1、弥漫大弥漫大B细胞淋巴瘤细胞淋巴瘤整体治疗策略整体治疗策略上海上海交通大学医学院附属交通大学医学院附属瑞金医院血液科瑞金医院血液科李军民李军民主要内容 一线治疗目的:以治愈为目标 标准治疗 vs 精准治疗:预后分层治疗 造血干移植（自体）的地位流行病学与形态学弥漫大B细胞淋巴瘤(DLBCL)是非霍奇金淋巴瘤(NHL)中最常见类型流行病学西方占NHL的31%34%其他NHLDLBCL在中国：非特指性DLBCL占所有NHL的37.9%，占所有淋巴瘤的33.3%DLBCL其他NHL形态学DLBCL是肿瘤性大B淋巴细胞呈弥漫性生长，肿瘤细胞的核与正常组织细胞的核相近或大于组织细胞的核，细胞体积不小于正
2、常淋巴细胞的2倍在WHO分类中，根据组织形态学改变将DLBCL分为中心母细胞型(cb)、免疫母细胞型(ib)以及间变型通过检测生发中心B细胞标志(CD10、bcl-6)和生发中心后的B细胞标志(MUM1)可将DLBCL分为GCB亚型和non-GCB亚型中心母细胞型大B淋巴细胞正常淋巴细胞免疫母细胞型大B淋巴细胞主要内容 一线治疗目的:以治愈为目标 标准治疗 vs 精准治疗:预后分层治疗 造血干移植（自体）的地位 二线方案的选择及造血干细胞移植的作用CHOP时代治愈率：35-40%Fisher RI,N Engl J Med 1993;328:10021006利妥昔单抗时代治愈率：50-60%时
3、间时间(年年)生存率生存率p 60岁 LDH正常值 PS 24 III或IV期 结外累及1个部位aaIPIAge-Adjusted International Prognostic Index60患者：III或IV期 LDH 正常值 PS 24The International Non-Hodgkins Lymphoma Prognostic Factors Project.N Engl J Med 1993;329(14):987-994.不同风险分组风险因素数量CRR(%)5年OS(%)低危0,18773低中危26751中高危35543高危4,54426不同风险分组风险因素数量CRR(%)
4、5年OS(%)低危09283低中危17869中高危25746高危34632 Whats New in the Lugano Classification?FDG-PET-CTStandard staging for FDG-avid lymphomasUsed to assess response in FDG-avid histologies using the 5-point scale Progressive Disease EvaluationPPD progression of single site defines progression.SPD eliminated for pr
5、ogression.Spleen EvaluationQuantified,13cm is enlarged on CT Modification of the Ann Arbor Classification Bone marrow biopsyNo longer indicated for the routine staging of HL and most DLBCL.Scan FrequencyRoutine surveillance scans are discouraged.GPS 格拉斯哥预后评分格拉斯哥预后评分CRPC-反应蛋白反应蛋白Alb血浆白蛋白血浆白蛋白GPS Glas
6、gow Prognostic Score非小细胞肺癌非小细胞肺癌头颈部肿瘤头颈部肿瘤胃癌胃癌结直肠癌结直肠癌肝细胞癌肝细胞癌P0.05P0.001P60岁岁60-80岁岁8R-CHOP21I AGELA 98-5研究研究8R-6CHOP14I CRICOVER 60研究研究80岁岁6R-miniCHOPIII BGELA LNH03-7B研究研究低危低危 aaIPI=0,无大无大包块包块6R-CHOP21I AMInT研究研究中低危中低危 aaIPI=1或或aaIPI=0,有大包块有大包块 6R-CHOP21+RT(b)或或8R-ACVBPII BMInT研究及研究及GELA LNH03-2B
7、研究研究中高危中高危 aaIPI=2目前没有统一标准方案目前没有统一标准方案 最常用的有：最常用的有：8R-CHOP21或或8R-6CHOP14III B基于临床经验及小样本研究基于临床经验及小样本研究强化治疗方案有：强化治疗方案有：6-8R-CHOEP14/ACVBPII B基于临床经验及小样本研究，缺乏基于临床经验及小样本研究，缺乏与与R-CHOP的对照的对照上述免疫化疗后，序贯上述免疫化疗后，序贯HDCT+ASCTII C基于基于II期研究结果期研究结果正常(%)89%PS 1(%)43%aaIPI评分：2/3(%)74/26%主要终点：2年PFS从50%(无HDT-ASCT组)升高至7
8、5%(HDT-ASCT)组次要终点：两个剂量增强组间的比较18-65岁，未治疗的DLBCL aaIPI 2-3(n=399)8R-CHOP146R-MegaCHOP144R-CHOP14+R-HDC+BEAM+ASCT4R-MegaCHOP14+R-HDC+BEAM+ASCTR无HDC-ASCT(n=200)HDC-ASCT(n=199)DLCL04研究结果：R-HDC+ASCT组显著改善3年PFS，但OS无显著改善CR(R-HDC+ASCT vs R-剂量增强化疗)=76%vs 72%R-HDC+ASCT组显著改善3年PFS，但未能转化为OS获益3年OS率R-HDC+ASCTR-剂量增强化疗
