惰性淋巴瘤規(guī)范化治療－08年NCCN治療指南解讀

惰性淋巴瘤標(biāo)準(zhǔn)化治療－08年NCCN治療指南解讀黃慧強(qiáng)中山大學(xué)附屬腫瘤醫(yī)院

淋巴瘤治療研究中心

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!過去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期濾泡性淋巴瘤:不同治療方案的OS1972-2002Liuetal,JCO2006;24:1582-1589Years%Alive0510152025020406080100CHOP-BleoCHOP-Bleo+IFNATTIFNATTIFNvsFNDIFNR-FND+IFNvsFNDR+IFNP<.01IV期濾泡性淋巴瘤:不同治療方案的生存,FLIPI評分3Liuetal,JCO2006;24:1582-1589Years%Failure-Free0510152025020406080100CHOP-BleoCHOP-Bleo+IFNATTIFNATTIFNvsFNDIFNR-FND+IFNvsFNDR+IFNP<.0001IV期濾泡性淋巴瘤:不同治療方案的FFS1972-2002Liuetal,JCO2006;24:1582-1589惰性淋巴瘤治療效果提高常規(guī)化療的改進(jìn)Rituximab，CD20RIT,Radio-immuno-therapyAHSCT/Allo-HSCT

Rituximab:惰性NHL(FL)單藥治療結(jié)論單藥：復(fù)發(fā)和難治的低度惡性NHL(RR48%)

單藥：初發(fā)的低度惡性NHL(RR73%)

聯(lián)合化療結(jié)論(Ⅲ期臨床研究)R-CVP療效明顯優(yōu)于CVP方案

R-CHOP明顯優(yōu)于CHOP方案(TTFPFSOS)CVP后+R維持治療進(jìn)一步增加療效(PFS)FCM+R明顯優(yōu)于FCM方案(RRCRPFSOS)

R+Leukeran>Leukeran

一線-濾泡性淋巴瘤治療:RandomizedHiddemannetal.CHOPR-CHOPp可評估患者205223反應(yīng)率90%96%0.011TTF31mNotreached<0.0001OS(estimated2-yOS)90%95%0.016Marcusetal.CVPR-CVPp可評估患者159162反應(yīng)率57%81%<0.0001PFS15m34m<0.0001OS(隨訪53m)71%81%<0.03Heroldetal.MCPR-MCPp可評估患者96105反應(yīng)率75%92%<0.001EFS19mNotreached<0.0001OS62mNotreached0.016Foussardetal.CHVP/IFN-αR-CHVP/IFN-αp可評估患者183175反應(yīng)率(CR/CRu)85%(49%)94%(76%)<0.0001EFS36mNotreached<0.0001OS(隨訪42m)84%91%<0.03Rituximab維持治療的進(jìn)展作者誘導(dǎo)CT對照組持續(xù)時間PFS/EFSOS時機(jī)病理1.JohnHainsworthRqw×4q6m×65y40%,8y29%M:39.8m

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

RIT單用治療復(fù)發(fā)耐藥NHLResponseDuration:RITonrelapsedorrefractoryNHLCD20-I131:FLandTransformedNHL:

Longtermoutcome11studies,1177ptsMage57(21-90),stage?90%,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

單一誘導(dǎo)后的CR率(%)

鞏固后CR率

(%)

ReferenceR-CHOP(3)+Zevalin

consolidationII-IVFL;60%stageIV2867Shipleyetal.

ASCO2005FM(6c)+

90Y-Ibritumomab

tiuxetan

consolidationII–IVFL;

88%stageIII–IV73100

(誘導(dǎo)后PR均轉(zhuǎn)為CR)Zinzanietal.

ASH2006R-CHOP+

90Y-Ibritumomab

tiuxetan

consolidation+R

maintenanceII–IVFL;

91%stageIII–IV;40%highFLIPI4189Jankowitzetal.

