彌漫大b細(xì)胞淋巴瘤治療新進(jìn)展

1、彌漫大B細(xì)胞淋巴瘤治療新進(jìn)展,張翼鷟天津醫(yī)科大學(xué)附屬腫瘤醫(yī)院血液科天津市腫瘤防治重點實驗室aprilzyz@yahoo.com,概述 流行病學(xué) 基于分子生物學(xué)改變的預(yù)后評價 治療進(jìn)展 初治的DLBCL 難治復(fù)發(fā)的DLBCL 新藥臨床試驗,概述,流行病學(xué),,,,,彌漫大B細(xì)胞淋巴瘤: 31%,濾泡性淋巴瘤:22%,邊緣區(qū)淋巴瘤:8%,套細(xì)胞淋巴瘤:6

2、%,小細(xì)胞淋巴瘤 7%,外周T細(xì)胞淋巴瘤:7%,,HL及NHL的發(fā)病率,,B-NHL 6632,66%,,UC 378,4%,,,HL 854,9%,,,T/NK-NHL 2138,21%,病例總數(shù)：10002,SMZL,41,1%,,,,,B-LBL,172,3%,UC,387,6%,DLBCL,NOS,3328,48%,,MCL,307,5%,,PCNs,221,3%,,BL,107,2%,MMZL,99,1%,LPL,57,1%,

3、,,,DLBCL,SS,378,6%,,MALTL,685,10%,,FL,551,8%,,CLL/SLL,424,6%,病例總數(shù)：6638,B-NHL亞型的發(fā)病率,DLBCL FL MALTL MCL CLL/SLL BL SMZL NMZL,彌漫大B細(xì)胞淋巴瘤,最常見的非霍奇金淋巴瘤: 31%發(fā)病高峰:60歲臨床表現(xiàn)及分子生物學(xué)特征: 高度異質(zhì)性 大細(xì)胞

4、 無淋巴濾泡結(jié)構(gòu)中位生存期: 數(shù)周/月(若不治療)30% 到 40% 伴有B 癥狀可能伴有結(jié)外病變(胃腸道, 中樞神經(jīng)系統(tǒng), 睪丸, 皮膚)Michallet AS, et al. Blood Rev. 2009;23:11-23.,2010年NCCN指南: Essential Diagnostic Assessments for DLBCL,對所有切片進(jìn)行血液病理學(xué)檢查(至少1個為含有腫瘤組織的

5、石蠟塊)淋巴結(jié)切檢當(dāng)淋巴結(jié)難以切除或切取活檢時,聯(lián)合FNA和空心針活檢并結(jié)合輔助檢查時免疫表型:(DLBCL typically CD20+, CD45+, CD3-)免疫組化(石蠟切片):CD20, CD3, CD4, CD10, CD45, BCL2, BCL6, Ki-67, IRF-4/MUM1流式細(xì)胞學(xué):CD45, CD3, CD5, CD19, CD10, CD20, kappa/lambdaNCCN Pr

6、actice Guidelines in Oncology. 2010.,彌漫大B細(xì)胞淋巴瘤的預(yù)后因素不良預(yù)后因素影響化療效果與生存期年齡>60歲LDH > 正常值一般狀態(tài)評分≥ 2Ann Arbor 分期 III/IV結(jié)外受累區(qū)> 1 個*,Prognostic for patients older than 60 yrs of age only.,International NHL Prognosis

7、Factors Project. N Engl J Med. 1993;329:987-994.,Yrs,Percent Survival,Very good,Good,Poor,P < .0001,基于修正IPI評分的總生存率,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,0,1,2,3,4,5,,,,Sehn LH, et al. Blood. 2007;109:1857-1861.,與彌

