滤泡淋巴瘤的治疗策略

内容概要什么是滤泡淋巴瘤？1滤泡淋巴瘤流行病学、诊断和病理分级2滤泡淋巴瘤预后3早期、晚期滤泡淋巴瘤治疗4滤泡淋巴瘤发病率

美国德国南非阿联酋香港台湾小淋巴细胞/慢淋7118131滤泡淋巴瘤311833786套细胞淋巴瘤781032边缘带69441021弥漫大B细胞283028594647Burkitt和Burkitt样2321322前体T细胞淋巴瘤/白血病212441非特异性外周T细胞型3482109间变大细胞213734结外NK/T细胞型，鼻型000084什么是滤泡淋巴瘤(FL)？发病率最高的惰性淋巴瘤起源于滤泡中心细胞至少部分呈滤泡样生长方式多数与t(14;18)染色体异位所致的Bcl-2

过表达有关滤泡淋巴瘤发病特点最常见的惰性淋巴瘤发病率随年龄增加增多，中位发病年龄60岁在亚洲和非洲裔人种中发病率低诊断多发淋巴结肿大，75%为晚期，骨髓受侵多见组织学特点：B细胞来源的肿瘤细胞（中心细胞和中心母细胞）形成滤泡样生长，期间混有基质细胞（如树突细胞、巨噬细胞和T细胞）。免疫组化：CD20+,CD10+,CD23+/-,CD5-,CyclinD1-特征性病理：t（14;18）异位所致的bcl-2过表达GradeIIIGradeIGradeII滤泡中心细胞混合中心母细胞病理分级>15中心母细胞/HPF6-15中心母细胞/HPF0-5中心母细胞/HPF“Smallcleavedfolliclecells”“largeblasticfolliclecells”惰性淋巴瘤侵袭性，DLBCL滤泡淋巴瘤国际预后指数（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受累淋巴结最大径>6cm骨髓受侵Hb<12g/Dl年龄>60岁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.基因型与预后单核细胞浸润T细胞浸润ExpressionSignature(Prognosis)RRofDeathPValueImmuneresponse1(favorable)0.15<.0001Immuneresponse2(unfavorable)9.35<.0001FL:10年OS提高20%美国惰性淋巴瘤患者的10年总生存对比LymphomaintheUSAgeRange,YrsSurvival,%1990-19922002-200415-44648445-54598155-64547365-74497075orolder3149Total5272PulteD,etal.ArchIntMed.2008;168:469-476.FL的治疗早期：50%可以治愈，放疗+化疗晚期：传统化疗不能治愈无治疗指征时，可以观察老年患者为主，合并症多，治疗选择复杂无明确标准化疗方案随着每一个治疗周期，缓解时间缩短早期FL：放疗IFRT的局部控制率>95%联合化疗是否获益并不肯定如果观察等待，7年时38%的患者需要治疗约40-50%患者可以治愈IFRT±化疗治疗I/II期FL晚期FL治疗：观察等待观察等待39%患者4年时未治

19%患者10年时未治自发消退：22%患者中可见治疗并不能降低组织学转化率无生存获益中位开始治疗时间：10年随机对照研究:惰性NHLBNLI:N=309随机分组：观察等待vs苯丁酸氮芥中位随访:16年OS和DSS无差别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治疗选择观察与等待放疗单药治疗美罗华+联合化疗骨髓移植晚期FL的治疗指征

骨髓受侵致血细胞减少威胁到重要器官功能病变导致症状大肿块6个月的时间内稳定进展组织学转化巨脾患者意愿治疗参加临床研究FL的一线化疗方案美罗华FL治疗的主要进展单药美罗华一线治疗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-化疗vs化疗一线治疗FL一线免疫化疗治疗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;26:4579-4586.一线免疫化疗治疗FL:NationalLymphoCareStudyCurrentstudyexaminedoutcomesofpatientsgivendifferentfrontlinerituximab+chemotherapyregimensStudysubjectsselectedamong2727patientswithnewlydiagnosedprimaryFLat265USstudysitesfrom2004-2007StudyobjectivesComparebaselinefeaturesofpatientstreatedwithrituximab+chemotherapyregimensIdentifyfactorsassociatedwithfrontlineregimenselectionEfficacyoutcomesassessedBestresponsePFSOSSafetydataontreatment-relatedtoxicityassessedbydeath,prematuretreatmentdiscontinuation,hospitalizationMedianfollow-up:58mosNastoupilL,etal.ASH2011.Abstract97.NationalLymphoCareStudy:患者一般状态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期滤泡淋巴瘤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期滤泡淋巴瘤PFSOverallSurvival159CVPR–CVPPatientsatrisk:StudyMonth162Event-FreeProbabilityP=0.05530612182430364248540600.10.20.30.40.50.60.70.80.91.01551621511601411551361501321441221357282384371400R-CVP:mediannotreachedCVP:mediannotreached中位随访:42月CHOPvsR-CHOP：III/IV期滤泡淋巴瘤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美罗华的维持治疗CompanyLogoE1496:ECOGandCALGB:CVPMaintenance

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

CVP诱导化疗后R维持治疗惰性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：复发

美罗华维持治疗RANDOMIZEDObservationRituximabmaintenance*CR

PR*375mg/m2every3monthsfor2yearsoruntilrelapse.EORTC：PFS结果Median:42.2mMedian:11.6mMedian:23.1mMedian:51.9mSubgroupsAccordingtoInductionTreatmentHazardratio:0.30Hazardratio:0.54

EORTC：OS结果

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:美罗华维持治疗vs观察PRIMA:中期分析结果维持组的获益与年龄、FLIPI、诱导化疗方案无关维持组中性粒细胞减少和感染的发生率高还需要更长时间的随访，获得OS结果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美罗华维持治疗FL:OS其他巩固治疗策略干扰素放射免疫抗体造血干细胞移植疫苗StiL:Bendamustine+RvsCHOP-R

一线治疗惰性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.惰性淋巴瘤另一治疗进展：苯达莫斯丁StiL:结果PFS：MCL,WM,FL患者显著获益滤泡淋巴瘤PFS:CHOP-R：46.7mR-bendamustine：未达到(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:不良反应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).