濾泡淋巴瘤的治療策略

內(nèi)容概要什么是濾泡淋巴瘤？1濾泡淋巴瘤流行病學(xué)、診斷和病理分級(jí)2濾泡淋巴瘤預(yù)后3早期、晚期濾泡淋巴瘤治療4濾泡淋巴瘤發(fā)病率

美國(guó)德國(guó)南非阿聯(lián)酋香港臺(tái)灣小淋巴細(xì)胞/慢淋7118131濾泡淋巴瘤311833786套細(xì)胞淋巴瘤781032邊緣帶69441021彌漫大B細(xì)胞283028594647Burkitt和Burkitt樣2321322前體T細(xì)胞淋巴瘤/白血病212441非特異性外周T細(xì)胞型3482109間變大細(xì)胞213734結(jié)外NK/T細(xì)胞型，鼻型000084什么是濾泡淋巴瘤(FL)？發(fā)病率最高的惰性淋巴瘤起源于濾泡中心細(xì)胞至少部分呈濾泡樣生長(zhǎng)方式多數(shù)與t(14;18)染色體異位所致的Bcl-2

過(guò)表達(dá)有關(guān)濾泡淋巴瘤發(fā)病特點(diǎn)最常見(jiàn)的惰性淋巴瘤發(fā)病率隨年齡增加增多，中位發(fā)病年齡60歲在亞洲和非洲裔人種中發(fā)病率低診斷多發(fā)淋巴結(jié)腫大，75%為晚期，骨髓受侵多見(jiàn)組織學(xué)特點(diǎn)：B細(xì)胞來(lái)源的腫瘤細(xì)胞（中心細(xì)胞和中心母細(xì)胞）形成濾泡樣生長(zhǎng)，期間混有基質(zhì)細(xì)胞（如樹突細(xì)胞、巨噬細(xì)胞和T細(xì)胞）。免疫組化：CD20+,CD10+,CD23+/-,CD5-,CyclinD1-特征性病理：t（14;18）異位所致的bcl-2過(guò)表達(dá)GradeIIIGradeIGradeII濾泡中心細(xì)胞混合中心母細(xì)胞病理分級(jí)>15中心母細(xì)胞/HPF6-15中心母細(xì)胞/HPF0-5中心母細(xì)胞/HPF“Smallcleavedfolliclecells”“l(fā)argeblasticfolliclecells”惰性淋巴瘤侵襲性，DLBCL濾泡淋巴瘤國(guó)際預(yù)后指數(shù)（FLIPI）CharacteristicRR(Death)Olderthan60yrsofage2.38StageIII-IV2.00Hemoglobin<12.0g/dL1.55ElevatedLDH1.50Nodalsites>41.39Solal-Céligny,etal.Blood.2004;104:1258-1265.FLIPIandOSRiskGroupRiskFactors,n5-YrOS,%10-YrOS,%Low0-19171Intermediate27851High≥35336FLIPI-2受累淋巴結(jié)最大徑>6cm骨髓受侵Hb<12g/Dl年齡>60歲Β2-微球蛋白>正常FedericoM,etal.JClinOncol.2009;27:4555-4562.FLIPI2

RiskGroupRiskFactors,nPatients,%3-YrPFS,%5-YrPFS,%HRLow0-12090.979.51.00Intermediate25369.351.23.19High3-52751.318.85.76Highvsint1.81DaveSS,etal.NEnglJMed.2004;351:2159-2169.基因型與預(yù)后單核細(xì)胞浸潤(rùn)T細(xì)胞浸潤(rùn)ExpressionSignature(Prognosis)RRofDeathPValueImmuneresponse1(favorable)0.15<.0001Immuneresponse2(unfavorable)9.35<.0001FL:10年OS提高20%美國(guó)惰性淋巴瘤患者的10年總生存對(duì)比LymphomaintheUSAgeRange,YrsSurvival,%1990-19922002-200415-44648445-54598155-64547365-74497075orolder3149Total5272PulteD,etal.ArchIntMed.2008;168:469-476.FL的治療早期：50%可以治愈，放療+化療晚期：傳統(tǒng)化療不能治愈無(wú)治療指征時(shí)，可以觀察老年患者為主，合并癥多，治療選擇復(fù)雜無(wú)明確標(biāo)準(zhǔn)化療方案隨著每一個(gè)治療周期，緩解時(shí)間縮短早期FL：放療IFRT的局部控制率>95%聯(lián)合化療是否獲益并不肯定如果觀察等待，7年時(shí)38%的患者需要治療約40-50%患者可以治愈IFRT±化療治療I/II期FL晚期FL治療：觀察等待觀察等待39%患者4年時(shí)未治

