1、滤泡淋巴瘤的治疗策略滤泡淋巴瘤的治疗策略内容概要内容概要什么是滤泡淋巴瘤？什么是滤泡淋巴瘤？1滤泡淋巴瘤流行病学、诊断和病理分级滤泡淋巴瘤流行病学、诊断和病理分级2滤泡淋巴瘤预后滤泡淋巴瘤预后3早期、晚期滤泡淋巴瘤治疗早期、晚期滤泡淋巴瘤治疗4滤泡淋巴瘤发病率滤泡淋巴瘤发病率 美国美国 德国德国南非南非阿联阿联酋酋香港香港台湾台湾小淋巴细胞小淋巴细胞/慢淋慢淋 7 118131滤泡淋巴瘤滤泡淋巴瘤 311833786套细胞淋巴瘤套细胞淋巴瘤 781032边缘带边缘带 69441021弥漫大弥漫大B细胞细胞 283028594647Burkitt 和和 Burkitt 样样 2321322前体前
2、体T细胞淋巴瘤细胞淋巴瘤/白血病白血病 212441非特异性外周非特异性外周T细胞型细胞型 3482109间变大细胞间变大细胞 213734结外结外 NK/T 细胞型，鼻型细胞型，鼻型 000084什么是滤泡淋巴瘤什么是滤泡淋巴瘤(FL)？v 发病率最高的惰性淋巴瘤发病率最高的惰性淋巴瘤v 起源于滤泡中心细胞起源于滤泡中心细胞v 至少部分呈滤泡样生长方式至少部分呈滤泡样生长方式v多数与多数与t(14;18)t(14;18)染色体异位所致的染色体异位所致的Bcl-2Bcl-2 过表达有关过表达有关滤泡淋巴瘤发病特点滤泡淋巴瘤发病特点v 最常见的惰性淋巴瘤最常见的惰性淋巴瘤v 发病率随年龄增加增多
3、，中位发病年龄发病率随年龄增加增多，中位发病年龄 6060岁岁v 在亚洲和非洲裔人种中发病率低在亚洲和非洲裔人种中发病率低诊断诊断v 多发淋巴结肿大，多发淋巴结肿大，75%75%为晚期，骨髓受侵多见为晚期，骨髓受侵多见v 组织学特点：组织学特点：B B细胞来源的肿瘤细胞（中心细胞和中心母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、巨噬细胞和胞、巨噬细胞和T T细胞）。细胞）。v 免疫组化：免疫组化：CD20+,CD10+,CD23+/-,CD5-,CyclinD1-CD20+,CD10+,CD23+/-
4、,CD5-,CyclinD1-v 特征性病理：特征性病理：t t（14;1814;18）异位所致的）异位所致的bcl-2bcl-2过表达过表达Grade IIIGrade IGrade II滤泡中心细胞滤泡中心细胞混合混合中心母细胞病理分级病理分级15 中心母细胞/HPF6-15 中心母细胞/HPF0-5 中心母细胞/HPF“Small cleaved follicle cells”“large blastic follicle cells”惰性淋巴瘤惰性淋巴瘤侵袭性，侵袭性，DLBCL滤泡淋巴瘤国际预后指数（滤泡淋巴瘤国际预后指数（FLIPI）CharacteristicRR(Death)O
5、lder than 60 yrs of age2.38Stage III-IV2.00Hemoglobin 41.39Solal-Cligny,et al.Blood.2004;104:1258-1265.FLIPI and OSRisk GroupRisk Factors,n5-Yr OS,%10-Yr OS,%Low0-19171Intermediate27851High 35336FLIPI-2 受累淋巴结最大径 6 cm 骨髓受侵 Hb 60 岁 2-微球蛋白 正常Federico M,et al.J Clin Oncol.2009;27:4555-4562.FLIPI2Risk Gr
6、oupRisk Factors,nPatients,%3-Yr PFS,%5-Yr PFS,%HRLow0-12090.979.51.00Intermediate25369.351.23.19High3-52751.318.85.76High vs int1.81Dave SS,et al.N Engl J Med.2004;351:2159-2169.基因型与预后基因型与预后单核细胞浸润 T细胞浸润Expression Signature(Prognosis)RR of Death P ValueImmune response 1(favorable)0.15.0001Immune resp
7、onse 2(unfavorable)9.3595%95%v联合化疗是否获益并不肯定联合化疗是否获益并不肯定v如果观察等待，如果观察等待，7 7年时年时 38%38%的患者需要治疗的患者需要治疗v约约40-50%40-50%患者可以治愈患者可以治愈IFRT 化疗治疗化疗治疗 I/II期期 FL晚期晚期FL治疗：观察等待治疗：观察等待v观察等待观察等待 39%患者4 年时未治 19%患者10年时未治v自发消退：自发消退：22%22%患者中可见患者中可见v治疗并不能降低组织学转化率无生存获益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年随机对照研究随机对照研究:惰性惰性 NHLv B
8、NLI:N=309BNLI:N=309v 随机分组：观察等待随机分组：观察等待 vs vs 苯丁酸氮芥苯丁酸氮芥v 中位随访中位随访:16:16年年v OSOS和和DSS DSS 无差别无差别TrialRegimens FFS OSYoung 19881ProMACE-MOPP+TNI vs watch and waitYesNoBrice 19972Prednimustine vs IF vs watch and waitNoNoArdeshna 20033Chl vs watch and waitYesNo1.Young RC,et al.Semin Hematol.1988;25(2 s