ASCO2007Zevalin穩(wěn)固治療FLCUPtrial:AHSCT歐洲多中心研究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復(fù)發(fā)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復(fù)發(fā)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期濾泡性淋巴瘤:不同治療方案的OS1972-2002Liuetal,JCO2006;24:1582-1589

患者(%)1987–19961976–19861960–1975

年100806040200

0 5 10 15 20 25 302000–2021??濾泡性淋巴瘤遠(yuǎn)期療效前瞻?常規(guī)化療RT造血細(xì)胞移植單克隆抗體,RIT干擾素新治療方法ADVANCESON

INDOLENTLYMPHOMA

Fludarabine(單藥)UntreatedFLCR14-47%RR47-81%TreatedFLCR6-48%RR31-72%FludarabinevsCVP(phaseIII)CR9%vs7%RR64%vs52%福達(dá)華+米托蒽琨初治初治福達(dá)華+環(huán)磷酰胺比較FCN+/-CD20單抗的療效49例患者進(jìn)行初步療效評價兩組的血液學(xué)和非血液學(xué)毒性相當(dāng)FCM=fludarabine/cyclophosphamide/mitoxantrone.HiddemannW,etal.SeminOncol.2003;30(1Suppl2):16-20.,DreylingMH,etal.Blood.2003;102Abstract351.40%FCN+CD20單抗n=25CRFCNn=2421%52%PR54%92%CR+PR75%福達(dá)華/環(huán)磷酰胺/米托蒽琨+/-CD20單抗治療復(fù)發(fā)難治濾泡性淋巴瘤FLUvsFLU-ID(FLU+Ida)

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

FND

followedbyanti-CD20vsFNDplusanti-CD20 concurrenty(MDACC)FMvsCHOPanti-CD20(Bologna)含福達(dá)華方案的III期隨機(jī)臨床研究FLU(%)FLU-ID(%)合計(%)CR473943PR374239.5CR+PR848182.5CR濾泡性淋巴瘤小淋巴細(xì)胞淋巴瘤淋巴漿細(xì)胞淋巴瘤套細(xì)胞淋巴瘤602923274043383350373131Zinzanietal.JClinOncol2000FLUvsFLUIDRANDOMIZEDPHASEIIITRIAL初步臨床療效評價8個療程的FND方案與ATT(CHOD-Bleo,ESHAP,NOPP)治療IV期惰性淋巴瘤的隨機(jī)對照研究報道的5年OS內(nèi)分子學(xué)CR情況兩組沒有差異(bcl-2-):84%FNDvs82%ATT;5-yearFFS:41%FNDvs50%ATTFNDvsATTRANDOMIZEDPHASEIIITRIALTSIMBERIDOUetal.Blood2002RANDOMIZEDPHASEIIITRIALFND+RvsFNDR6個療程的FND方案同時使用或序貫使用CD20單抗治療IV期惰性淋巴瘤的隨機(jī)對照研究5年FFS:FND+Rvs

FNDR

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

初治濾泡性淋巴瘤隨機(jī)對照研究140例初治濾泡性NHL入組標(biāo)準(zhǔn)：CD20+濾泡性I-II級AnnArborII-IV期ECOG0-2CHOP(n=68)FM(n=72)隨機(jī)分組28天為一療程共6個療程CR/PRSD/PD退出研究CD20單抗觀察CR-CR+PR+PR-+:bcl2陽性-:bcl2陰性Zinzanietal.JClinOncol2004;22(13):2654-2661RANDOMIZEDPHASEFND+RvsFNDFM比照CHOP：

