彌漫性大B細(xì)胞淋巴瘤的診斷與治療現(xiàn)狀和進(jìn)展

1、MZL + MALT17%MCL6%DLBCL30%LL 1%BL3%HIV/PTL2%Unclassified2%SLL/CLL10%CTCL1%FL21%-35%ALCL1%PTCL6%B細(xì)胞慢性淋巴細(xì)胞白血病濾胞型淋巴瘤彌漫性大細(xì)胞性淋巴瘤Burkitt淋巴瘤套細(xì)胞淋巴瘤間變型大細(xì)胞淋巴瘤皮膚型T細(xì)胞淋巴瘤T細(xì)胞白血病結(jié)外邊緣區(qū)B細(xì)胞淋巴瘤黃色字體的分類是在2007年3月由WHO淋巴瘤臨床咨詢委員會(huì)建議增加的。DLBCLDLBCL的細(xì)胞來(lái)源的細(xì)胞來(lái)源原發(fā)結(jié)外：原發(fā)結(jié)外：CNS、皮膚、胃、睪丸等、皮膚、胃、睪丸等v直接發(fā)生直接發(fā)生(de novo)v低度惡性淋巴瘤轉(zhuǎn)化而來(lái)原發(fā)結(jié)淋巴：原發(fā)結(jié)

2、淋巴：DLBCLDLBCL臨床病理亞型臨床病理亞型v原發(fā)縱隔原發(fā)縱隔(胸腺胸腺)B細(xì)胞淋巴瘤細(xì)胞淋巴瘤v原發(fā)滲出性原發(fā)滲出性淋巴瘤淋巴瘤v血管內(nèi)大血管內(nèi)大B細(xì)胞淋巴瘤細(xì)胞淋巴瘤Plasmablastic lymphoma ALK positivePossible distinct entitiesMorphological variantsCentroblasticImmunoblasticT-cell/histiocytic richA suite of transcription factors shapes the phenotype of the germinal-centerB ce

3、ll (Fig. 1).一系列轉(zhuǎn)錄因子使生發(fā)中心B細(xì)胞表型成型 示意圖1例NHL 彌漫大B 治療前治療后IPI：低危 0-1 低中危 2 高中危 3 高危 4-5所有患者：危險(xiǎn)因素所有患者：危險(xiǎn)因素 年齡60 LDH1正常值 PS 24 或 結(jié)外累及1個(gè)部位年齡調(diào)整年齡調(diào)整IPI (aaIPI) : 患者患者60危險(xiǎn)因素危險(xiǎn)因素 或或 PS 2-4 LDH1正常值正常值The International Non-Hodgkins Lymphoma Prognostic Factors Project. N Engl J Med 1993; 329:987994.Low riskLow inte

4、rmediate riskHigh intermediate riskHigh riskTime (years)Proportion (%)02550751000248610Overall survival(n = 2,031)Rosenwald A et al. N Engl J Med. 2002;346:1937-1947.ActivatedB-celllikeType 3Germinal-centerB-celllikeOverall survival (years)Probability02468101.00.50.0HighLevel of geneexpressionLowGer

5、minal-centerB-celllikeType 3ActivatedB-celllikeGenesDLBCLDLBCL的治療的治療六、六、其他方案：CHOEPCHOP14R-CHOP14IPI評(píng)分AaIPI評(píng)分R-CHOP成為新的標(biāo)準(zhǔn)一線治療方案利妥昔單抗免疫化療CHOP 成為標(biāo)準(zhǔn)一線治療方案第三代化療方案CHOP21世紀(jì)1990s晚期1990s早期1980s晚期1980s早期CRPrimary RefractoryCureRelapseSecond Line R - ChemotherapySecond Line R - ChemotherapyInvestigational or B

6、SCNRCR/PRInvestigational or BSCHDT/SCT (R)-CHOPDLBCL的治療策略的治療策略Glick J et al. Proc Am Soc Clin Oncol. 1995:391.Miller TP et al. N Engl J Med. 1998;339:21-26.Horning S et al. Blood. 2001;98:724a. Abstract 3023.Fillet G et al. Blood. 2002;100:92a. Abstract.ECOG 試驗(yàn)試驗(yàn)(Glick J 等；等；Horning S 等等) I期巨塊型和期巨塊型