9、uppl 2):11-16.2.Brice P,et al.J Clin Oncol.1997;15:1110-1117.3.Ardeshna KM,et al.Lancet.2003;362:516-522.晚期晚期FL治疗选择治疗选择v观察与等待观察与等待v放疗放疗v单药治疗单药治疗v美罗华美罗华+联合化疗联合化疗v骨髓移植骨髓移植 晚期晚期FL的治疗指征的治疗指征 v骨髓受侵致血细胞减少骨髓受侵致血细胞减少v威胁到重要器官功能威胁到重要器官功能v病变导致症状病变导致症状v大肿块大肿块v6 6个月的时间内稳定进展个月的时间内稳定进展v组织学转化组织学转化v巨脾巨脾v患者意愿治疗患者意愿治疗
10、v参加临床研究参加临床研究FL的一线化疗方案的一线化疗方案美罗华美罗华FL治疗的主要进展治疗的主要进展单药美罗华一线治疗单药美罗华一线治疗FL1FL1Measuren(%)95%CIORR,n(%)26(72)57-84CR,n(%)13(36)23-51PR,n(%)13(36)23-51PFS(median),yrs 2.2 1.3-not yet reachedPFS:normal LDH(median),yrs2.6-PFS:elevated LDH,yrs0.5-*N=37.Patients with elevated LDH ORR was 33%.Witzig TE,et al.
11、J Clin Oncol.2005;23:1103-1108.PFS,%OS,%RegimenNR-ChemoChemoR-Chemo ChemoCHOP142882*6495*90CHVP-IFN235852*378479CVP332154*1783*77MCP420171*4087*74*Statistically significant improvement for R-chemo vs chemo.1.Hiddemann W,et al.Blood.2005;106:3725-3732.2.Salles G,et al.Blood.2008;112:4824-4831.3.Marcu
12、s R,et al.J Clin Oncol.2008;26:4579-4586.4.Herold M,et al.J Clin Oncol.2007;25:1986-1992.R-化疗化疗 vs 化疗一线治疗化疗一线治疗FL一线免疫化疗治疗一线免疫化疗治疗FL:National LymphoCare Study v No consensus exists on standard of care for frontline treatment of FL in US;previous National LymphoCare Study report showed variety of stra
13、tegies used1 Rituximab+chemotherapy:51.9%Observation:17.7%Rituximab monotherapy:13.9%Clinical trial:6.1%Radiation therapy:5.6%Chemotherapy alone:3.2%v Response rates with alkylating agents 70%to 80%2 Addition of anthracycline or use of fludarabine-based treatments does not improve OS3-5 However,OS s
14、ignificantly improved when rituximab added to chemotherapy6,7v Current lack of observational data on relative efficacy of different chemotherapy regimens in combination with rituximab as frontline therapy1.Friedberg JW,et al.J Clin Oncol.2009;27:1202-1208.2.Portlock CS,et al.Cancer.1976;37:1275-1282
15、.3.Kimby E,et al.Ann Oncol.1994;5(suppl 2):67-71.4.Peterson BA,et al.J Clin Oncol.2003;21:5-15.5.Hagenbeek A,et al.J Clin Oncol.2006;24:1590-1596.6.Hiddemann W,et al.Blood.2005;106:3725-3732.7.Marcus R,et al.J Clin Oncol.2008;26:4579-4586.一线免疫化疗治疗一线免疫化疗治疗FL:National LymphoCare Study v Current study
16、examined outcomes of patients given different frontline rituximab+chemotherapy regimensv Study subjects selected among 2727 patients with newly diagnosed primary FL at 265 US study sites from 2004-2007 v Study objectives Compare baseline features of patients treated with rituximab+chemotherapy regim
17、ens Identify factors associated with frontline regimen selectionv Efficacy outcomes assessed Best response PFS OSv Safety data on treatment-related toxicity assessed by death,premature treatment discontinuation,hospitalizationv Median follow-up:58 mosNastoupil L,et al.ASH 2011.Abstract 97.National L
