惰性淋巴瘤规范化治疗－08年NCCN治疗指南解读

惰性淋巴瘤标准化治疗－08年NCCN治疗指南解读黄慧强中山大学附属肿瘤医院

淋巴瘤治疗研究中心

Hungary,Budapest20212021LuganoICML,InternationalConferenceMaglinantLympphomaWHOLymphomaClassificationBcellBcellchroniclymphocyticMantlecellFollicularlymphomaMarginalBcelllymphoma,MALTtypePlasmacellmyeloma/plasmocytomaDiffuselargeBcelllymphomaBurkitt’slymphomaPrecursorBlymphoblasticleukemia/lymphomaTcellMycosisfungoidesPeripheralTcelllymphoma,unspecifiedAngioimmunoblasticTcelllymphomaExtranodalNK/TcelllymphomaAdultTcellleukemia/lymphoma(HTLV1+)Anaplasticlargecelllymphoma,primarysystemicPrecursorTcelllymphoblasticleukemia/lymphomaDistributionofNHLsubtypesIntheUK(population~60m),thereare8,450newNHLcases/year1AcrosstheEU(population~490m)

thisequatestoanincidenceof69,000newNHLcases/yearALBCLOtherDLBCLFLMALTlymphomaMatureT-cell

lymphomaCLL/SLLMCLPMLBCLBurkitt’slymphomaLiuQ,etal.Blood.2003;102.Abstract1446.

Regimen生存TreatmentPeriodNo.ofPatients5yr(%)10yr(%)15yr(%)CHOP–BleoCHOP–Bleo->IFNATT->IFNATT->IFNvs.FND->IFNFND-Rvs.FND->R(+IFN)1977–19821982–19881988–19921992–19971997–2002961311361422006475828290375260----2942------IFN:interferon;ATT:alternatingtripletherapywithCHOD-B/ESHAP/NOPP;FND:fludarabine,mitoxantrone,anddexamethasone;Bleo:bleomycin;CHOP:cyclophosphamide,doxorubicin,vincristine,prednisoneYes,SurvivalHasImproved!过去25年惰性淋巴瘤的生存是否有改善?Years%

存活率0510152025020406080100CHOP-BleoCHOP-Bleo+IFNATTIFNATTIFNvsFNDIFNR-FND+IFNvsFNDR+IFNP<.0001IV期滤泡性淋巴瘤:不同治疗方案的OS1972-2002Liuetal,JCO2006;24:1582-1589Years%Alive0510152025020406080100CHOP-BleoCHOP-Bleo+IFNATTIFNATTIFNvsFNDIFNR-FND+IFNvsFNDR+IFNP<.01IV期滤泡性淋巴瘤:不同治疗方案的生存,FLIPI评分3Liuetal,JCO2006;24:1582-1589Years%Failure-Free0510152025020406080100CHOP-BleoCHOP-Bleo+IFNATTIFNATTIFNvsFNDIFNR-FND+IFNvsFNDR+IFNP<.0001IV期滤泡性淋巴瘤:不同治疗方案的FFS1972-2002Liuetal,JCO2006;24:1582-1589惰性淋巴瘤治疗效果提高常规化疗的改进Rituximab，CD20RIT,Radio-immuno-therapyAHSCT/Allo-HSCT

Rituximab:惰性NHL(FL)单药治疗结论单药：复发和难治的低度恶性NHL(RR48%)

单药：初发的低度恶性NHL(RR73%)

联合化疗结论(Ⅲ期临床研究)R-CVP疗效明显优于CVP方案

R-CHOP明显优于CHOP方案(TTFPFSOS)CVP后+R维持治疗进一步增加疗效(PFS)FCM+R明显优于FCM方案(RRCRPFSOS)

R+Leukeran>Leukeran

一线-滤泡性淋巴瘤治疗:RandomizedHiddemannetal.CHOPR-CHOPp可评估患者205223反应率90%96%0.011TTF31mNotreached<0.0001OS(estimated2-yOS)90%95%0.016Marcusetal.CVPR-CVPp可评估患者159162反应率57%81%<0.0001PFS15m34m<0.0001OS(随访53m)71%81%<0.03Heroldetal.MCPR-MCPp可评估患者96105反应率75%92%<0.001EFS19mNotreached<0.0001OS62mNotreached0.016Foussardetal.CHVP/IFN-αR-CHVP/IFN-αp可评估患者183175反应率(CR/CRu)85%(49%)94%(76%)<0.0001EFS36mNotreached<0.0001OS(随访42m)84%91%<0.03Rituximab维持治疗的进展作者诱导CT对照组持续时间PFS/EFSOS时机病理1.JohnHainsworthRqw×4q6m×65y40%,8y29%M:39.8m