7、和II期期 CHOP (6-8個(gè)周期個(gè)周期) 達(dá)完全緩解的患者，接受放射治達(dá)完全緩解的患者，接受放射治療療(RT) vs CHOP治療治療 10年時(shí)，年時(shí)， CHOP-RT組的組的 DFS (無(wú)病生存無(wú)病生存) 和和TTP (至進(jìn)展時(shí)間至進(jìn)展時(shí)間) 更佳，但兩治療組的疾病特異性生存率更佳，但兩治療組的疾病特異性生存率均為均為 81% SWOG 試驗(yàn)試驗(yàn)(Miller TP等等) I 和和II期，非巨塊型期，非巨塊型 CHOP (3 個(gè)周期個(gè)周期) + RT vs CHOP (8 個(gè)周期個(gè)周期) 9年時(shí)，年時(shí)， CHOP-RT組的組的 DFS and TTP更佳更佳 ，且，且毒性更低，但毒性更低

8、，但OS (總體生存總體生存) 相似相似 GELA 試驗(yàn)試驗(yàn)(Fillet G等等) 老年，老年，IPI = 0 CHOP (4 個(gè)周期個(gè)周期) + RT vs CHOP CR、5年年EFS或或5年年OS均無(wú)改善均無(wú)改善RCHOP x 4CHOP x 4 + RT020406080100012345678910 11YearsSurvival (%)CHOP x 4 (n = 277)CHOP x 4 + RT (n = 299)P = 0.6Median follow-up: 6.6 yearsFillet G, et al. ASH 2005; Abstract accepted. pts

9、 60 y; aa-IPI 0 SWOG 0014無(wú)進(jìn)展生存無(wú)進(jìn)展生存SWOG-0014登記后年數(shù) 風(fēng)險(xiǎn)例數(shù) 復(fù)發(fā)或死亡 2年估計(jì)值S0014 62 694% SWOG 0014100806040200051015YearsFisher. N Engl J Med 1993;328:10026Overall survival (%)Milpied N, et al. New Engl J Med 2004; 350:12871295 updated. IPI 2: n = 101100806040200706050403020100MonthsEvent-free survivalP = 0.

10、002BEAM + auto: n = 55 CHOP: n = 4656%27%Haioun C, et al. J Clin Oncol 2000; 18:30253030. MonthsDFSP = 0.02020406080100024487296120144% survival100Induction phase ACVBP: 4 cyclesCRSequential consolidationMTX / IFM- VP16 / L-Aspa / Ara-CMTX / CBV + autoRANDOMIZATIONIPI 23: n = 236OSP = 0.040204060800

11、24487296120144Months 10 12 14 16 18 20 22 26WeeksACVBPRESPONSERESPONSE0 2(3) 4(6) 6(9) MTX 3 g/m Ara-C S.C 100 mg/m/d x 4dI II III IVCONSOLIDATIONINDUCTIONDoxorubicin75 mg/m d1Cyclophosphamide 1200 mg/m d1Vindesine2 mg/m d1, d5Bleomycin10 mg d1, d5Prednisone60 mg/m d1 to d5MTX intra-thecal15 mg d2G-

12、CSF 5 g/kg d6 to d13Doxorubicin50 mg/mCyclophosphamide 750 mg/mVincristine 1.4 mg/mPrednisone60 mg/m8 cycles, d1 = d21 Standard CHOPIFM 1500 mg/mVP16 300 mg/mTilly H, et al. Blood 2003; 102:42844289.ACVBPCHOPP = 0.030366039121315171819 21 23 25 2791521ACVBPCHOPMTX IFM - VP16 ARA-CWeekWeekACVBPCHOPP

13、= 0.005OSDFS02040608010002468Years% survival02040608010002468Years% survivaln = 635; 6169 yearsaa-IPI 1 = 35%aa-IPI 2 = 43%aa-IPI 3 = 23%Tilly H, et al. Blood 2003; 102:42844289.All patients n = 647CHOP + radiotherapy n = 329OS (%)020406080100012345678910 11Years after randomizationACVBP n = 318P =

14、0.001Median follow-up: 7.7 yearsReyes F, et al. New Engl J Med 2005; 352:11971205. Non-bulky patients n = 574CHOP + radiotherapy n = 288ACVBP n = 286P = 0.01Median follow-up: 7.7 years020406080100012345678910 11Years after randomizationRACVBP x 3 + sequential consolidationCHOP x 3 + involved field r