18、ymphoCare Study:患者一患者一般状态般状态Nastoupil L,et al.ASH 2011.Abstract 97.CharacteristicR-CHOP(n=547)R-CVP(n=238)R-Flu(n=116)Median age,*yrs(range)58(22-88)64(39-89)58(32-85)Male,*%554447ECOG PS,%0605270 140 4830FL grade,*%1285452 2333238 3341210Mixed520FLIPI risk,*%Good151317 Intermediate352642*P .05 for
19、differences between treatment groups.n=National LymphoCare Study:Resultsv Age,sex,FL grade,and geographic location influenced frontline treatment choicev ORR significantly higher with R-CHOP or R-Flu vs R-CVP(P .05 for each comparison)in overall group of patients with stage III/IV disease Among pati
20、ents with poor-risk FLIPI score,ORR significantly higher with R-CHOP vs R-CVP(P .05)Nastoupil L,et al.ASH 2011.Abstract 97.R-CHOPR-CVPR-FluORR(%)100806040200All PatientsPatients With Poor-Risk FLIPI523 224 109214 11835948895958897P .05P .05P age 60,stage III/IV 18-month median follow-up1GLGLSG Hidde
21、mann et al.Blood.2005;106:3725 PFS 3 Yrs OS 3 Yrs R-CHOP x 6-8 75%95%CHOP x 6-8 51%87%P.001 P=.016HR(95%CI)Heterogeneity:Chi2=3.Observation90Y-ibritumomab tiuxetanBendamustine-Rituximab q4w x 6(n=260)Poor-risk FLIPI左腹股沟淋巴结活检病理：滤泡淋巴瘤1级，滤泡淋巴瘤国际预后指数（FLIPI）Study MonthEORTC：复发 美罗华维持治疗R-CHOP x 6-8 75%95%E
22、COG 1496:PFS美罗华的维持治疗美罗华的维持治疗E1496:ECOG and CALGB:CVPMaintenance Rituximab After CVP Results in Superior Clinical Outcome in Follicular LymphomaHoward S.Hochster,Edie Weller,Randy D.Gascoyne,Theresa S.Ryan,Thomas M.Habermann,Stanley R.Frankel,and Sandra J.HorningECOG 1496:CVP诱导化疗后诱导化疗后R维持治疗惰性维持治疗惰性NH
23、LRANDOMIZATIONUntreatedlow-gradeIWF B-CCVPCyclophosphamide day 1Vincristine day 1Prednisone days 1-5 every 21 days,6-8 cyclesRESTAGINGCR,PR,SDRANDOMIZATIONRituximab MaintenanceRituximab 375 mg/m2weekly x 4every 6 monthsObservationLR one-sided PHR 0.4(0.3,0.6)Years From Maintenance RandomizationProba
24、bility01234560.00.20.40.60.81.0MR(120)OBS(117)ECOG 1496:PFSMedian PFS From Randomization:15 mo vs.61 mo*21 and 67 mo from study entry.LR one-sided PHR=0.5(0.3,1.1)Years From Maintenance RandomizationProbability01234560.00.20.40.60.81.0MR(120)OBS(117)ECOG 1496:OSOS at 42*mo From Randomization:91%vs.7
25、5%*48 mo from study entry.RANDOMIZEDCHOP every21 daysmaximum 6 cyclesRituximab+CHOP every21 daysmaximum 6 cycles EORTC：复发：复发 美罗华维持治疗美罗华维持治疗RANDOMIZEDObservationRituximab maintenance*CRPR*375 mg/m2 every 3 months for 2 years or until relapse.(years)0123450102030405060708090100ONNumber of patients at