9、P=0.556Vitolo U,et al.2012 ASH abs688.3年PFS：70%vs 59%HR=0.64(0.46-0.91)P=0.0121.000.750.500.250.0001224364860R-HDC+ASCTR-剂量增强化疗PFSGOELAMS 075研究：R-CHOP vs R-HDT-ASCT治疗IPI2的DLBCL随机随机D1CHOPRTDM&PETTEP阴性阴性TEP阳性阳性TEP阴性阴性DHAP3BEAMRBEAMD15CHOPRD29CHOPRD43CHOPRD1D16D22D37CEEPRCEEPRRMCR疗效评估疗效评估疗效评估疗效评估D57CHO
10、PRD71CHOPRD85CHOPRD99CHOPRD56干细胞移植干细胞移植分层：中心、aaIPI:0-1/2/3主要研究终点：EFS次要研究终点：OS、PFS、DFSR-CHOP(n=156)R-HDT(n=156)P值中位年龄(岁)(范围)49(18-60)49(19-60)NSPS：0-1/1(%)90/981/190.02分期：1-2/2(%)21/7726/72NSLDH：正常/正常(%)28/7224/76NSIPI：0-1/2(%)40/6040/60NSMilpied NJ,et al.2011 ASCO 8003.GOELAMS 075研究：R-HDT-ASCT未能改善患者
11、生存aaIPI=2-30.60.40.2EFS时间(月)00.81.0030102040506070OS时间(月)00.20.40.60.81.0040103060702050aaIPI=2-3Milpied NJ,et al.2011 ASCO 8003.Javeed Iqbal1 et al.Clin Cancer Res;2011 17(24);778595.Javeed Iqbal1 et al.Clin Cancer Res;17(24);778595.ABC-DLBCLGCB-DLBCL主要内容 一线治疗目的:以治愈为目标 标准治疗 vs 精准治疗:预后分层治疗 造血干移植（自体）
12、的地位A new anti-lymphoma combination:LBR3+3 design with 10 additional subjects at the MTDLenalidomide-BR untreated CLLBendamustine-RituximabBendamustine 90mg/m2 days 1-2 of 28 day cycle;Rituximab 375mg/m2 on day 1 of cycle 1,then 500mg/m2 on day 1 of cycles 2-6Lenalidomide:3 dose levels planned Lenali
13、domide 2.5mg daily days 8-21(cycle 1 only),then 2.5mg daily days 1-21(cycles 2-6)Lenalidomide 2.5mg daily days 8-21(cycle 1 only),then 5mg daily days 1-21(cycles 2-6)Lenalidomide 5mg daily days 8-21(cycle 1 only),then10mg daily days 1-21(cycles 2-6)Supportive care with allopurinol(through day 14 cyc
14、le 2),pegfilgrastim,aspirin(or other anticoagulant),acyclovir and Bactrim(or equivalent).Clinical adverse events Any events in 10%of subjects,and grade 3-4 in 1 subject*Includes one case each of CMV reactivation,disseminated Zoster,and thrush Includes one case each of CMV reactivation,disseminated Z
15、oster,and thrushPercentage(%)Grade 1-2(%)Grade 3-4(%)ResponseORCR+CRiPRPDNEAll Patients(n=23)20(87%)95%CI 66%-97%9(39%)11(48%)03(13%)MTD only(n=13)12(92%)95%CI 64%-100%4(31%)8(62%)01(8%)ResponseSummary and ConclusionsLenalidomide added to BR results in high efficacy in previously untreated CLLNotabl
16、e toxicities were rash,neutropenia despite pegfilgrastim support,and pulmonary embolism despite aspirin.No DLTs were observed at the target dose level of 10mg lenalidomide,but dose reductions in later cycles were common due to accruing toxicity.L LB BR RL LB BR RL LB BR RL LB BR RL LB BR RL LB BR RL
17、 LL LL LL LL LL LL L1 5 9 13 17 21 25 29 33 37 41 45 49WeeksCTCT,PETMRDCT,PETMRDLenalidomide-Rituximab-Bendamustine in first line for patients 65 with mantle cell lymphoma:Final results of the Nordic Lymphoma Group MCL4Rituximab:375 mg/m2 day 1Bendamustine:90 mg/m2 day 1-2Lenalidomide:at MTD.Initial