15、adiotherapypts 61 y; aa-IPI 0CHOP-21CHOP-21CHOEP-21CHOEP-21R R-CHO(E)P-21-CHO(E)P-21R R-CHOP-21-CHOP-21隨機(jī)隨機(jī)2x2 變量因子變量因子 研究設(shè)計(jì)研究設(shè)計(jì)N=7106 x CHOP-21+ 36 Gy (Bulk, E)6 x CHOEP-21+ 36 Gy (Bulk, E)6 x CHOP-14+ 36 Gy (Bulk, E)6 x CHOEP-14+ 36 Gy (Bulk, E)DSHNHL 09-19-00年輕低危年輕低危DLBCLDLBCL的的NHL-B-1NHL-B-1研究研究

16、 CHOP vs. CHOEP CHOP vs. CHOEP 無(wú)失敗時(shí)間無(wú)失敗時(shí)間 (TTF) (TTF)比較比較9080706050403020100..月月Pfreundschuh et al., Blood 2004, 104: 626-633Pfreundschuh et al., Blood 2004, 104: 626-633CHOEP-21CHOEP-21CHOP-21CHOP-21(n=362)(n=362)(n=348)(n=348)p=0.004p=0.004概率概率顯示顯示CHOEP方案優(yōu)方案優(yōu)于于CHOP6 CHOP樣樣 +

17、利妥昔單抗利妥昔單抗 30-40 Gy*(n=413)RANDOMIZE初治初治CD20+ DLBCL年齡年齡 18-60 y,II-IV期或期或伴有巨塊伴有巨塊 的的 I 期期IPI 0 or 1(N=824)6 CHOP樣樣 30-40 Gy*(n=410)*RT given to bulky or EN sites.Updated from Pfreundschuh et al. Blood. 2004;104:48a. Abstract 157.此項(xiàng)分析對(duì)比了此項(xiàng)分析對(duì)比了 CHOP 和和CHOEP方案的患者方案的患者, 因此因此, MACOP-B 和和 PMitCEBO 方案的患者沒

18、有包括在研究方案的患者沒有包括在研究之內(nèi)之內(nèi).Pfreundschuh et al. JCO 23: 567s, 2005 (abst 6529).CR/CRuCR/CRuPRPRNCNCPDPD治療期間死亡治療期間死亡美羅華美羅華-Chemo-Chemo(n=350)(n=350)* * (%)(%) 86%86%* * *5%5%3%3%4%4%* * * *1%1%ChemoChemo(n=346)(n=346)* *(%)(%) 68%68% 15%15%5%5%11%11%* * * 1%1%* * * * p=0.001p=0.001* * * p0.000 00005p0.000

19、 00005 Pfreundschuh M, et al. Blood 2004;104:40a (Abstract 157)* * 可評(píng)估患者可評(píng)估患者CHOPCHOP類類方案方案 美羅華美羅華治療初治治療初治DLBCL(MInTDLBCL(MInT研究研究) )緩解率緩解率50454035302520151050Time to treatment failure1.00.20.080% R-Chemo61% ChemoP 0.0001median follow-up: 22 months CR + CRu = 86%CR + CRu = 68%Pfreundschuh M

20、, et al. Blood 2004; 104:Abstract 157. MonthsPfreundschuh M, et al. Blood 2004; 104:Abstract 157. Lymphoma-associated deaths:Chemo: 42R-Chemo:13R-ChemoChemo95%86%P 0.0002median observation time: 23 monthsTime to treatment failure1.00.20.050454035302520151050MonthsR-CHOP (N = 199, 82.9%)R-CH

21、OEP (N = 181, 80.4%)CHOP (N = 19, 55.3%)CHOEP (N = 180, 65.1%)P .0001P = 0.67P = .0006P = .04Pfreundschuh et al. JCO 23: 567s, 2005 (abst 6529).2年年TTF Pfreundschuh M, et al. Lancet Oncol 2006;7:379-91CHOPCHOP類方案方案 美羅華治療初治美羅華治療初治DLBCL (MInTDLBCL (MInT研研究究) ) 美羅華CHOP治療初治年輕低危DLBCL 顯示生存益處顯示生存益處: 不增加化療毒性