26、risk:Treatment55 6931114132 766138204ObservationMabtheraProgression free survivalafter CHOPOverall Logrank test:p0.0001(years)0123450102030405060708090100ONNumber of patients at risk:Treatment55 98593113434 916548278ObservationMabtheraProgression free survivalafter R-CHOPOverall Logrank test:p=0.004
27、EORTC：PFS结果结果Subgroups According to Induction Treatment EORTC：OS结果结果 Van Oers,et al.Untreated patients with high tumor burden follicular lymphomaInduction Immunochemotherapy8 cyclesR-CHOP orR-CVP orR-FCMRituximab maintenance375 mg/m2 q8w for 2 yrs(n=505)Observation(n=513)Response*(N=1019)*Only patie
28、nts with CR/CRu/PR randomized to maintenance therapy;1 patient died during randomization.Stratified by response to induction,chemotherapy regimen,and geographic location prior to 1:1 randomization5-yr follow-upSalles GA,et al.ASCO 2010.Abstract 8004.PRIMA:美罗华维持治疗美罗华维持治疗vs 观察观察PRIMA:中期分析结果中期分析结果v 维持组
29、的获益与年龄、维持组的获益与年龄、FLIPIFLIPI、诱导化疗方案无关、诱导化疗方案无关v 维持组中性粒细胞减少和感维持组中性粒细胞减少和感染的发生率高染的发生率高v 还需要更长时间的随访，获还需要更长时间的随访，获得得OSOS结果结果Treatment Arm,%3-Yr PFS95%CI P ValueRituximab maintenance7570.9-78.9.0001Observation5853.2-62.0Salles GA,et al.Lancet.2011;377:42-51.Maint Rituximab vs Retreatment in Low Tumor Burd
30、en FL:Ph III E4402(RESORT)v Primary endpoint:TTFv Secondary endpoints:time to first cytotoxic chemotherapy,safety/toxicity,QoLKahl BS,et al.ASH 2011.Abstract LBA-6.Patients with FL and low tumor burden who received frontline rituximab*(N=384)Maintenance Rituximab 375 mg/m2every 3 mos(n=140)Retreatme
31、nt at ProgressionRituximab 375 mg/m2/wk x 4 mos(n=134)Patients with CR or PR(N=274)Continue until rituximab treatment failureMedian follow-up:3.8 yrs*375 mg/m2/wk for 4 wks.Stratified by age(60 vs 60 yrs)and time from diagnosis(1 vs 1 yr)E4402(RESORT):Baseline CharacteristicsCharacteristicRituximab
32、Retreatment(n=134)Maintenance Rituximab(n=140)Male,%4646Median age,yrs(range)59.5(26-86)58.9(25-86)FLIPI score,%0-11516 24643 3-53941FL disease stage,%III5648 IV4351Elevated 2-microglobulin,%4639Disease status,%CR/unconfirmed CR1418 PR8178Kahl BS,et al.ASH 2011.Abstract LBA-6.E4402(RESORT):Resultsv
33、No difference in time to treatment failure between rituximab maintenance and retreatment groups(P=.80);P=.39 by sensitivity analysisKahl BS,et al.ASH 2011.Abstract LBA-6.Failure Type,nRituximab Retreatment(n=134)Maintenance Rituximab(n=140)No response180Time to progression 6 mos1125Alternative thera
