弥漫大B细胞淋巴瘤治疗新进展-(1).ppt

弥漫大弥漫大B细胞淋巴瘤细胞淋巴瘤治疗新进展治疗新进展 张翼鷟张翼鷟天津医科大学附属肿瘤医院血液科天津市肿瘤防治重点实验室 概述概述 流行病学流行病学 基于分子基于分子生物学生物学改变改变的的预后评价预后评价 治疗进展治疗进展 初治的初治的DLBCL 难治复发的难治复发的DLBCL 新药临床试验新药临床试验概述流行病学流行病学弥漫大B细胞淋巴瘤:31%滤泡性淋巴瘤:22%边缘区淋巴瘤:8%套细胞淋巴瘤:6%小细胞淋巴瘤 7%外周T细胞淋巴瘤:7%HL及及NHL的发病率的发病率B-NHL 6632,66%UC 378,4%HL 854,9%T/NK-NHL 2138,21%病例总数：10002SMZL,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%DLBCL,SS,378,6%MALTL,685,10%FL,551,8%CLL/SLL,424,6%病例总数：6638B-NHL亚型的发病率亚型的发病率DLBCL FL MALTL MCL CLL/SLL BL SMZL NMZL弥漫大B细胞淋巴瘤最常最常见见的非霍奇金淋巴瘤的非霍奇金淋巴瘤:31%发发病高峰病高峰:60岁岁临临床表床表现现及分子生物学特征及分子生物学特征:高度异高度异质质性性 大大细细胞胞 无淋巴无淋巴滤滤泡泡结结构构中位生存期中位生存期:数周数周/月月(若不治若不治疗疗)30%到到 40%伴有伴有B 症状症状可能伴有可能伴有结结外病外病变变(胃胃肠肠道道,中枢神中枢神经经系系统统,睾丸睾丸,皮肤皮肤)Michallet AS,et al.Blood Rev.2009;23:11-23.2010年年NCCN指南指南:Essential Diagnostic Assessments for DLBCL对所有切片进行血液病理学检查对所有切片进行血液病理学检查(至少至少1个为含有肿瘤组织的石蜡块个为含有肿瘤组织的石蜡块)淋巴结切检淋巴结切检当淋巴结难以切除或切取活检时当淋巴结难以切除或切取活检时,联合联合FNA和空心针活检并结合辅助检查和空心针活检并结合辅助检查时免疫表型时免疫表型:(DLBCL typically CD20+,CD45+,CD3-)免疫组化免疫组化(石蜡切片石蜡切片):CD20,CD3,CD4,CD10,CD45,BCL2,BCL6,Ki-67,IRF-4/MUM1流式细胞学流式细胞学:CD45,CD3,CD5,CD19,CD10,CD20,kappa/lambdaNCCN Practice Guidelines in Oncology.2010.危险分组危险分组危险因素危险因素,n完全完全缓解缓解,%5年生存年生存率率,%Patients(all ages)低危0-18773中低危26751中高危 35543高危4-54426Patients 60 yrs of age or younger低危09283中低危17869中高危25746高危34632弥漫大弥漫大B细胞淋巴瘤的细胞淋巴瘤的预后因素预后因素不良预后因素影响化疗效果与生存期年龄60岁LDH 正常值一般状态评分 2Ann Arbor 分期 III/IV结外受累区 1 个*Prognostic for patients older than 60 yrs of age only.International NHL Prognosis Factors Project.N Engl J Med.1993;329:987-994.YrsPercent SurvivalVery goodGoodPoorP .0001基于修正基于修正IPI评分的总生存率评分的总生存率1.00.90.80.70.60.50.40.30.20.10012345Sehn LH,et al.Blood.2007;109:1857-1861.与弥漫大与弥漫大B细胞淋巴瘤相关的分子遗传学改变细胞淋巴瘤相关的分子遗传学改变遗传学异常较常见染色体异位:50%DNA 失衡:高达67%Gene(s)Affected/DisregulatedFrequency,%Predominant Causal Genetic AbnormalityMultiple45Aberrant SHMBcl-635-403q27 translocationsBcl-215/24t(14;18)/amplificationFas(CD95)2010q24 mutationsp531617p mutations/deletionsc-Myc15t(8;14)Potentially c-Rel142p13 amplificationAbramson JS,et al.Blood.2005;106:1164-1174.YrsOSDLBCL 亚型亚型5年生存率年生存率,%PMBL64GCB DLBCL59ABC DLBCL30基因表达谱基因表达谱-分子水平将分子水平将DLBCL分为不同的临床分为不同的临床亚型亚型1.00.80.60.40.200246810Rosenwald A,et al.J Exp Med.2003;198:851-862.Rosenwald A,et al.N Engl J Med.2002;346:1937-1947.Copyright 2002 Massachusetts Medical Society.All rights reserved.00.20.40.60.81.0048Probability of Survival6102P 10 yrs 经过微阵列处理的相关性研究指标:比例风险模式(FFS,OS)Winter JN,et al.ASH 2011.Abstract 87.基于基因表达的风险评分基于基因表达的风险评分-预测预测DLBCL临床结果临床结果N=183合格者,可评估案例6 genes for R-CHOP5 genes for CHOP(single gene overlap LMO2)High-vs low-gene risk scores significantly predicted E4494 clinical outcome(median follow-up:9.4 yrs)Winter JN,et al.ASH 2011.Abstract 87.