22、不增加化療毒性 6療程美羅華療程美羅華CHOP成為標(biāo)準(zhǔn)方案成為標(biāo)準(zhǔn)方案小小 結(jié)結(jié)0 0202040400 01 12 23 34 4CHOP-21CHOP-21(1975-2001)(1975-2001)CHOEP-21CHOEP-21(2001-2003)(2001-2003)R-CHOP-21R-CHOP-21(2005)(2005)% % 生存生存月月年輕低危年輕低危DLBCLDLBCL的一線治療的方案演進(jìn)從的一線治療的方案演進(jìn)從CHOEP-21CHOEP-21到到R R-CHOP-21 -CHOP-21 MInT MInT研究研究對(duì)于年輕預(yù)后良好患者對(duì)于年輕預(yù)后良好患者CHOP-21C

23、HOP-21CHOP-14CHOP-14R-CHOP-21R-CHOP-21R-CHOP-14 ?R-CHOP-14 ?特殊措施特殊措施: 正式療程前的治療正式療程前的治療正式療程前的治療正式療程前的治療:Vincristin 1 mgi.v. Day 7Prednisone 100 mgp.o. Days 7 to 1效果效果: 改善一般狀況改善一般狀況 防止腫瘤溶解綜合征防止腫瘤溶解綜合征% therapy-associated deaths* DSHNHL NHL-B2 Trial 9080706050403020100..CHOEP-14 (

24、n=169)CHOEP-21 (n=170)CHOP-21 (n=178)CHOP-14 (n=172)月月56 %56 %42 %42 %69 %69 %49 %49 %CHOP-14 CHOP-14 vs. vs. CHOP-21CHOP-21p 0.001p 0.001NHL-B-2NHL-B-2研究（研究（DSHNHLDSHNHL） CHOP-14 vs. CHOP-21 (CHOP-14 vs. CHOP-21 (老年老年DLBCL)DLBCL)總生存時(shí)間總生存時(shí)間 (OS)(OS)n = 6896 cyclesAa-IPI 01: 76%020406080100CHOEP-21CH

25、OP-21CHOEP-14CHOP-14Relative risk CHOP-14 vs CHOP-21 = 0.58(P 60 y01020304050607080011: 6 x CHOP 14 (n=307)2: 8 x CHOP 14(n=305)3: 6 x R-CHOP 14(n=306)4: 8 x R-CHOP 14(n=304)1, 2: p=0.6161, 3: p0.0011, 4: p=0.0013, 4: p=0.317MonthsProportionRICOVER-60- Progression-free Sur

26、vival -3-year rates:73.4%68.8%56.9%56.9%8x CHOP 146x CHOP 148x R - 6x CHOP 14Pfreundschuh et al., Lancet Oncol. (2008)8x R - 8x CHOP 14DLBCL利妥昔單抗維持治療 1. 1. 應(yīng)用試驗(yàn)性藥物應(yīng)用試驗(yàn)性藥物 2. 2. 增加化療密度或強(qiáng)度的化療方案聯(lián)合增加化療密度或強(qiáng)度的化療方案聯(lián)合 美羅華的研究尚在進(jìn)行中美羅華的研究尚在進(jìn)行中 3. 3. 干細(xì)胞移植干細(xì)胞移植 HDT-ASCT作為一線治療作為一線治療用于預(yù)后不良的侵襲性用于預(yù)后不良的侵襲性NHL復(fù)發(fā)復(fù)發(fā)/難治

27、性難治性DLBCL的解救治療的解救治療DLBCL一線化療后的結(jié)果一線化療后的結(jié)果 5%10%為原發(fā)耐藥為原發(fā)耐藥 5%15%僅獲得部分緩解僅獲得部分緩解 (PR) 20%在完全緩解在完全緩解 (CR) 后復(fù)發(fā)后復(fù)發(fā) 根據(jù)根據(jù)IPI，30%的低危和的低危和60%的高?；颊咝枰邮艿母呶；颊咝枰邮?解救治療解救治療 需要更好的一線化療和解救治療方案需要更好的一線化療和解救治療方案 需要個(gè)體化治療需要個(gè)體化治療難治性難治性/復(fù)發(fā)病例復(fù)發(fā)病例不適宜大劑量治療不適宜大劑量治療適宜大劑量治療適宜大劑量治療臨床試驗(yàn)或二線治療臨床試驗(yàn)或二線治療推薦的方案推薦的方案CR或或PRNR適宜造血干細(xì)胞移植適宜造血干