1线FL2.JohnHainsworthRqw×4Retreatedq6m×6M31.1m＞R-treat.7.4m(P=0.0051)7y33%remission1线FL3.SandraSHorning(USA)CVP观察qw×4,q6m×4PFS:M>Ob1线FL4.AntonHagenbeek(Holland)R-CHOP/CHOP观察q3m×8M:Ob51.6Vs15(m)R-CHOP/CHOP,CRM>Ob,P<3y:85.1%Vs77.1%P=0.011(PR,CHOP后M较好)2/3线R/refFL5.MicheleGhielminiRqw×4观察q2m×4EFS:23Vs12P=0.002(FL)(vV>FV>FF)(FL)1线FL/MCL6.MartinDreylingFCM/R-FCM观察q4m×2R-mbetter(FL,MCL)R-matainencebetter1线FL/MCLIndolentNHL:inductionandMaintenanced8afterASCTRituximabbeforeandafterASCT

forrelapsedaggressiveB-NHLCyclophosphamide4–7g/m2

G-CSF

10μg/kg/dBEAM/ASCTRituximab

1g/m2Rituximab

1g/m2Rituximab1g/m2Rituximab

375mg/m2d–1d7d1afterASCTKhouriIF,etal.JClinOncol2005;23:2240–2247.HistoricalcomparisonN=67RituximabsignificantlyimprovesoutcomeswhencombinedwithHDTandASCTKhouriIF,etal.JClinOncol2005;23:2240–2247.OverallsurvivalMonthspost-transplant0.01.0630912151821242730p=0.004Norituximab(n=30)Rituximab(n=67)0.20.40.60.8Monthspost-transplant0.01.0630912151821242730p=0.0020.20.40.60.8Disease-freesurvivalNorituximab(n=30)Rituximab(n=67)Radio-Immuno-Therapy单用有效率：

RIT单用治疗复发耐药NHLResponseDuration:RITonrelapsedorrefractoryNHLCD20-I131:FLandTransformedNHL:

Longtermoutcome11studies,1177ptsMage57(21-90),stage¾90%,tumor>5cm47%,BM+44%

1st(141)2rd(226)3rd(228)4th(540)ResponseR.95735846M.d.response-351612CR(%)78463223M.d.CR--3559PFS>1Y(%)82594227ASCO2005,abstract6561USAmulticenters

方案

患者

单一诱导后的CR率(%)

巩固后CR率

(%)

ReferenceR-CHOP(3)+Zevalin

consolidationII-IVFL;60%stageIV2867Shipleyetal.

ASCO2005FM(6c)+

90Y-Ibritumomab

tiuxetan

consolidationII–IVFL;

88%stageIII–IV73100

(诱导后PR均转为CR)Zinzanietal.

ASH2006R-CHOP+

90Y-Ibritumomab

tiuxetan

consolidation+R

maintenanceII–IVFL;

91%stageIII–IV;40%highFLIPI4189Jankowitzetal.

ASCO2007Zevalin稳固治疗FLCUPtrial:AHSCT欧洲多中心研究SchoutenH,etal.JClinOncol2003;21:3918–27RelapsedfollicularNHLRegistration3cyclesofchemotherapyRestageRandomisationHighdosetherapy

+unpurgedstem

cellsupport

(n=33)Highdosetherapy

+purgedstem

cellsupport

(n=32)3cycles

ofchemotherapy

(n=24)Follow-upCRorPR

and<20%B-lymphocytesNRorPD

and>20%B-lymphocytesn=140**Priortorandomisationcliniciansmustdecidewhether

bonemarroworperiperalbloodwillbeusedasastemcellsupport复发FLCUPtrial:progression-freesurvival1.00.80.60.40.20

