs100MDACC美国126例，49（18-75），初治33，

预处理：BEAM4年OS

PFS

CR18767

敏感复发3936

难治2415PTCLU4248ALCL4737NK/T667LBL14AHSCT考虑一线应用

AutoHSCTvs

alloHSCT

T-NHL:CIBMTRanalysis(1996–2006)自体，autoHCT(n=115)moreinALCL(53%vs.40%,p=0.04)lessadvanced:

CR1(35%

vs.14%,p=0.001),chemosensitivedisease(86%vs.60%,p<0.0001)2linespriortherapy(65%vs.44%,p<0.001)异基因，alloHCT(n=126,76matchedsiblings)100dTRM1yrOS3yrOS复发死亡

autoHCT2%62%53%73%alloHCT

17%52%41%44%SonaliSmith,etal.ASH2010,Abstract689.HematopoieticCellTransplantationforSystemicMatureT-CellNon-HodgkinLymphomaNRM:nonrelapsemortalitySonaliM.JClinOncol31:3100-3109.

241pts-ALCL(112)-PTCL-U(102)-AITL(27)≤60yrLinespriortotransplantation-˂3(164)-≥3(73)

autoHCTN=115PrimaryoutcomesPFSNRMOS

alloHCTN=126OSPFSNRMNRMPFSOSSonaliM.JClinOncol31:3100-3109.HematopoieticCellTransplantationforSystemicMatureT-CellNon-HodgkinLymphomaPFSOSNRMPFSOSHematopoieticCellTransplantationforSystemicMatureT-CellNon-HodgkinLymphomaSonaliM.JClinOncol31:3100-3109.PCorradini.Leukemia(2014),1–7Intensifiedchemo-immunotherapy±SCTinnewlydiagnosedPTCL

AL:alemtuzumabHyperCHidam:-HD-MTX1.6g/m2d1,-CTX300mg/m2Q12hd1-3-HD-Ara-C2g/m2Q12hd1-3PCorradini.Leukemia(2014),1–7

ClinAstudy-4yrOS49%-4yrPFS44%-4yrDFS65%Intensifiedchemo-immunotherapy±SCTinnewlydiagnosedPTCLPCorradini.Leukemia(2014),1–7

ClinBstudy-4yrOS32%-4yrPFS26%-4yrDFS44%Intensifiedchemo-immunotherapy±SCTinnewlydiagnosedPTCL晚期、复发NK/T淋巴瘤中山大学肿瘤医院SUNYAT-SENUNIVERSITYCANCERCENTER，

自体外周血造血干细胞移植:NKT淋巴瘤，1st获益患者CR、III-IV期预后不良

（kimHJ,etal.BoneMarrowTransplant.2006)

自体移植:III/IV期和复发难治NK/TPromising3-yOS78.6%±13.9%3-yPFS63.6%±14.5%,Huanghui-qiang,

etalinpress中山大学肿瘤医院SYSUCCP-Gemox

CR/PR自体移植YDM,女，24岁，IVBNK/T

腹部巨大肿块，PS=2腹腔肠道广泛受累1疗程后肠穿孔，人工肛，PEG-Gemox6疗程，CRASCT后12个月CCRUpfrontAutologuosStem-CellTransplantationinPeripheralT-CellLymphoma:NLG-T-015y-OS51%5y-PFS41%JClinOncol.

2013May1;31(13):1624-30.

4.FL，

滤泡型淋巴瘤中山大学肿瘤医院SUNYAT-SENUNIVERSITYCANCERCENTERRandomizedTrialsofUpfrontAutologousTransplantationforFLTrialMeasureTransplant,%Control,%PValueGOELAMS[1]9-yrPFS6439.004GLSG[2]5-yrPFS6236<.0001GELA[3]7-yrEFS3828.11GITMO/IIL[4]4-yrEFS6128<.0011.GyanE,etal.Blood.2009;113:995-1001.2.LenzG,etal.Blood.2004;104:2667-2674.

3.SebbanC,etal.Blood.2006;108:2540-2544.4.LadettoM,etal.Blood.2008;111:4004-4013.TrialOSTransplant,%Control,%PValueGOELAMS[1]9yrs7680.55GLSG[2]------GELA[3]7yrs7671.53GITMO/IIL[4]4yrs8180.96

LongtermoutcomeofAHSCT

复发滤泡型248pts,age47(20-67)yMedianpriorchemotherapies2,110ptsAHSCTonlyMedianF/U6years(1-16)y47%progression13%diedwithoutNHL44%5YEFS63%5yOS2005ASCO,abstract6567JVoseetalUniversityofNebraskamedicalcenterCUPtrial:PFS,1.00.80.60.40.20 0 12 24 36 48 60 72 84MonthsProportionprogression-free Events TotalChemotherapy 20 24Unpurged 9 22Purged 11 24SchoutenH,etal.JClinOncol2003;21:3918–27TandemTransplantfor，双移植

FollicularNHL<60y36ptsadvanced/recurrentFL;previouslyuntreated26.Treatment:

C2H2OP×2

Melphalan140mg/m2

CTX120mg/kg+TBICR(%)30.662.994.3MedianF/U86m.10yDFS60%10yOS83%Conclusion

--tandemtransplantissafeandcouldbecurativeforselectedFL--Nocorrelationbetweenmolecularandclinicalrelapse.

ChristiamRecher.France2003ASH

研究流程复发FL:移植前利妥昔单抗净化和/或移植后维持EBMT一项前瞻性研究,ASCTRuthP.JClinOncol31:1624-163010yrPFS:48.6%vs.42%(P=0.18)EffectonPFS10yrPFS:54%vs.37%(P=0.12)是否Rituximab净化是否Rituximab维持RuthP.JClinOncol31:1624-1630复发FL:移植前利妥昔单抗净化和/或移植后维持EBMT一项前瞻性研究,ASCTSequentialtherapywithalternatingshortcoursesofR-chopandR-FMfollowedbyASCTresultsinlongtermremissioninadvancedFLEnricoD.bjh.2014.12894

10yrOS87%10yrPFS65%10yrOS(treatedatdiseaserelapse)70%10yrPFS(treatedatdiseaserelapse)60%AuthorNF/UPFS(%)OS(%)Foran292952(48)50(102)Friedberg273646(60)58(60)Williams505930(60)37(60)Chen355231(60)37