基于基因表达的风险评分基于基因表达的风险评分-预测预测DLBCL临床结果临床结果CHOPR-CHOPWinter JN,et al.ASH 2011.Abstract 87.Probability1.00.80.60.40.201202468 10YrsFFSP=.003 Median Median1.00.80.60.40.201202468 10YrsOSP=.001 Median Median1.00.80.60.40.201202468 10YrsFFSP=.0011.00.80.60.40.201202468 10YrsOSP=.0015基于基因表达的风险评分基于基因表达的风险评分-预测预测DLBCL临床结果临床结果High-vs low-gene risk scores significantly predicted OSCHOP(median follow-up:7.6 yrs;P .0001)R-CHOP(median follow-up:2.8 yrs;P=.0014)基因风险评分对调整后的IPI多元分析具有预测意义Multivariate Analysis VariableHR for OSP ValueCHOP gene risk score2.39.0001CHOP IPI0.28.0001R-CHOP gene risk score1.82.06R-CHOP IPI0.38.002Winter JN,et al.ASH 2011.Abstract 87.基于基因表达的风险评分基于基因表达的风险评分-预测预测DLBCL临床结果临床结果该预测模型也可区分一些不同来源的细胞的差异CHOP:significant difference among nongerminal 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 patientsWinter JN,et al.ASH 2011.Abstract 87.IPI AdjustmentHRP ValueCHOPNone0.30.0001Gene risk score0.28.0001Cell of origin0.32.0001R-CHOPNone0.35.0006Gene risk score0.38.0016Cell of origin0.40.0026弥漫大弥漫大B细胞淋巴瘤的细胞淋巴瘤的治疗进展治疗进展初治初治DLBCLCHOP Rituximab in DLBCL:GELA LNH-98.5 Phase III StudyPrimary endpoint:EFSSecondary endpoints:OS,RRR-CHOPevery 3 wks for 8 cycles(n=202)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)AssessmentCoiffier B,et al.N Engl J Med.2002;346:235-242.Feugier P,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:FFSMorrison VA,et al.ASCO 2007.Abstract 8011.Habermann TM,et al.J Clin Oncol.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)Maintenance Rituximabq6mos x 2 yrs,starting 4 wks after last cycle(n=207)Observation(n=208)Stratified by IPI score,CR/PR,inductionCunningham D,et al.ASCO 2009.Abstract 8506.Newly diagnosed CD20+DLBCLpatients(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 ageR-CHOP-14 vs R-CHOP-21 in Newly Diagnosed DLBCL(Phase III Study)Primary endpoint:OSSecondary endpoint:FFS,toxicity,response ratesResponse(Based on End of Treatment Scan),%R-CHOP-21(n=405*)R-CHOP-14(n=426*)CR/CRu(P=.183)6358CR/CRu/PR(P=.139)8891 CR4940 CRu1418 PR2432SD65PD/relapse64Cunningham D,et al.ASCO 2009.Abstract 8506.*249 patients not evaluable or data missing.R-CHOP-14 vs R-CHOP-21 in Newly Diagnosed DLBCL:ResponsesLNH03-6B GELA:R-CHOP-14 vs R-CHOP-21 in Elderly DLBCL PatientsPrimary endpoint:EFSSecondary endpoints:CR or CRu,ORR,PFS,DFS,OS,dose intensity,toxicityDelarue 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=202)ProphylacticDarbepoetin alfaConventional treatmentfor chemotherapy-induced anemiaProphylacticDarbepoetin alfaConventional treatmentfor chemotherapy-induced anemiaLNH03-6B GELA