0 12 24 36 48 60 72 84MonthsProportionprogression-free

Events TotalChemotherapy 20 24Unpurged 9 22Purged 11 24SchoutenH,etal.JClinOncol2003;21:3918–27复发LFAutoPBSCTin1stRemissionFLTrialInductionConditioningEFSOverallsurvivalLenzet

al(GLSG)CHOP/MCPTBI/Cyclo(n

=

153)64·7%vs.33·3%*(P

<

0·0001)NotyetavailableCHOP/MCPIFN(n

=

154)Deconincket

al(GOELAMS)VCAPTBI/Cyclo(n

=

86)60%vs.48%(P

<

0·050)MedianNRNosignificantdifferenceCHVP/IFN-αCHVPIFN-α(n

=

80)Sebbanet

al(GELA)CHOPTBI/Cyclo(n

=

192)45%vs.36%‡(P

=

0·5)86%vs.74%(7-yearOS)CHVP/IFNαCHVPIFN-α(n

=

209)After:Hiddemann,W.BritJHaem2006AHSCT1st-line:follicularlymphoma540pts,randomizedtrial5-yestimatedPFS27%CHOP-IFN-alphamaintenance,65%CHOP-ASCT,68%R-CHOP-IFN-alphamaintenance80%R-CHOP-ASCT.C.Buske1,M,2021Luganoabstract028Rituximaband/orHigh-DoseTherapywithAutotransplantatTimeofRelapseinFL

ImprovedsupportivetherapyandoutcomeafterAuto

vs.Allo

transplantation?AllogeneicSCTovertimeAutologousSCTovertimeBut: -retrospectivestudywithheterogenouspatientpopulation -TBIconditioningregimensignificantlylowerrelapserate(p=0.02) -nospecificprognosticfactorsafterautologous/allogeneictransplantationvanBesnienetal.Blood2003HowItreatindolentlymphomaJohnG.Gribben，InstituteofCancer,BartsandTheLondonQueenMarySchoolofMedicine,London,UnitedKingdom;.Blood2021.3Years%

存活率0510152025020406080100CHOP-BleoCHOP-Bleo+IFNATTIFNATTIFNvsFNDIFNR-FND+IFNvsFNDR+IFNP<.0001IV期滤泡性淋巴瘤:不同治疗方案的OS1972-2002Liuetal,JCO2006;24:1582-1589

患者(%)1987–19961976–19861960–1975

年100806040200

0 5 10 15 20 25 302000–2021??滤泡性淋巴瘤远期疗效前瞻?常规化疗RT造血细胞移植单克隆抗体,RIT干扰素新治疗方法ADVANCESON

INDOLENTLYMPHOMA

Fludarabine(单药)UntreatedFLCR14-47%RR47-81%TreatedFLCR6-48%RR31-72%FludarabinevsCVP(phaseIII)CR9%vs7%RR64%vs52%福达华+米托蒽琨初治初治福达华+环磷酰胺比较FCN+/-CD20单抗的疗效49例患者进行初步疗效评价两组的血液学和非血液学毒性相当FCM=fludarabine/cyclophosphamide/mitoxantrone.HiddemannW,etal.SeminOncol.2003;30(1Suppl2):16-20.,DreylingMH,etal.Blood.2003;102Abstract351.40%FCN+CD20单抗n=25CRFCNn=2421%52%PR54%92%CR+PR75%福达华/环磷酰胺/米托蒽琨+/-CD20单抗治疗复发难治滤泡性淋巴瘤FLUvsFLU-ID(FLU+Ida)

(Bologna)FNDvsATT(MDACC)FCvsCVPAnti-20(ECOG)

FND

followedbyanti-CD20vsFNDplusanti-CD20 concurrenty(MDACC)FMvsCHOPanti-CD20(Bologna)含福达华方案的III期随机临床研究FLU(%)FLU-ID(%)合计(%)CR473943PR374239.5CR+PR848182.5CR滤泡性淋巴瘤小淋巴细胞淋巴瘤淋巴浆细胞淋巴瘤套细胞淋巴瘤602923274043383350373131Zinzanietal.JClinOncol2000FLUvsFLUIDRANDOMIZEDPHASEIIITRIAL初步临床疗效评价8个疗程的FND方案与ATT(CHOD-Bleo,ESHAP,NOPP)治疗IV期惰性淋巴瘤的随机对照研究报道的5年OS内分子学CR情况两组没有差异(bcl-2-):84%FNDvs82%ATT;5-yearFFS:41%FNDvs50%ATTFNDvsATTRANDOMIZEDPHASEIIITRIALTSIMBERIDOUetal.Blood2002RANDOMIZEDPHASEIIITRIALFND+RvsFNDR6个疗程的FND方案同时使用或序贯使用CD20单抗治疗IV期惰性淋巴瘤的随机对照研究5年FFS:FND+Rvs