8、漫大B細(xì)胞淋巴瘤相關(guān)的分子遺傳學(xué)改變,遺傳學(xué)異常較常見染色體異位: ~ 50%DNA 失衡: 高達(dá)67%,Abramson JS, et al. Blood. 2005;106:1164-1174.,Yrs,OS,基因表達(dá)譜-分子水平將DLBCL分為不同的臨床亞型,1.0,0.8,0.6,0.4,0.2,0,0,2,4,6,8,10,,,,Rosenwald A, et al. J Exp Med. 2003;198:851-862

9、.,Rosenwald A, et al. N Engl J Med. 2002;346:1937-1947. Copyright © 2002 Massachusetts Medical Society. All rights reserved.,,,,0,0.2,0.4,0.6,0.8,1.0,0,4,8,Probability of Survival,,,,,,,,,,,,,6,10,,2,,,P < .001,Y

10、rs,不同亞型的DLBCL的生存期,Germinal-center B-cell like,Type 3,Activated B-cell like,基因表達(dá)譜-分子水平將DLBCL分為不同的臨床亞型,Bea S, et al. Blood. 2005;106:3183-3190.,Lenz G, et al. N Engl J Med. 2008;359:2313-2323.,CHOP-R治療方案對DLBCL亞型的預(yù)后具有價值,CHO

11、P-RituximabOS,1.0,0.8,0.6,0.4,0.2,0,Probability,0,1,2,3,4,5,6,Yrs,P = 4 x 10-3,,,CHOP-RituximabPFS,CHOPOS,1.0,0.8,0.6,0.4,0.2,0,0,1,2,3,4,5,6,Yrs,P = 1 x 10-4,,,1.0,0.8,0.6,0.4,0.2,0,0,1,2,3,4,5,Yrs,6,P = 8 x 10-6,,,G

12、CB DLBCL,ABC DLBCL,基于基因表達(dá)的風(fēng)險評分-- 預(yù)測DLBCL臨床結(jié)果,潛在的疾病生物學(xué)尚未確定研究目的:CHOP- 及R-CHOP治療后的DLBCL病人的基因表達(dá)特征III 期隨機(jī)實驗,E4494存檔的組織, (N = 632)CHOP vs R-CHOP ± rituximab 維持治療老年DLBCL病人石蠟包埋組織儲存> 10 yrs 經(jīng)過微陣列處理的相關(guān)

13、性研究指標(biāo):比例風(fēng)險模式 (FFS, OS),Winter JN, et al. ASH 2011. Abstract 87.,基于基因表達(dá)的風(fēng)險評分-- 預(yù)測DLBCL臨床結(jié)果,N = 183合格者, 可評估案例6 genes for R-CHOP5 genes for CHOP (single gene overlap [LMO2])High- vs low-gene risk scores

14、significantly predicted E4494 clinical outcome (median follow-up: 9.4 yrs),Winter JN, et al. ASH 2011. Abstract 87.,基于基因表達(dá)的風(fēng)險評分-- 預(yù)測DLBCL臨床結(jié)果,CHOP,R-CHOP,Winter JN, et al. ASH 2011. Abstract 87.,Probabilit

15、y,< Median≥ Median,< Median≥ Median,1.0,0.8,0.6,0.4,0.2,0,12,0,2,4,6,8,10,Yrs,FFS,P = .001,,,,,基于基因表達(dá)的風(fēng)險評分-- 預(yù)測DLBCL臨床結(jié)果,High- vs low-gene risk scores significantly predicted OSCHOP (median follo

16、w-up: 7.6 yrs; P < .0001)R-CHOP (median follow-up: 2.8 yrs; P = .0014)基因風(fēng)險評分—對調(diào)整后的IPI多元分析具有預(yù)測意義,Winter JN, et al. ASH 2011. Abstract 87.,基于基因表達(dá)的風(fēng)險評分-- 預(yù)測DLBCL臨床結(jié)果,該預(yù)測模型也可區(qū)分一些不同來源的細(xì)胞的差異CHOP: signific

17、ant difference among non–germinal center B-cell (GCB) cases (P = .0002)R-CHOP: significant difference among GCB cases (P = .03)Molecular predictors largely independent of IPI in both CHOP, R-CHOP patients,Winter JN, e