Trial:Results OutcomeR-CHOP-21(n=99)R-CHOP-14(n=103)P Value2-yr EFS,%6148.11Median EFS,mosNot reached22-2-yr PFS,%6349.12Median PFS,mosNot reached23-2-yr DFS,%7057.40Median 2-yr OS,%7067.37End of treatment response rates CR+CRu7567NS PR914NS ORR8481NSDelarue 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 toxicityLNH03-6B GELA Trial:ToxicitiesR-CHOP-14R-CHOP-21111522213650222669837383Patients(%)1009080706050403020100Grade 3/4LeukocytesGrade 3/4NeutrophilsGrade 3/4HemoglobinRBCTransfusionGrade 3/4PlateletsPlateletTransfusionDelarue 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 untreated 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)Cycle 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 regimenMInT:6-Yr Follow-up DataCurrent study presented 6-yr findings(N=823)Multivariate 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.Measure,%(95%CI)With RituximabWithout RituximabLog Rank P ValueEFS74.0(69.0-78.3)55.7(50.3-60.8).0001PFS79.9(75.1-83.3)63.8(58.2-68.8).001OS89.9(86.0-92.6)80.0(75.3-83.9).001R-EPOCH 方案方案Given 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 750 mg/m2 IV on Day 5Doxorubicin 15 mg/m2 continuous IV on Days 2-4Ph II Study of Dose-Adjusted EPOCH-R in DLBCL(CALGB 50103):PFS by IPI ScoreMedian potential follow-up:54 mos5-yr PFS:79%Low risk IPI:91%Low-int 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 DLBCLPrimary endpoints:EFS,molecular predictors of outcome for each regimenSecondary endpoints:RR,OS,toxicity,use of molecular profiling for pathological diagnosisR-CHOPevery 3 wks for 6 cyclesR-EPOCHDoxorubicin,etoposide,vincristine on Days 1-4,cyclophosphamide on Day 5,prednisone on Days 1-5Untreated patients with newly diagnosedDLBCL(N=478)ClinicalTrials.gov.NCT00118209.Primary endpoints:OS and PFSClosed:12/15/07 with 276 randomized patientsPatients with bulky stage II-IV,high-int or high-risk CD20+NHL(N=276)CHOP or R-CHOP for 5 cyclesPR or CRCHOP or R-CHOP for 3 coursesNo additional therapy until progressionCHOP or R-CHOP for 1 course+ASCTStratified by disease risk(int-high vs high)Off therapy if PRClinicalTrials.gov.NCT00004031.Early vs Delayed HDT in High-Int/High-Risk DLBCL:Phase III S9704 Study复发难治复发难治 DLBCLNCCN Guideline Recommendations for Treatment of Relapsed DLBCLSecond-line therapy in candidates for high-dose therapy+ASCTDHAP rituximabESHAP rituximabGDP rituximabGemOx rituximabICE rituximabminiBEAM rituximabMINE rituximabSecond-line therapy for patients who are not candidates for high-dose therapyClinical trialRituximabCEPP rituximabPEPC EPOCH rituximabNCCN Practice Guidelines in Oncology.2010.