28、細(xì)胞移植臨床試驗(yàn)、個(gè)體化治療臨床試驗(yàn)、個(gè)體化治療2周期周期DHAP(n=215)4周期周期DHAP放療放療(n=54)BEAC+ABMT+放療放療(n=55)隨隨機(jī)機(jī)化化CR/PR（n=109） Relapsed intermediate and high-grade (Working Formulation) No bone marrow (BM) or central nervous system (CNS) involvementPhilip T, et al. N Engl J Med 1995;333;1540 & ASCO 1998:17:16ap = 0.002Trans

29、plantation(N = 55)41%13%Conventional treatment(N = 54)% Event-free survivalMonths after randomizationPhilip T, et al. N Engl J Med 1995;333:15405誘導(dǎo)化療誘導(dǎo)化療各種二線方案的選擇？各種二線方案的選擇？Bosly et al. 2001Most Used 2nd Line Regimens誘導(dǎo)化療誘導(dǎo)化療美羅華在誘導(dǎo)化療的作用？美羅華在誘導(dǎo)化療的作用？來(lái)自來(lái)自MSKCC的前瞻性研究的前瞻性研究ICERICEP valueCR2-yPFS27%43%56

30、%53%54%67%0.010.250.53Moskowitz C, et al. J Clin Oncol 1999; 17:3776Kewalramani T, et al. Blood 2004; 103:3684+=2-y OS無(wú)論哪種化療方案，均可聯(lián)合美羅華無(wú)論哪種化療方案，均可聯(lián)合美羅華誘導(dǎo)化療誘導(dǎo)化療在利妥昔單抗時(shí)代，什么是最佳的挽救治療方案在利妥昔單抗時(shí)代，什么是最佳的挽救治療方案? ? R-ICE比較比較 R-DHAP 治療復(fù)發(fā)治療復(fù)發(fā)CD20陽(yáng)性彌漫大陽(yáng)性彌漫大B細(xì)胞細(xì)胞淋巴瘤（淋巴瘤（DLBCL）患者繼之自身干細(xì)胞移植）患者繼之自身干細(xì)胞移植: CORAL研究研究 C.

31、Gisselbrecht, B. Glass, N. Mounier, D. Gill, D. C. Linch, M. Trneny,A. Bosly, O. Shpilberg, H. Hagberg, N. Ketterer, D. Ma, P. Gaulard,C. Moskowitz, and N. Schmitz. R-ICE x 3R-DHAP x 3RANDOMIZERANDOMIZESD/PD OffPR/CR A BS EC AT MRx6觀察觀察N=400l 哪種挽救方案更好哪種挽救方案更好?l 移植后免疫治療的地位移植后免疫治療的地位? Orlando ASCO May

32、 2009 / Coral study C. GisselbrechtCD20+ DLBCL復(fù)發(fā)復(fù)發(fā)/難治難治Orlando ASCO May 2009 / Coral study C. GisselbrechtOrlando ASCO May 2009 / Coral study C. GisselbrechtR-ICE Versus R-DHAP Followed By ASCT and Maintenance Rituximab or Observation in Relapsed DLBCL (CORAL): EfficacyGisselbrecht et al. J Clin Onc

33、ol 2009; 27(suppl): 793s (abstract 8509).R-ICE Versus R-DHAP Followed By ASCT and Maintenance Rituximab or Observation in Relapsed DLBCL (CORAL): Survival OutcomesGisselbrecht et al. J Clin Oncol 2009; 27(suppl): 793s (abstract 8509).Orlando ASCO May 2009/Coral study C. GisselbrechtOverall survivalA

34、ccording to TreatmentARM (Induction ITT)Progression-free SurvivalAccording to Treatment ARM (Induction ITT)Orlando ASCO May 2009/Coral study C. GisselbrechtProgression-freeSurvival According toFailure fromDiagnosis (Induction ITT)Progression-free SurvivalAccording to Prior Rituximab(Induction ITT)Event-free Survi