19%患者10年時(shí)未治自發(fā)消退：22%患者中可見(jiàn)治療并不能降低組織學(xué)轉(zhuǎn)化率無(wú)生存獲益中位開始治療時(shí)間：10年隨機(jī)對(duì)照研究:惰性NHLBNLI:N=309隨機(jī)分組：觀察等待vs苯丁酸氮芥中位隨訪:16年OS和DSS無(wú)差別TrialRegimensFFSOSYoung1988[1]ProMACE-MOPP+TNIvswatchandwaitYesNoBrice1997[2]PrednimustinevsIFvswatchandwaitNoNoArdeshna2003[3]Chl

vswatchandwaitYesNo1.YoungRC,etal.SeminHematol.1988;25(2suppl2):11-16.

2.BriceP,etal.JClinOncol.1997;15:1110-1117.

3.ArdeshnaKM,etal.Lancet.2003;362:516-522.晚期FL治療選擇觀察與等待放療單藥治療美羅華+聯(lián)合化療骨髓移植晚期FL的治療指征

骨髓受侵致血細(xì)胞減少威脅到重要器官功能病變導(dǎo)致癥狀大腫塊6個(gè)月的時(shí)間內(nèi)穩(wěn)定進(jìn)展組織學(xué)轉(zhuǎn)化巨脾患者意愿治療參加臨床研究FL的一線化療方案美羅華FL治療的主要進(jìn)展單藥美羅華一線治療FL1Measuren(%)95%CIORR,?n(%)26(72)57-84CR,n(%)13(36)23-51PR,n(%)13(36)23-51PFS(median),yrs2.21.3-notyetreachedPFS:normalLDH(median),yrs2.6--PFS:elevatedLDH,yrs0.5--*N=37.

?PatientswithelevatedLDHORRwas33%. WitzigTE,etal.JClinOncol.2005;23:1103-1108.PFS,%OS,%RegimenNR-ChemoChemoR-ChemoChemoCHOP[1]42882*6495*90CHVP-IFN[2]35852*378479CVP[3]32154*1783*77MCP[4]20171*4087*74*StatisticallysignificantimprovementforR-chemovschemo.1.HiddemannW,etal.Blood.2005;106:3725-3732.2.SallesG,etal.Blood.2008;112:4824-4831.

3.MarcusR,etal.JClinOncol.2008;26:4579-4586.4.HeroldM,etal.JClinOncol.2007;25:1986-1992.R-化療vs化療一線治療FL一線免疫化療治療FL:NationalLymphoCareStudyNoconsensusexistsonstandardofcareforfrontlinetreatmentofFLinUS;previousNationalLymphoCareStudyreportshowedvarietyofstrategiesused[1]Rituximab+chemotherapy:51.9%Observation:17.7%Rituximabmonotherapy:13.9%Clinicaltrial:6.1%Radiationtherapy:5.6%Chemotherapyalone:3.2%Responserateswithalkylatingagents~70%to80%[2]Additionofanthracyclineor

useoffludarabine-basedtreatmentsdoesnotimproveOS[3-5]However,OSsignificantlyimprovedwhenrituximabaddedtochemotherapy[6,7]Currentlackofobservationaldataonrelativeefficacyofdifferentchemotherapyregimensincombinationwithrituximabasfrontlinetherapy1.FriedbergJW,etal.JClin