34、py81Adverse event17Complicating diagnosis66Death11Patient withdrawal1626Other/unknown43R-CVP:median 34 monthsJ Clin Oncol.2008;26:4579-4586.1GLGLSG Hiddemann et al.Heterogeneity:Chi2=3.Study objectivesMorschhauser F,et al.Nastoupil L,et al.CHOP x 6 cyclesIFRT 化疗治疗 I/II期 FLAll grades,n of patients5-y
35、r follow-up*HRs show comparisons of high vs low risk.Marcus R,et al.18-month median follow-up2003;21:5-15.联合化疗是否获益并不肯定E4402(RESORT):Resultsv Time to cytotoxic therapy:maintenance rituximab slightly superior to retreatment,but uses 3.5 times as much rituximab Kahl BS,et al.ASH 2011.Abstract LBA-6.Pro
36、bability001234567Yr2-sided log-rank P=.03RetreatmentMaintenanceE4402(RESORT):ResultsvAt 12 mos post randomization,no difference between groups noted in quality-of-life,anxiety measuresvFew grade 3/4 adverse events reported in either arm,with grade 3 fatigue in 3 patients receiving maintenance rituxi
37、mab as most common toxicityKahl BS,et al.ASH 2011.Abstract LBA-6.Adverse Events,nRituximab Retreatment(n=134)Maintenance Rituximab(n=140)Grade 34 10Grade 420Deaths10 12Second malignancies97Vidal L,et al.J Natl Cancer Inst.2009;101:248-255.Study or SubgroupMaintenance after first inductionGhielmini 2
38、004Hochster 2005Hochster 2007Subtotal(95%CI)Heterogeneity:CHi2=3.57;df=2(P=.17);I2=44%Test for overall effect:Z=1.25(P=.21)Maintenance after 2 or more inductionsForstpointner 2006Ghielmini 2004Hainsworth 2005van Oers 2006Subtotal(95%CI)Heterogeneity:Chi2=3.09,df=3(P=.38);I2=3%Test for overall effect
39、:Z=3.43(P=.0006)Log(HR)SEWeight,%19.473.37.310010.220.732.137.0100HR(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)Favors MRFavors Control110100美罗华维持治疗美罗华维持治疗 FL:OS其他巩固治疗策略其他巩固治疗策略v干扰素干扰素v放射免疫抗体放
40、射免疫抗体v造血干细胞移植造血干细胞移植v疫苗疫苗StiL:Bendamustine+R vs CHOP-R 一线治疗惰性一线治疗惰性NHLPatients withfrontlineiNHL or MCL(N=549)CHOP-R q3w x 6(n=253)Bendamustine-Rituximab q4w x 6(n=260)(n=513 evaluable patients)Rituximab 375 mg/m2 on Day 1;(bendamustine 90 mg/m2 on Days 1-2 q28 days)or(standard CHOP q21 days)x 6Rumm
41、el MJ,et al.Blood.2009;114.Abstract 405.惰性淋巴瘤另一治疗进展：苯达莫斯丁惰性淋巴瘤另一治疗进展：苯达莫斯丁StiL:结果结果v PFS：MCL,WM,FL患者显著获益患者显著获益v 滤泡淋巴瘤滤泡淋巴瘤PFS:CHOP-R：46.7 m R-bendamustine：未达到：未达到 (P=.0281)Rummel MJ,et al.Blood.2009;114.Abstract 405.OutcomeCHOP-RR-BendamustineP ValueORR,%92.791.3-CR,%30.840.1.0323PFS,mos34.854.9.000
42、12EFS,mos3154.0002Median observation time:32 mos StiL:PFS for FL PatientsReprinted with permission.Rummel MJ,et al.Blood.2009;114.Abstract 405.00122436486072MosProbability of PFSR-bendamustineCHOP-RR-bendamustine:not reached vs CHOP-R:46.7 mos(median)HR:0.63(95%CI:0.42-0.95;P=.0281)StiL:不良反应不良反应Adve