18、t al. ASH 2011. Abstract 87.,彌漫大B細(xì)胞淋巴瘤的治療進(jìn)展,初治DLBCL,CHOP ± Rituximab in DLBCL: GELA LNH-98.5 Phase III Study,Primary endpoint: EFSSecondary endpoints: OS, RR,R-CHOPevery 3 wks for 8 cycles(n = 202)

19、,CHOPevery 3 wks for 8 cycles(n = 197),Untreated elderly patients with stage II-IV DLBCL(N = 399),,Stratified by risk factors (0-1 vs 2-3),Assessment,,,,Coiffier B, et al. N Engl J Med. 2002;346:235-242. Feugier P,

20、 et al. J Clin Oncol. 2005;23:4117-4126.,Maint. Ritux. After R-CHOP or CHOP in Older DLBCL (E4494/C9793 Ph III Study),Primary endpoint: FFS,Morrison VA, et al. ASCO 2007. Abstract 8011.Habermann TM, et al. J Clin Oncol.

21、 2006;24:3121-3127.,Untreated patients with CD20+ DLBCL, 60 yrs of age or older, PS 0-3(N = 632),R-CHOP x 6-8 cycles(n = 318),CHOP x 6-8 cycles(n = 314),,,Stratified by IPI score (0-1 vs 2-4),,Responders(n = 415),M

22、aintenance Rituximabq6mos x 2 yrs, starting 4 wks after last cycle(n = 207),Observation(n = 208),,,Stratified by IPI score, CR/PR, induction,Cunningham D, et al. ASCO 2009. Abstract 8506.,Newly diagnosed CD20+ DLBCL

23、patients(N = 1080),R-CHOP-14 x 6 cycles +Rituximab x 8 cycles +Lenograstim on Days 4-12(n = 540),R-CHOP-21 x 8 cycles +Rituximab x 8 cycles(n = 540),,,Stratified by IPI score and age,R-CHOP-14 vs R-CHOP-21 in Newl

24、y Diagnosed DLBCL (Phase III Study),Primary endpoint: OSSecondary endpoint: FFS, toxicity, response rates,,Cunningham D, et al. ASCO 2009. Abstract 8506.,*249 patients not evaluable or data missing.,R-CHOP-14 vs R-CHOP-

25、21 in Newly Diagnosed DLBCL: Responses,LNH03-6B GELA: R-CHOP-14 vs R-CHOP-21 in Elderly DLBCL Patients,Primary endpoint: EFSSecondary endpoints: CR or CRu, ORR, PFS , DFS, OS, dose intensity, t

26、oxicity,Delarue R, et al. ASH 2009. Abstract 406.,R-CHOP every 14 days for 8 cycles + IT MTX for 4 cycles (n = 103),R-CHOP every 21 days for 8 cycles + IT MTX for 4 cycles (n = 99),DLBCL patients60-80 yrs of age(N

27、 = 202),,,,,,,ProphylacticDarbepoetin alfa,Conventional treatmentfor chemotherapy-induced anemia,ProphylacticDarbepoetin alfa,Conventional treatmentfor chemotherapy-induced anemia,LNH03-6B GELA Trial: Results,Delar

28、ue R, et al. ASH 2009. Abstract 406.,Hematologic toxicities greater for R-CHOP-14Patients on R-CHOP-14 had higher rates of febrile neutropenia, hospitalization, and death due to toxicity,LNH03-6B GELA Trial: Toxic

29、ities,,,,,,,,,,,,,,,R-CHOP-14,R-CHOP-21,11,15,22,21,36,50,22,26,69,83,73,83,Patients (%),100,90,80,70,60,50,40,30,20,10,0,Grade 3/4Leukocytes,Grade 3/4Neutrophils,Grade 3/4Hemoglobin,RBCTransfusion,Grade 3/4Platelet