Oncol.2009;27:1202-1208.2.PortlockCS,etal.Cancer.1976;37:1275-1282.3.KimbyE,etal.AnnOncol.1994;5(suppl2):67-71.4.PetersonBA,etal.JClin

Oncol.2003;21:5-15.5.HagenbeekA,etal.JClin

Oncol.2006;24:1590-1596.6.HiddemannW,etal.Blood.2005;106:3725-3732.7.MarcusR,etal.JClin

Oncol.2008;26:4579-4586.一線免疫化療治療FL:NationalLymphoCareStudyCurrentstudyexaminedoutcomesofpatientsgivendifferentfrontlinerituximab+chemotherapyregimensStudysubjectsselectedamong2727patientswithnewlydiagnosedprimaryFLat265USstudysitesfrom2004-2007StudyobjectivesComparebaselinefeaturesofpatientstreatedwithrituximab+chemotherapyregimensIdentifyfactorsassociatedwithfrontlineregimenselectionEfficacyoutcomesassessedBestresponsePFSOSSafetydataontreatment-relatedtoxicityassessedbydeath,prematuretreatmentdiscontinuation,hospitalizationMedianfollow-up:58mosNastoupilL,etal.ASH2011.Abstract97.NationalLymphoCareStudy:患者一般狀態(tài)NastoupilL,etal.ASH2011.Abstract97.CharacteristicR-CHOP(n=547)R-CVP(n=238)R-Flu(n=116)Medianage,*yrs(range)58(22-88)64(39-89)58(32-85)Male,*%554447ECOGPS,%0605270≥1404830FLgrade,*%128545223332383341210Mixed520FLIPIrisk,*%Good151317Intermediate352642*P<.05fordifferencesbetweentreatmentgroups.n=NationalLymphoCareStudy:ResultsAge,sex,FLgrade,andgeographiclocationinfluencedfrontlinetreatmentchoiceORRsignificantlyhigherwith

R-CHOPorR-FluvsR-CVP

(P<.05foreachcomparison)

inoverallgroupofpatientswithstageIII/IVdiseaseAmongpatientswithpoor-riskFLIPIscore,ORRsignificantlyhigherwithR-CHOPvsR-CVP(P<.05)NastoupilL,etal.ASH2011.Abstract97.R-CHOPR-CVPR-FluORR(%)100806040200AllPatientsPatientsWith

Poor-RiskFLIPI52322410921411835948895958897P<.05P<.05P<.05NationalLymphoCareStudy:OSandPFSOutcomeR-CHOPR-CVPR-FluR-CHOPvsR-CVPAdjustedHR*(95%CI)R-FluvsR-CVPAdjustedHR*

(95%CI)MedianOS,mosAllstageIII/IVNRNRNR0.64(0.39-1.04)0.72

(0.35-1.47)Poor-riskFLIPINRNRNR0.38(0.23-0.63)0.59(0.29-1.19)MedianPFS,mosAllstageIII/IV7757NR0.83(0.60-1.14)0.61(0.38-0.98)Poor-riskFLIPI6541550.66(0.45-0.96)0.62(0.35-1.09)NastoupilL,etal.ASH2011.Abstract97.*Adjustedforsex,FLIPIfactors(age,numberofnodalsites,lactatedehydrogenase,hemoglobin),histologygrade,bonemarrowinvolvement,geographiclocation,treatmentsetting,andcontinuedrituximabmaintenance.CVPvsR-CVP：III/IV期濾泡淋巴瘤Observation1471013161922WksCVP

armR-CVP

armRANDOMI

Z

AT

IONMarcusR,etal.JClinOncol.2008;26:4579-4586.OutcomeCVPCVP+RituximabCR,%1041Durationofresponse,mos14384-yrsurvival,%7783159CVPR–CVPPatientsatrisk:Study