43、rse Event R-BendamustineR-CHOP P ValueGrade 3/4,%of cycles(n=1450)(n=1408)-Neutropenia10.746.5.0001 Leukocytopenia12.138.2.0001All grades,n of patients(n=260)(n=253)Alopecia-+.0001 Infectious complications96127.0025 Paresthesias1873.0001 Stomatitis1647.0001Rummel MJ,et al.ASH 2009.Abstract 405.First
44、-line CHOP+Rituximab vs CHOP vs 131I-Tositumomab for FL:SWOG S0016 vPrimary endpoints:OS,PFSSecondary endpoints:response,safety/toxicity,human antimouse antibody formationPress O,et al.ASH 2011.Abstract 98.CHOP x 6 cyclesRituximab x 6 doses(n=279)CHOP x 6 cycles(n=275)Patients with untreatedadvanced
45、 FL(bulky stage II,III,or IV)(N=554)2 wksTositumomab/131I-tositumomabCHOP-R:cyclophosphamide 750 mg/m2,doxorubicin 50 mg/m2,vincristine 1.4 mg/m2,prednisone 100 mg/day for 5 days+rituximab 375 mg/m2 on Days 1,6,48,90,134,and 141.CHOP-RIT:cyclophosphamide 750 mg/m2,doxorubicin 50 mg/m2,vincristine 1.
46、4 mg/m2,prednisone 100 mg/day for 5 days,followed 4 wks later by dosimetric infusion of tositumomab/131I-tositumomab,and followed 1 wk later by 131I-tositumomab to a total dose of 75 cGY.CHOP-RCHOP-RITSWOG S0016:Results v No difference in response rates between treatments v No difference in serious
47、toxicities between treatmentsv More thrombocytopenia with CHOP-RIT than CHOP-R(18%vs 2%)Press O,et al.ASH 2011.Abstract 98.1008060402000246810Yrs From RegistrationMedian FU:4.9 yrsCHOP-RITCHOP-RCHOP-RITCHOP-R2-sided,multivariate P=.11At Risk265267Event861062-YrEstimate80%76%1008060402000246810Yrs Fr
48、om RegistrationMedian FU:4.9 yrsCHOP-RITCHOP-RCHOP-RITCHOP-R2-sided,multivariate P=.08At Risk265267Event40262-YearEstimate93%97%Patients(%)PFSOSSWOG S0016:Prognostic Factor AnalysisModelHR(95%CI)P ValueOutcome:PFS LDH alone1.59(1.17-2.17).003 Serum 2-microglobulin alone1.70(1.27-2.28).0004 Serum 2-m
49、icroglobulin and LDH*2.25(1.23-1.82).0001 FLIPI*2.28(1.54-3.35).0001Outcome:OS LDH alone2.46(1.49-4.07).0004 Serum 2-microglobulin alone2.22(1.31-3.76).003 Serum 2-microglobulin and LDH*3.96(2.02-7.78).0001 FLIPI*3.65(1.82-7.18).0002Press O,et al.ASH 2011.Abstract 98.*HRs show comparisons of high vs
50、 low risk.病例病例1v周海玲，女，周海玲，女，4646岁岁v发现右上颈肿物发现右上颈肿物v原肿物上方又出现一约原肿物上方又出现一约1cm1cm肿物，伴轻度潮热、肿物，伴轻度潮热、盗汗盗汗v右颈肿物活检病理：滤泡淋巴瘤右颈肿物活检病理：滤泡淋巴瘤II II级，级，CD20+,CD10+,BCL-2+,BCL-6+,KI-67+30%CD20+,CD10+,BCL-2+,BCL-6+,KI-67+30%vCTCT：双腮腺区、右颈临界多发淋巴结，大小：双腮腺区、右颈临界多发淋巴结，大小病例病例1v分期？分期？IIAv治疗？治疗？2010.2 双颈放疗双颈放疗 30Gyv月月CT：内乳、纵隔