30、s,PlateletTransfusion,Delarue R, et al. ASH 2009. Abstract 406.,Pfreundschuh M, et al. Lancet Oncol. 2006;7:379-391.,MInT: Ph III Study of CHOP-like Chemo ± Rituximab in Adv DLBCL (Younger Pts),Patients with untrea

31、ted CD20+ stage II-IV DLBCL (or bulky stage I), IPI 0-1, 18-60 yrs of age(N = 823),CHOP-like regimen*+ 30-40 Gy radiotherapy(n = 410),CHOP-like regimen* + Rituximab 375 mg/m2 + 30-40 Gy radiotherapy(n = 413),,,Cyc

32、le 6,,*CHOP-21, CHOEP-21, MACOP-B, or PMitCEBO.,Stratified by age-adjusted IPI score (0-1 vs 2-3), bulky disease, treatment center, and regimen,MInT: 6-Yr Follow-up Data,Current study presented 6-yr findings (N = 823),M

33、ultivariate analysis showed EFS influenced byRituximab (HR: 0.49; P < .001)Age-adjusted IPI (HR: 1.73; P < .001)Bulky disease (HR: 1.43; P = .004),Pfreundshuh M, et al. ASH 2010. Abstract 111.,R-EPOCH 方案,Give

34、n every 21 days for 4-6 cyclesRegimen consists ofRituximab 375 mg/m2 on Day 1Etoposide 65 mg/m2 continuous IV on Days 2-4Prednisone 60 mg/m2 PO on Day 1-14Vincristine 0.5 mg continuous IV on Day 2-4Cyclophosphamide

35、 750 mg/m2 IV on Day 5Doxorubicin 15 mg/m2 continuous IV on Days 2-4,Ph II Study of Dose-Adjusted EPOCH-R in DLBCL (CALGB 50103): PFS by IPI Score,Median potential follow-up: 54 mos5-yr PFS: 79%Low risk IPI: 91%Low-i

36、nt risk IPI: 90%High-int risk IPI: 67%High risk IPI: 47%IPI score significantly associated with PFS (P = .007),Wilson WH, et al. J Clin Oncol. 2008;26:2717-2724.,CALGB 50303: R-CHOP vs R-EPOCH in Newly Diagnosed DLBC

37、L,Primary endpoints: EFS, molecular predictors of outcome for each regimenSecondary endpoints: RR, OS, toxicity, use of molecular profiling for pathological diagnosis,R-CHOPevery 3 wks for 6 cycles,R-EPOCHDoxorubicin,

38、 etoposide, vincristine on Days 1-4, cyclophosphamide on Day 5,prednisone on Days 1-5,Untreated patients with newly diagnosedDLBCL(N = 478),,,ClinicalTrials.gov. NCT00118209.,Primary endpoints: OS and PFSClosed:

39、12/15/07 with 276 randomized patients,Patients with bulky stage II-IV, high-int or high-risk CD20+ NHL(N = 276),CHOP or R-CHOP for 5 cycles,,,PR or CR,CHOP or R-CHOP for 3 coursesNo additional therapy until progres

40、sion,CHOP or R-CHOP for 1 course + ASCT,,,Stratified by disease risk (int-high vs high),,Off therapy if < PR,ClinicalTrials.gov. NCT00004031.,Early vs Delayed HDT in High-Int/High-Risk DLBCL: Ph

41、ase III S9704 Study,復(fù)發(fā)難治 DLBCL,NCCN Guideline Recommendations for Treatment of Relapsed DLBCL,Second-line therapy in candidates for high-dose therapy + ASCTDHAP ± rituximabESHAP ± rituximabGDP ± rituxim

42、abGemOx ± rituximabICE ± rituximabminiBEAM ± rituximabMINE ± rituximab,Second-line therapy for patients who are not candidates for high-dose therapyClinical trialRituximabCEPP ± rituximab