FNDR

分别为70%和44%(p=0.009)Jiangetal,ASH2003(#1444)FM比照CHOP〔±CD20〕

初治滤泡性淋巴瘤随机对照研究140例初治滤泡性NHL入组标准：CD20+滤泡性I-II级AnnArborII-IV期ECOG0-2CHOP(n=68)FM(n=72)随机分组28天为一疗程共6个疗程CR/PRSD/PD退出研究CD20单抗观察CR-CR+PR+PR-+:bcl2阳性-:bcl2阴性Zinzanietal.JClinOncol2004;22(13):2654-2661RANDOMIZEDPHASEFND+RvsFNDFM比照CHOP：

完全缓解率和分子学完全缓解率显著提高 FM CHOP p值化疗后 cCR 68% 42% .003 mCR 39% 19% .001对未达CR-用CD20单抗稳固后 cCR 90% 81% - mCR 71% 51% .01cCR:临床完全缓解mCR:分子学完全缓解Zinzanietal.JClinOncol2004;22(13):2654-2661RANDOMIZEDPHASEFND+RvsFNDFM比照CHOP：RFSRFS:Relapse-freesurviveZinzanietal.JClinOncol2004;22(13):2654-2661RANDOMIZEDPHASEFND+RvsFNDFM比照CHOP：耐受性显著提高Zinzanietal.JClinOncol2004;22(13):2654-2661III/IV级毒性FM(n=72)CHOP(n=68)p值中性粒细胞减少30%39%差别不显著恶心呕吐3%22%<0.001脱发14%85%<0.001外周神经系统毒性026%<0.001便秘032%<0.001两组无一例出现III/IV级贫血或血小板减少两组无一例因毒性或感染而死亡RANDOMIZEDPHASEFND+RvsFND含福达华方案联合环磷酰胺〔FC〕三药联合:FCM联合米托蒽琨〔FN〕ORR71-94%，CR20-47%83%ORR，66%CRORR

72-88%，27-66%CR1.含Fludarabine联合方案

治疗复发恶性NHL

中山大学肿瘤医院内科黄慧强等(2003)

ObjectiveResponseResponseWholeLGIntermediateuntreatedRelapse〔n=25〕(n=21)〔n=4〕(n=13)(n=12)CR323803925PR404804633SD2414751533PD402508CR+PR7286085582.含Fludarabine方案治疗初治/复治

惰性淋巴瘤广东协作组初步报告南方医院中山大学一附院广东省人民医院中山大学第二附属医院广州医学院二附院广州军区陆军总医院中山大学肿瘤医院疗效N%ORCR2141.1878.43%PR1937.25GPR11.96SD23.92总体平均疗程：3.76(1-6)M有效患者的平均疗程：4.22

滤泡性淋巴瘤治疗Meta分析CR率化疗或联合化疗*37%Rituximab±化疗53%Fludarabine单药/联合68%放射免疫治疗,RIT79%*化疗方案不含福达华01－06年,25篇临床文献、2421例ASH2006,Abstract275410mg迅速释放的片剂药代动力学研究

Foranetal.,JClinOncol1999

40-50mg/m2

口服相当于25mg/m2i.v.生物利用度不受食物影响

Oscieretal.,HematolJ2001福达华口服剂型－方便口服vs静脉:疗效相当〔单药CLL〕Boogaertsetal.,JCO200152例，FL有效率65%，CR率30%62%既往CD20单抗治疗缓解者

OralFludarabine+CTX:

75untreatedCLL:FinalresponseandF/U

DurationofR.(CR/PR)1085days

Oralfludarabine+CTX:75untreatedCLLFinalresponseandF/U

口服Fludarabine+CTX治疗惰性淋巴瘤初步结果报告

中山大学附属肿瘤医院内科

淋巴瘤治疗和研究中心2021.8.OralFludarabine+CTXInitalAgeGenderDiagnosisCyclesResponseSideeffect169650ZGM66FMALTⅠAR-FC*3PRⅡ骨髓抑制1程,Ⅲ呕吐第2程,Ⅰ胃肠反应170962JYZ48FCLLR-FC*1无168159LJM74MSLLR-FC*5CR无170581YQT55MMCLⅢAR-FM*2FM*2GPRⅢ-Ⅳ骨髓抑制16980LCX57F鼻咽MALTⅢAR-FC*1无170581HMT37F幼淋巴细胞白血病R-FC*1畏寒、发热等输注反应C225816LRZ67MSLLⅢAFC*2无C223385WHL35FSLLⅣAFC*3CRuⅠ-Ⅱ恶心、纳差

ResponseRate

联合化疗：Oralfludarabine+CTX7FC-Rituximab6OralFludarabie+Mitoxantrane1共20疗程，1-5疗程有效率：100％(8/8)CR:37%(3/8)OralFludarabine30--40mg/m2d1-3CTX500-600mg