完全緩解率和分子學(xué)完全緩解率顯著提高 FM CHOP p值化療后 cCR 68% 42% .003 mCR 39% 19% .001對未達(dá)CR-用CD20單抗穩(wěn)固后 cCR 90% 81% - mCR 71% 51% .01cCR:臨床完全緩解mCR:分子學(xué)完全緩解Zinzanietal.JClinOncol2004;22(13):2654-2661RANDOMIZEDPHASEFND+RvsFNDFM比照CHOP：RFSRFS:Relapse-freesurviveZinzanietal.JClinOncol2004;22(13):2654-2661RANDOMIZEDPHASEFND+RvsFNDFM比照CHOP：耐受性顯著提高Zinzanietal.JClinOncol2004;22(13):2654-2661III/IV級毒性FM(n=72)CHOP(n=68)p值中性粒細(xì)胞減少30%39%差別不顯著惡心嘔吐3%22%<0.001脫發(fā)14%85%<0.001外周神經(jīng)系統(tǒng)毒性026%<0.001便秘032%<0.001兩組無一例出現(xiàn)III/IV級貧血或血小板減少兩組無一例因毒性或感染而死亡RANDOMIZEDPHASEFND+RvsFND含福達(dá)華方案聯(lián)合環(huán)磷酰胺〔FC〕三藥聯(lián)合:FCM聯(lián)合米托蒽琨〔FN〕ORR71-94%，CR20-47%83%ORR，66%CRORR

72-88%，27-66%CR1.含F(xiàn)ludarabine聯(lián)合方案

治療復(fù)發(fā)惡性NHL

中山大學(xué)腫瘤醫(yī)院內(nèi)科黃慧強(qiáng)等(2003)

ObjectiveResponseResponseWholeLGIntermediateuntreatedRelapse〔n=25〕(n=21)〔n=4〕(n=13)(n=12)CR323803925PR404804633SD2414751533PD402508CR+PR7286085582.含F(xiàn)ludarabine方案治療初治/復(fù)治

惰性淋巴瘤廣東協(xié)作組初步報告南方醫(yī)院中山大學(xué)一附院廣東省人民醫(yī)院中山大學(xué)第二附屬醫(yī)院廣州醫(yī)學(xué)院二附院廣州軍區(qū)陸軍總醫(yī)院中山大學(xué)腫瘤醫(yī)院療效N%ORCR2141.1878.43%PR1937.25GPR11.96SD23.92總體平均療程：3.76(1-6)M有效患者的平均療程：4.22

濾泡性淋巴瘤治療Meta分析CR率化療或聯(lián)合化療*37%Rituximab±化療53%Fludarabine單藥/聯(lián)合68%放射免疫治療,RIT79%*化療方案不含福達(dá)華01－06年,25篇臨床文獻(xiàn)、2421例ASH2006,Abstract275410mg迅速釋放的片劑藥代動力學(xué)研究

Foranetal.,JClinOncol1999

40-50mg/m2

口服相當(dāng)于25mg/m2i.v.生物利用度不受食物影響

Oscieretal.,HematolJ2001福達(dá)華口服劑型－方便口服vs靜脈:療效相當(dāng)〔單藥CLL〕Boogaertsetal.,JCO200152例，F(xiàn)L有效率65%，CR率30%62%既往CD20單抗治療緩解者

OralFludarabine+CTX:

75untreatedCLL:FinalresponseandF/U

DurationofR.(CR/PR)1085days

Oralfludarabine+CTX:75untreatedCLLFinalresponseandF/U

口服Fludarabine+CTX治療惰性淋巴瘤初步結(jié)果報告

中山大學(xué)附屬腫瘤醫(yī)院內(nèi)科

淋巴瘤治療和研究中心2021.8.OralFludarabine+CTXInitalAgeGenderDiagnosisCyclesResponseSideeffect169650ZGM66FMALTⅠAR-FC*3PRⅡ骨髓抑制1程,Ⅲ嘔吐第2程,Ⅰ胃腸反應(yīng)170962JYZ48FCLLR-FC*1無168159LJM74MSLLR-FC*5CR無170581YQT55MMCLⅢAR-FM*2FM*2GPRⅢ-Ⅳ骨髓抑制16980LCX57F鼻咽MALTⅢAR-FC*1無170581HMT37F幼淋巴細(xì)胞白血病R-FC*1畏寒、發(fā)熱等輸注反應(yīng)C225816LRZ67MSLLⅢAFC*2無C223385WHL35FSLLⅣAFC*3CRuⅠ-Ⅱ惡心、納差

ResponseRate

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