43、PEPC EPOCH ± rituximab,NCCN Practice Guidelines in Oncology. 2010.,治療DLBCL的新藥臨床試驗,DLBCL研究中的藥物 (Off-Label Use),Bevacizumab 貝伐單抗 —recombinant, humanized, monoclonal VE

44、GF antibodyBortezomib 硼替佐米—proteasome inhibitorEnzastaurin —PKCβ-selective inhibitorEpratuzumab 依帕珠單抗—recombinant, humanized, monoclonal CD22 antibodyEverolimus

45、 依維莫司—mTOR inhibitorLenalidomide 雷利度胺—immunomodulator, antiangiogenicRadioimmunotherapy Fostamatinib —specific inhibitor of Syk in B-cell signaling pathway,治療DLBCL的研究中

46、的藥物: Phase II Data,1. Micallef IN, et al. ASCO 2008. Abstract 8500. 2. Zinzani PL, et al. Ann Oncol. 2008;19:769-773. 3. Haioun C, et al. ASCO 2010. Abstract 8069. 4. Friedberg JW, et al. Blood. 2010;115:2578-2585. 5.

47、Wiernik PH, et al. J Clin Oncol. 2008;26:4952-4957.,Bortezomib (硼替佐米)+ CHOP-R作為DLBCL的一線治療,Phase I/IIN = 40 patients with previously untreated DLBCLCHOP-21 + rituximab 375 mg/m2 each cycle Bortezomib given at 3 differ

48、ent dosesArm 0 (n = 4): 0.7 mg/m2Arm 1 (n = 8): 1.0 mg/m2Arm 2 (n = 28): 1.3 mg/m2,Median follow-up: 21 mos (range: 9-35)ORR resultsITT (n = 40): 90% (CR/CRu: 68%)Evaluable (n = 36): 100% (CR/CRu: 75%)Estimated 2

49、-yr PFS: 72%Treatment generally well tolerated4 deaths prior to first response assessment,Leonard JP, et al. ASCO 2007. Abstract 8031.,Bendamustine (苯達(dá)莫司汀) + Rituximab for Rel/Ref DLBCL: Phase II Study,Day 1: bendamust

50、ine 120 mg/m2 + rituximab 375 mg/m2 ; Day 2: bendamustine 120 mg/m2ORR of 60% required by study design,Bendamustine + Rituximab28-day cycles for 6 cycles,Patients with relapsed/refractory DLBCL whofailed at least

51、1 previous therapy(N = 25, ITT),Vacirca JL, et al. ASCO 2010. Abstract 8041.,Bendamustine+ Rituximab for Rel/Ref DLBCL: Preliminary Phase II Results,Vacirca JL, et al. ASCO 2010. Abstract 8041.,Everolimus(依維莫司): Ongoi

52、ng Phase II and III Studies in DLBCL,Phase IIEverolimus plus rituximab in relapsed/refractory DLBCL[1]Everolimus, panobinostat, or both in relapsed/refractory DLBCL[2]Everolimus in relapsed/refractory lymphoma[3]Phas

53、e IIIEverolimus as adjuvant therapy following CR to first-line rituximab-chemotherapy in patients with poor-risk DLBCL[4],1. ClinicalTrials.gov. NCT00869999. 2. ClinicalTrials.gov. NCT00978432. 3. ClinicalTrials.gov.

54、NCT00436618. 4. ClinicalTrials.gov. NCT00790036.,Phase IIR-CHOP plus bevacizumab for first-line treatment of DLBCL[1]Bevacizumab plus R-CHOP for first-line treatment of stage II-IV DLBCL[2]Phase IIIR-CHOP vs R-CHOP

55、plus bevacizumab for first-line treatment of DLBCL[3],Bevacizumab(貝伐單抗): Ongoing Phase II and III Studies in DLBCL,ClinicalTrials.gov. NCT00788606. ClinicalTrials.gov. NCT00121199. 3. ClinicalTrials.gov. NCT00486759,謝謝