濾泡淋巴瘤的治療策略

1、內(nèi)容概要,濾泡淋巴瘤發(fā)病率,什么是濾泡淋巴瘤(FL)？,發(fā)病率最高的惰性淋巴瘤 起源于濾泡中心細胞 至少部分呈濾泡樣生長方式多數(shù)與t(14;18)染色體異位所致的Bcl-2 過表達有關(guān),濾泡淋巴瘤發(fā)病特點,最常見的惰性淋巴瘤發(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，骨髓受侵多見組織學特點： B細胞來源的腫瘤細胞（中心細胞和中心母細胞）形成濾泡樣生長

2、，期間混有基質(zhì)細胞（如樹突細胞、巨噬細胞和T細胞）。免疫組化：CD20+,CD10+,CD23+/-,CD5-,CyclinD1-特征性病理：t（14;18）異位所致的bcl-2過表達,Grade III,Grade I,Grade II,濾泡中心細胞,混合,中心母細胞,病理分級,>15 中心母細胞/HPF,6-15 中心母細胞/HPF,0-5 中心母細胞/HPF,“Small cleaved follicle cells”,

3、“l(fā)arge blastic follicle cells”,,惰性淋巴瘤,,侵襲性，DLBCL,濾泡淋巴瘤國際預(yù)后指數(shù)（FLIPI）,Solal-Céligny, et al. Blood. 2004;104:1258-1265.,FLIPI and OS,FLIPI-2,受累淋巴結(jié)最大徑> 6 cm骨髓受侵Hb 60 歲Β2-微球蛋白 >正常,Federico M, et al. J Clin Onco

4、l. 2009;27:4555-4562.,Dave SS, et al. N Engl J Med. 2004;351:2159-2169.,基因型與預(yù)后,,,單核細胞浸潤,T細胞浸潤,FL: 10年OS提高20%,美國惰性淋巴瘤患者的10年總生存對比Lymphoma in the US,Pulte D, et al. Arch Int Med. 2008;168:469-476.,FL的治療,早期：50%可以治愈，放療+化

5、療晚期：傳統(tǒng)化療不能治愈無治療指征時，可以觀察老年患者為主，合并癥多，治療選擇復(fù)雜無明確標準化療方案隨著每一個治療周期，緩解時間縮短,,,,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 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 年時未治 19% 患者1

6、0年時未治自發(fā)消退：22%患者中可見治療并不能降低組織學轉(zhuǎn)化率無生存獲益,中位開始治療時間：10年,,隨機對照研究: 惰性 NHL,BNLI: N = 309隨機分組：觀察等待 vs 苯丁酸氮芥中位隨訪: 16年OS和DSS 無差別,1. Young RC, et al. Semin Hematol. 1988;25(2 suppl 2):11-16.2. Brice P, et al. J Clin Oncol. 1997

7、;15:1110-1117.3. Ardeshna KM, et al. 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,骨髓受侵致血細胞減少威脅到重要器官功能病變導(dǎo)致癥狀大腫塊6個月的時間內(nèi)穩(wěn)定進展組織學轉(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治療的主要進展,單藥美羅華一線治療FL1,*N =

8、37.?Patients with elevated LDH ORR was 33%.,Witzig TE, et al. J Clin Oncol. 2005;23:1103-1108.,*Statistically significant improvement for R-chemo vs chemo.,1. Hiddemann W, et al. Blood. 2005;106:3725-3732. 2. Salles G,

9、et al. Blood. 2008;112:4824-4831. 3. Marcus R, et al. J Clin Oncol. 2008;26:4579-4586. 4. Herold M, et al. J Clin Oncol. 2007;25:1986-1992.,R-化療 vs 化療一線治療FL,一線免疫化療治療FL: National LymphoCare Study,No consensus exists on s

10、tandard of care for frontline treatment of FL in US; previous National LymphoCare Study report showed variety of strategies used[1]Rituximab + chemotherapy: 51.9%Observation: 17.7%Rituximab monotherapy: 13.9%Clinical