治疗治疗DLBCL的新药临床试验的新药临床试验DLBCL研究中的药物研究中的药物(Off-Label Use)Bevacizumab 贝伐单抗贝伐单抗 recombinant,humanized,monoclonal VEGF antibodyBortezomib 硼替佐米硼替佐米proteasome inhibitorEnzastaurin PKC-selective inhibitorEpratuzumab 依帕珠单抗依帕珠单抗recombinant,humanized,monoclonal CD22 antibodyEverolimus 依维莫司依维莫司mTOR inhibitorLenalidomide 雷利度胺雷利度胺immunomodulator,antiangiogenicRadioimmunotherapy Fostamatinib specific inhibitor of Syk in B-cell signaling Management Strategies in Non-Hodgkins Lymphoma治疗治疗DLBCL的研究中的药物的研究中的药物:Phase II DataIntervention,%ORREpratuzumab195CR/CRu:65PPR:33CHOP+90Y-Ibritumomab2100%R-GemOx+enzastaurin357CR/CRu:19PR:38Fostamtinib441CR:1PR:17SD:17Lenalidomide535CR/CRu:121.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.Wiernik PH,et al.J Clin Oncol.2008;26:4952-4957.Bortezomib(硼替佐米硼替佐米)+CHOP-R作为作为DLBCL的一线治疗的一线治疗Phase I/IIN=40 patients with previously untreated DLBCLCHOP-21+rituximab 375 mg/m2 each cycle Bortezomib given at 3 different dosesArm 0(n=4):0.7 mg/m2Arm 1(n=8):1.0 mg/m2Arm 2(n=28):1.3 mg/m2Median follow-up:21 mos(range:9-35)ORR resultsITT(n=40):90%(CR/CRu:68%)Evaluable(n=36):100%(CR/CRu:75%)Estimated 2-yr PFS:72%Treatment generally well tolerated4 deaths prior to first response assessmentLeonard JP,et al.ASCO 2007.Abstract 8031.Bendamustine(苯达莫司汀苯达莫司汀)+Rituximab for Rel/Ref DLBCL:Phase II StudyDay 1:bendamustine 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 cyclesPatients with relapsed/refractory DLBCL whofailed at least 1 previous therapy(N=25,ITT)Vacirca JL,et al.ASCO 2010.Abstract 8041.Bendamustine+Rituximab for Rel/Ref DLBCL:Preliminary Phase II ResultsResponse Median,3 cycles N=25,ITTN=23,modified ITTORR53%CRPRSDPD12%41%18%29%Grade 3/4 Adverse Events(n)NeutropeniaHematologic events1(grade 4)9(grade 3)Vacirca JL,et al.ASCO 2010.Abstract 8041.Everolimus(依维莫司依维莫司):Ongoing Phase II and III Studies in DLBCLPhase IIEverolimus plus rituximab in relapsed/refractory DLBCL1Everolimus,panobinostat,or both in relapsed/refractory DLBCL2Everolimus in relapsed/refractory lymphoma3Phase IIIEverolimus as adjuvant therapy following CR to first-line rituximab-chemotherapy in patients with poor-risk DLBCL41.ClinicalTrials.gov.NCT00869999.2.ClinicalTrials.gov.NCT00978432.3.ClinicalTrials.gov.NCT00436618.4.ClinicalTrials.gov.NCT00790036.Phase IIR-CHOP plus bevacizumab for first-line treatment of DLBCL1Bevacizumab plus R-CHOP for first-line treatment of stage II-IV DLBCL2Phase IIIR-CHOP vs R-CHOP plus bevacizumab for first-line treatment of DLBCL3Bevacizumab(贝伐单抗贝伐单抗):Ongoing Phase II and III Studies in DLBCL1.ClinicalTrials.gov.NCT00788606.2.ClinicalTrials.gov.NCT00121199.3.ClinicalTrials.gov.NCT00486759谢谢！