Month162Event-Free

Probability0612182430364248540600.10.20.30.40.50.60.70.80.91.01291448713264112511053984297314405160500R-CVP:median34monthsCVP:median15monthsP<0.0001CVPvsR-CVP：III/IV期濾泡淋巴瘤PFSOverallSurvival159CVPR–CVPPatientsatrisk:StudyMonth162Event-FreeProbabilityP=0.05530612182430364248540600.10.20.30.40.50.60.70.80.91.01551621511601411551361501321441221357282384371400R-CVP:mediannotreachedCVP:mediannotreached中位隨訪:42月CHOPvsR-CHOP：III/IV期濾泡淋巴瘤428ptsFL,20%IPI3-5,40%>age60,stageIII/IV18-monthmedianfollow-up1GLGLSGHiddemannetal.Blood.2005;106:3725

PFS3Yrs

OS3Yrs

R-CHOPx6-875%95%CHOPx6-851%87%

P<.001P=.016美羅華的維持治療CompanyLogoE1496:ECOGandCALGB:CVPMaintenance

RituximabAfterCVPResultsinSuperiorClinicalOutcomeinFollicularLymphomaHowardS.Hochster,EdieWeller,RandyD.Gascoyne,TheresaS.Ryan,ThomasM.Habermann,StanleyR.Frankel,andSandraJ.HorningECOG1496:

CVP誘導(dǎo)化療后R維持治療惰性NHLRANDOMIZATIONUntreatedlow-gradeIWFB-CCVPCyclophosphamideday1Vincristineday1Prednisonedays1-5every21days,6-8cyclesRESTAGINGCR,PR,SDRANDOMIZATIONRituximabMaintenanceRituximab375mg/m2weeklyx4every6monthsObservationLRone-sidedP=0.0000003HR0.4(0.3,0.6)YearsFromMaintenanceRandomizationProbability01234560.00.20.40.60.81.0MR(120)OBS(117)ECOG1496:PFSMedianPFSFromRandomization:15movs.61mo**~21and~67mofromstudyentry.LRone-sidedP=0.03HR=0.5(0.3,1.1)YearsFromMaintenanceRandomizationProbability01234560.00.20.40.60.81.0MR(120)OBS(117)ECOG1496:OSOSat42*moFromRandomization:91%vs.75%*~48mofromstudyentry.RANDOMIZEDCHOPevery

21days

maximum6cyclesRituximab+CHOPevery

21days

maximum6cyclesEORTC：復(fù)發(fā)

美羅華維持治療RANDOMIZEDObservationRituximabmaintenance*CR

PR*375mg/m2every3monthsfor2yearsoruntilrelapse.EORTC：PFS結(jié)果Median:42.2mMedian:11.6mMedian:23.1mMedian:51.9mSubgroupsAccordingtoInductionTreatmentHazardratio:0.30Hazardratio:0.54

EORTC：OS結(jié)果

VanOers,etal.Untreatedpatientswith

hightumorburdenfollicularlymphomaInductionImmunochemotherapy8cyclesR-CHOPorR-CVPorR-FCMRituximabmaintenance375mg/m2q8wfor

2yrs(n=505)Observation(n=513)Response*(N=1019)*OnlypatientswithCR/CRu/PRrandomizedtomaintenancetherapy;1patientdiedduringrandomization.Stratifiedbyresponsetoinduction,chemotherapyregimen,andgeographiclocationpriorto1:1randomization5-yrfollow-upSallesGA,etal.ASCO2010.Abstract8004.PRIMA:美羅華維持治療vs觀察PRIMA:中期分析結(jié)果維持組的獲益與年齡、FLIPI、誘導(dǎo)化療方案無(wú)關(guān)維持組中性粒細(xì)胞減少和感染的發(fā)生率高還需要更長(zhǎng)時(shí)間的隨訪，獲得OS結(jié)果TreatmentArm,%3-YrPFS95%CIPValueRituximabmaintenance7570.9-78.9.0001Observation5853.2-62.0SallesGA,etal.Lancet.2011;377:42-51.MaintRituximabvsRetreatmentinLowTumorBurdenFL:PhIIIE4402(RESORT)Primaryendpoint:TTFSecondaryendpoints:timetofirstcytotoxicchemotherapy,safety/toxicity,QoLKahlBS,etal.ASH2011.AbstractLBA-6.PatientswithFLandlowtumorburdenwhoreceivedfrontlinerituximab*(N=384)Maintenance