11、 trial: 6.1%Radiation therapy: 5.6%Chemotherapy alone: 3.2%,Response rates with alkylating agents ~ 70% to 80%[2]Addition of anthracycline or use of fludarabine-based treatments does not improve OS[3-5]However, OS s

12、ignificantly improved when rituximab added to chemotherapy[6,7]Current lack of observational data on relative efficacy of different chemotherapy regimens in combination with rituximab as frontline therapy,1. Friedberg J

13、W, et al. J Clin Oncol. 2009;27:1202-1208. 2. Portlock CS, et al. Cancer. 1976;37:1275-1282. 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.

14、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.,一線免疫化療治療FL: National LymphoCare Study,Current study examined outcomes of patients gi

15、ven different frontline rituximab + chemotherapy regimensStudy subjects selected among 2727 patients with newly diagnosed primary FL at 265 US study sites from 2004-2007 Study objectivesCompare baseline features of pa

16、tients treated with rituximab + chemotherapy regimensIdentify factors associated with frontline regimen selection,Efficacy outcomes assessedBest responsePFSOSSafety data on treatment-related toxicity assessed by dea

17、th, premature treatment discontinuation, hospitalizationMedian follow-up: 58 mos,Nastoupil L, et al. ASH 2011. Abstract 97.,National LymphoCare Study: 患者一般狀態(tài),Nastoupil L, et al. ASH 2011. Abstract 97.,*P < .05 for di

18、fferences between treatment groups.,n =,,,,,,,National LymphoCare Study: Results,Age, sex, FL grade, and geographic location influenced frontline treatment choiceORR significantly higher with R-CHOP or R-Flu vs R-CVP

19、(P < .05 for each comparison) in overall group of patients with stage III/IV diseaseAmong patients with poor-risk FLIPI score, ORR significantly higher with R-CHOP vs R-CVP (P < .05),Nastoupil L, et al. ASH 2011.

20、 Abstract 97.,,,,R-CHOP,R-CVP,R-Flu,ORR (%),100,80,60,40,20,0,All Patients,Patients With Poor-Risk FLIPI,523,224,109,214,118,35,94,88,95,95,88,97,P < .05,P < .05,P < .05,National LymphoCare Study: OS and PFS,Na

21、stoupil L, et al. ASH 2011. Abstract 97.,*Adjusted for sex, FLIPI factors (age, number of nodal sites, lactate dehydrogenase, hemoglobin), histology grade, bone marrow involvement, geographic location, treatment setting,

22、 and continued rituximab maintenance.,CVP vs R-CVP ：III/IV期濾泡淋巴瘤,Observation,,1,4,7,10,13,16,19,22,,,,,,,,,,,,,,,,,,Wks,,,,,,,,,CVParm,R-CVParm,RANDOMIZATION,,,,,,,Marcus R, et al. J Clin Oncol. 2008;26:4579-4586.,1

23、59,CVP,R–CVP,Patients at risk:,Study Month,162,Event-Free Probability,0,6,12,18,24,30,36,42,48,54,0,60,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,,,,,,,,,1.0,,,,,,,,,,,,,,129,144,87,132,64,112,51,105,39,84,29,73,14,40,5,16,0,5,

24、0,0,,,R-CVP: median 34 months,CVP: median 15 months,P < 0.0001,,CVP vs R-CVP ：III/IV期濾泡淋巴瘤,PFS,Overall Survival,159,CVP,R–CVP,Patients at risk:,Study Month,162,Event-Free Probability,P = 0.0553,0,6,12,18,24,30,36,42,4

25、8,54,0,60,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,,,,,,,,,1.0,,,,,,,,,,,,,,155,162,151,160,141,155,136,150,132,144,122,135,72,82,38,43,7,14,0,0,,,,R-CVP: median not reached,CVP: median not reached,中位隨訪: 42月,CHOP vs R-CHOP ：I

26、II/IV 期濾泡淋巴瘤,428 pts FL, 20% IPI 3-5, 40% > age 60, stage III/IV18-month median follow-up,1GLGLSG Hiddemann et al. Blood. 2005;106:3725,PFS 3 Yrs OS 3 Yrs R-CHOP x 6-8 75% 95%

27、 CHOP x 6-8 51% 87% P<.001 P=.016,美羅華的維持治療,,Company Logo,E1496: ECOG and CALGB : CVPMaintenance Rituximab After CVP Results in Superior Clinical

28、Outcome in Follicular LymphomaHoward S. Hochster, Edie Weller, Randy D. Gascoyne, Theresa S. Ryan, Thomas M. Habermann, Stanley R. Frankel, and Sandra J. Horning,,,ECOG 1496: CVP誘導(dǎo)化療后R維持治療惰性NHL,RANDOMIZATI

29、ON,Untreatedlow-gradeIWF B-C,CVPCyclophosphamide day 1Vincristine day 1Prednisone days 1-5 every 21 days, 6-8 cycles,RESTAGING,CR,PR,SD,RANDOMIZATION,,,Rituximab MaintenanceRituximab 375 mg

30、/m2weekly x 4every 6 months,Observation,,,,,,,LR one-sided P = 0.0000003HR 0.4 (0.3,0.6),Years From Maintenance Randomization,Probability,MR (120),OBS (117),,ECOG 1496: PFS,Median PFS From Randomization: 15 mo vs. 6

31、1 mo*,* ~21 and ~67 mo from study entry.,LR one-sided P = 0.03HR = 0.5 (0.3,1.1),Years From Maintenance Randomization,Probability,MR (120),OBS (117),,ECOG 1496: OS,OS at 42* mo From Randomization: 91% vs. 75%,* ~48 mo

32、from study entry.,RANDOMIZED,CHOP every21 daysmaximum 6 cycles,Rituximab + CHOP every21 daysmaximum 6 cycles,EORTC ：復(fù)發(fā) 美羅華維持治療,RANDOMIZED,Observation,Rituximab maintenance*,CRPR,,*375 mg/m2 every 3

33、 months for 2 years or until relapse.,EORTC ：PFS結(jié)果,Median: 42.2m,Median: 11.6m,Median: 23.1m,Median: 51.9m,Subgroups According to Induction Treatment,Hazard ratio: 0.30,Hazard ratio: 0.54,,,,EORTC ：OS結(jié)果,,Van Oers, et al.

34、,Untreated patients with high tumor burden follicular lymphoma,Induction Immunochemotherapy8 cyclesR-CHOP orR-CVP orR-FCM,Rituximab maintenance375 mg/m2 q8w for 2 yrs(n = 505),Observation(n = 513),,,,,Response*

35、(N = 1019),*Only patients 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 randomizat

36、ion,,,5-yr follow-up,Salles GA, et al. ASCO 2010. Abstract 8004.,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)化療方案無關(guān)維持組中性粒細胞減少和感染的發(fā)生率高還需要更長時間的隨訪，獲得OS結(jié)果,Salles GA, et al. Lancet. 2011;377:42-51.,Maint Rituximab v

37、s Retreatment in Low Tumor Burden FL: Ph III E4402 (RESORT),Primary endpoint: TTFSecondary endpoints: time to first cytotoxic chemotherapy, safety/toxicity, QoL,Kahl BS, et al. ASH 2011. Abstract LBA-6.,,Patients with F

38、L and low tumor burden who received frontline rituximab*(N = 384),Maintenance Rituximab 375 mg/m2every 3 mos(n = 140),Retreatment at ProgressionRituximab 375 mg/m2/wk x 4 mos(n = 134),,,Patients with CR or PR(N

39、= 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 Chara

40、cteristics,Kahl BS, et al. ASH 2011. Abstract LBA-6.,E4402 (RESORT): Results,No difference in time to treatment failure between rituximab maintenance and retreatment groups (P = .80); P = .39 by sensitivity analysis,Kahl