Rituximab375mg/m2every3mos(n=140)RetreatmentatProgressionRituximab375mg/m2/wkx4mos(n=134)PatientswithCRorPR(N=274)Continueuntilrituximab

treatmentfailureMedianfollow-up:3.8yrs*375mg/m2/wkfor4wks.Stratifiedbyage(<60vs

≥60yrs)andtimefromdiagnosis(<1vs≥1yr)E4402(RESORT):BaselineCharacteristicsCharacteristicRituximabRetreatment(n=134)MaintenanceRituximab(n=140)Male,%4646Medianage,yrs(range)59.5(26-86)58.9(25-86)FLIPIscore,%0-11516246433-53941FLdiseasestage,%III5648IV4351Elevatedβ2-microglobulin,%4639Diseasestatus,%CR/unconfirmedCR1418PR8178KahlBS,etal.ASH2011.AbstractLBA-6.E4402(RESORT):ResultsNodifferenceintimetotreatmentfailurebetweenrituximabmaintenanceandretreatmentgroups(P=.80);P=.39bysensitivityanalysisKahlBS,etal.ASH2011.AbstractLBA-6.FailureType,nRituximabRetreatment

(n=134)MaintenanceRituximab

(n=140)Noresponse180Timetoprogression<6mos1125Alternativetherapy81Adverseevent17Complicatingdiagnosis66Death11Patientwithdrawal1626Other/unknown43E4402(RESORT):ResultsTimetocytotoxictherapy:maintenancerituximabslightlysuperiortoretreatment,butuses3.5timesasmuchrituximabKahlBS,etal.ASH2011.AbstractLBA-6.Probability1.00.80.60.40.2001234567Yr2-sidedlog-rankP=.03Retreatment

MaintenanceE4402(RESORT):ResultsAt12mospostrandomization,nodifferencebetweengroupsnotedinquality-of-life,anxietymeasuresFewgrade3/4adverseeventsreportedineitherarm,withgrade3fatiguein3patientsreceivingmaintenancerituximabasmostcommontoxicityKahlBS,etal.ASH2011.AbstractLBA-6.AdverseEvents,nRituximabRetreatment(n=134)MaintenanceRituximab(n=140)Grade3410Grade420Deaths10

12Secondmalignancies97VidalL,etal.JNatlCancerInst.2009;101:248-255.StudyorSubgroupMaintenanceafterfirst

induction

Ghielmini2004

Hochster2005

Hochster2007

Subtotal(95%CI)Heterogeneity:CHi2=3.57;df=2(P=.17);I2=44%

Testforoveralleffect:Z=1.25(P=.21)Maintenanceafter2ormore

inductions

Forstpointner2006

Ghielmini2004

Hainsworth2005

vanOers2006

Subtotal(95%CI)Heterogeneity:Chi2=3.09,df=3(P=.38);I2=3%

Testforoveralleffect:Z=3.43(P=.0006)Log(HR)-0.025

-0.6733

1.5067

-0.72

-0.862

-0.1526

-0.6676SE0.7072

0.3637

1.155

0.5

0.3516

0.2819

0.2629Weight,%19.4

73.3

7.3

10010.2

20.7

32.1

37.0

100HR(95%CI)0.98(0.24-3.90)

0.51(0.25-1.04)

4.51(0.47-43.40)

0.68(0.37-1.25)0.49(0.18-1.30)

0.42(0.21-0.84)

0.86(0.49-1.49)

0.51(0.31-0.86)

0.58(0.42-0.79)HR(95%CI)FavorsMRFavorsControl0.010.1110100美羅華維持治療FL:OS其他鞏固治療策略干擾素放射免疫抗體造血干細(xì)胞移植疫苗StiL:Bendamustine+RvsCHOP-R