41、 BS, et al. ASH 2011. Abstract LBA-6.,E4402 (RESORT): Results,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

42、-6.,Probability,1.0,0.8,0.6,0.4,0.2,0,0,1,2,3,4,5,6,7,Yr,2-sided log-rank P = .03,RetreatmentMaintenance,,,E4402 (RESORT): Results,At 12 mos post randomization, no difference between groups noted in quality-of-life, anx

43、iety measuresFew grade 3/4 adverse events reported in either arm, with grade 3 fatigue in 3 patients receiving maintenance rituximab as most common toxicity,Kahl BS, et al. ASH 2011. Abstract LBA-6.,Vidal L, et al. J Na

44、tl Cancer Inst. 2009;101:248-255.,Study or SubgroupMaintenance after first inductionGhielmini 2004Hochster 2005Hochster 2007Subtotal (95% CI)Heterogeneity: CHi2 = 3.57; df = 2 (P = .17); I2 = 44%Test for overall

45、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

46、 effect: Z = 3.43 (P = .0006),Log (HR)-0.025-0.67331.5067-0.72-0.862-0.1526-0.6676,SE0.70720.36371.1550.50.35160.28190.2629,Weight, %19.473.37.310010.220.732.137.0100,HR (95% CI)

47、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 MR,Favors Control,0.01,0.1,1,10,100,,,,,,,,

48、,,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胞移植疫苗,StiL: Bendamustine+R vs CHOP-R 一線治療惰性NHL,,,Patients withfrontlineiNHL or MCL(N = 549),CHOP-R q3w x 6(n = 253),Bendamustine-Rituximab q4w x 6(n = 260),(n = 513 evalua

49、ble patients),Rituximab 375 mg/m2 on Day 1; (bendamustine 90 mg/m2 on Days 1-2 q28 days) or (standard CHOP q21 days) x 6,Rummel MJ, et al. Blood. 2009;114. Abstract 405.,惰性淋巴瘤另一治療進展：苯達莫斯丁,StiL: 結(jié)果,PFS： MCL, WM, FL患者顯著獲益

50、濾泡淋巴瘤PFS : CHOP-R ： 46.7 m R-bendamustine ：未達到 (P = .0281),Rummel MJ, et al. Blood. 2009;114. Abstract 405.,Median observation time: 32 mos,StiL: PFS for FL Patients,Reprinted with permission. R

51、ummel MJ, et al. Blood. 2009;114. Abstract 405.,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,0,12,24,36,48,60,72,Mos,Probability of PFS,R-bendamustine,CHOP-R,,,R-bendamustine: not reached vs CHOP-R: 46.7 mos (median)HR: 0.

52、63 (95% CI: 0.42-0.95; P = .0281),StiL: 不良反應(yīng),Rummel MJ, et al. ASH 2009. Abstract 405.,First-line CHOP + Rituximab vs CHOP vs 131I-Tositumomab for FL: SWOG S0016,Primary endpoints: OS, PFSSecondary endpoints: response,

53、safety/toxicity, human anti–mouse antibody formation,Press 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 FL (bulky stage II, I

54、II, or IV)(N = 554),,,2 wks,,Tositumomab/ 131I-tositumomab,CHOP-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,

55、 134, and 141. CHOP-RIT: cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2, prednisone 100 mg/day for 5 days, followed 4 wks later by dosimetric infusion of tositumomab/131I-tositumomab, and follo

56、wed 1 wk later by 131I-tositumomab to a total dose of 75 cGY.,CHOP-R,CHOP-RIT,SWOG S0016: Results,No difference in response rates between treatments No difference in serious toxicities between treatmentsMore thrombocy

57、topenia with CHOP-RIT than CHOP-R (18% vs 2%),Press O, et al. ASH 2011. Abstract 98.,100,80,60,40,20,0,0,2,4,6,8,10,Yrs From Registration,Median FU: 4.9 yrs,CHOP-RIT,CHOP-R,CHOP-RIT,CHOP-R,2-sided, multivariate P = .11,A

58、t Risk265267,Event86106,2-YrEstimate80%76%,,,100,80,60,40,20,0,0,2,4,6,8,10,Yrs From Registration,Median FU: 4.9 yrs,CHOP-RIT,CHOP-R,CHOP-RIT,CHOP-R,2-sided, multivariate P = .08,At Risk265267,Event4026,2-Year

59、Estimate93%97%,,,Patients (%),PFS,OS,SWOG S0016: Prognostic Factor Analysis,Press O, et al. ASH 2011. Abstract 98.,*HRs show comparisons of high vs low risk.,病例1,周海玲，女，46歲2009.6發(fā)現(xiàn)右上頸腫物1.5cm2009.10原腫物上方又出現(xiàn)一約1cm腫物，伴輕度

60、潮熱、盜汗2009.11右頸腫物活檢病理：濾泡淋巴瘤II級，CD20++,CD10++, BCL-2++, BCL-6+,KI-67+ 30%CT：雙腮腺區(qū)、右頸臨界多發(fā)淋巴結(jié)，1.5cm大小,病例1,分期？,IIA,治療？,2009.12～2010.2 雙頸放療 30Gy,2011.3月CT：內(nèi)乳、縱隔淋巴結(jié)增大,治療2？,我們選擇：R-CVP+ R維持,病例2,XXX，男，45歲2002發(fā)現(xiàn)右側(cè)腹股溝蠶豆大腫物，質(zhì)地較軟，之后

61、發(fā)現(xiàn)左腹股溝腫物，3×2cm，無明顯增大左腹股溝淋巴結(jié)活檢病理：濾泡淋巴瘤1級， BCL-2+,BCL-6+, KI-67+ 約5%,病例2,2010.9月再次發(fā)現(xiàn)雙頸部多發(fā)淋巴結(jié)，右頸明顯，伴輕壓痛CT:雙頸、縱隔、腹腔、腹膜后、腋窩、腹股溝多發(fā)淋巴結(jié)，大者6.6cm,治療？,觀察等待,治療？,R-化療+R維持,病例3,李志龍，男，22歲2002發(fā)現(xiàn)右側(cè)腹股溝蠶豆大腫物，質(zhì)地較軟，之后發(fā)現(xiàn)左腹股溝腫物，3

62、15;2cm，無明顯增大2010.9月再次發(fā)現(xiàn)雙頸部多發(fā)淋巴結(jié)，右頸明顯，伴輕壓痛左腹股溝淋巴結(jié)活檢病理：濾泡淋巴瘤3級， BCL-2+,BCL-6+, KI-67+ 約50%CT:雙頸、縱隔、腹腔、腹膜后、腋窩、腹股溝多發(fā)淋巴結(jié)，大者6.6cm,病例3,分期？,IIIA,治療？,,應(yīng)選擇： 按照DLBCL:R-CHOP×6-8,謝謝大家 !,放射免疫治療,131I-tositumomab90Y-ibritum

63、omab tiuxetan,一線惰性淋巴瘤研究,Morschhauser F, et al. J Clin Oncol. 2008;26:5156-5164.,Induction,Start of Study,Consolidation,First-line therapy with chlorambucil, CVP, CHOP, CHOP-like, fludarabine combinations, or rituximab co

64、mbination,Notreached,PD,No inclusion,CR,Unconfirmed CR,PR,Random assignment,Rituximab 250 mg/m2 IVon Days -7 and 0 +90Y-ibritumomab tiuxetan14.8 MBq/kg (max 1148 MBq/kg) on Day 0,No additional treatment,Control,,,,,

65、SWOG 0016: R-CHOP vs CHOP + 131I-Tositumomab in Untreated FL,Endpoints: PFS, response rates, toxicity, and molecular response ratesResults expected in 2010,,R-CHOP x 6,CHOP x 6+ Tositumomab + 131I-tositumomab,RAND