一線治療惰性NHLPatientswith

frontline

iNHLorMCL

(N=549)CHOP-Rq3wx6

(n=253)Bendamustine-Rituximabq4wx6

(n=260)(n=513evaluablepatients)Rituximab375mg/m2onDay1;(bendamustine90mg/m2onDays1-2q28days)

or(standardCHOPq21days)x6RummelMJ,etal.Blood.2009;114.Abstract405.惰性淋巴瘤另一治療進(jìn)展：苯達(dá)莫斯丁StiL:結(jié)果PFS：MCL,WM,FL患者顯著獲益濾泡淋巴瘤PFS:CHOP-R：46.7mR-bendamustine：未達(dá)到(P=.0281)RummelMJ,etal.Blood.2009;114.Abstract405.OutcomeCHOP-RR-BendamustinePValueORR,%92.791.3--CR,%30.840.1.0323PFS,mos34.854.9.00012EFS,mos3154.0002Median

observation

time:32mosStiL:PFSforFLPatientsReprintedwithpermission.RummelMJ,etal.Blood.2009;114.Abstract405.1.00.90.80.70.60.50.40.30.20.100122436486072MosProbabilityofPFSR-bendamustineCHOP-RR-bendamustine:notreachedvsCHOP-R:46.7mos(median)HR:0.63(95%CI:0.42-0.95;P=.0281)StiL:不良反應(yīng)AdverseEventR-BendamustineR-CHOPPValueGrade3/4,%ofcycles(n=1450)(n=1408)--Neutropenia10.746.5<.0001Leukocytopenia12.138.2<.0001Allgrades,nofpatients(n=260)(n=253)Alopecia-+++<.0001Infectiouscomplications96127.0025Paresthesias1873<.0001Stomatitis1647<.0001RummelMJ,etal.ASH2009.Abstract405.First-lineCHOP+RituximabvsCHOPvs131I-TositumomabforFL:SWOGS0016Primaryendpoints:OS,PFSSecondaryendpoints:response,safety/toxicity,humananti–mouseantibodyformationPressO,etal.ASH2011.Abstract98.CHOPx6cycles

Rituximabx6doses

(n=279)CHOPx6cycles(n=275)Patientswithuntreated

advancedFL(bulkystageII,III,orIV)

(N=554)2wksTositumomab/

131I-tositumomabCHOP-R:cyclophosphamide750mg/m2,doxorubicin50mg/m2,vincristine1.4mg/m2,prednisone

100mg/dayfor5days+rituximab375mg/m2onDays1,6,48,90,134,and141.CHOP-RIT:

cyclophosphamide750mg/m2,doxorubicin50mg/m2,vincristine1.4mg/m2,prednisone100mg/dayfor

5days,followed4wkslaterbydosimetricinfusionoftositumomab/131I-tositumomab,andfollowed1wk

laterby131I-tositumomabtoatotaldoseof75cGY.CHOP-RCHOP-RITSWOGS0016:ResultsNodifferenceinresponseratesbetweentreatmentsNodifferenceinserioustoxicitiesbetweentreatmentsMorethrombocytopeniawithCHOP-RITthanCHOP-R(18%vs2%)PressO,etal.ASH2011.Abstract98.1008060402000246810YrsFromRegistrationMedianFU:4.9yrsCHOP-RITCHOP-RCHOP-RITCHOP-R2-sided,multivariateP=.11AtRisk265

267Event86

1062-Yr

Estimate80%

76%1008060402000246810YrsFromRegistrationMedianFU:4.9yrsCHOP-RITCHOP-RCHOP-RITCHOP-R2-sided,multivariateP=.08AtRisk265

267Event40

262-Year

Estimate93%

97%Patients(%)PFSOSSWOGS0016:PrognosticFactorAnalysisModelHR(95%CI)P

ValueOutcome:PFSLDHalone1.59(1.17-2.17).003Serumβ2-microglobulinalone1.70(1.27-2.28).