18、ly d 1-21,after amendment d 1-14Response:CT/BM MRD BM/PB PET(6m+12m)Lenalidomide:at MTD d 1-21ResponseConclusions LBR is a very active regimen in different lymphoprolipherative diseases The combination is very toxic if the drugs are give at full dose A safe schedule seems to be:Bendamustine 70 mg/m2
19、 d1+2Rituximab 375 mg/m2 d1Lenalidomide 10 mg/d d1-14 q28d This regimen,although active,needs to be compared to standard regimens in randomised trialsFL remains an incurable diseaseEven when the most potent treatment is appliedLadetto,M.et al.Blood 2008FL remains an incurable diseaseIndependent revi
20、ew of CT responses in the trial SAKK 35/10 comparing rituximab with rituximab plus lenalidomide in untreated follicular lymphoma patients in need of therapyEmanuele Zucca,Anna Vanazzi,Bjorn Ostenstad,Ulrich JM Mey,Daniel Rauch,Bjrn E Wahlin,Felicitas Hitz,Micaela Hernberg,Ann-SofieJohansson,Peter de
21、 Nully Brown,Hans Hagberg,Andrs JM Ferreri,Andreas Lohri,Urban Novak,Thilo Zander,Hanne Bersvendsen,Mario Bargetzi,Walter Mingrone,Fatime Krasniqi,Stephan Dirnhofer,Hanne Hawle,Simona Berardi,Steffi Demmel,Stephanie Rondeau,and Eva Kimby Zucca et al.Hematol Oncol(13-ICML Abstracts).2015;33:105-6 abs
22、.011SAKK-NLG 35/10:R vs R-LenSensitivity Analysis(Response at wk23)InvestigatorAssessmentORR,82%vs 61%nIRR considered only the target lesions measurable on CT scansn12 pts(10 receiving R+L)had bone marrow involved at baseline and not re-assessed at week 23n4 pts(3 receiving R+L)had bone marrow invol
23、ved at baseline and still involved at week 23IRRAssessmentORR,78%vs 57%Zucca et al.Hematol Oncol(13-ICML Abstracts).2015;33:105-6 abs.011Chemo-free triplet:Phase IAbstr.106 Ublituximab new anti-CD20(other epitope)TGR-1202=new Pi3Kd(DELTA)inhibitorIbrutinibWell tolerated:ORR 86%in R/R pts主要内容 一线治疗目的:
24、以治愈为目标 标准治疗 vs 精准治疗:预后分层治疗 造血干移植（自体）的地位 二线方案的选择及造血干细胞移植的作用MHCPD-L1PD-1PD-1T-cellreceptorPD-L2T cellNFBOtherPI3KTumor cellIFNRIFNShp-2New options in 2015:“targeted therapy”and“immunotherapy”PD-1 BlockadeAnti-CD30 antibody drug conjugate Brentuximab VedotinNivolumab 50Abstr.010CHL(n=23)ORR 87%CR 17%B-
25、NHL(n=31)ORR 26%CR 10%T NHL(n=23)ORR 17%B-NHL中重要的细胞通路：BCR信号通路BCR信号通路的靶向药物Bruton酪氨酸激酶(BTK)Bruton酪氨酸激酶抑制剂：IburtinbLancet Oncol2014;15:101926 免疫调节药物 LenalidomideLenalidomide 是新一代的抗癌免疫调节剂（是新一代的抗癌免疫调节剂（IMiD），可通），可通过改变细胞因子的生成来影响免疫系统，达到提升免疫过改变细胞因子的生成来影响免疫系统，达到提升免疫反应、增加免疫细胞活性及抑制炎症反应的效果反应、增加免疫细胞活性及抑制炎症反应的效果
26、亦可抑制亦可抑制VEGF 来抑制肿瘤细胞血管生成，直接抑制肿瘤来抑制肿瘤细胞血管生成，直接抑制肿瘤细胞的增生细胞的增生其不良反应较其不良反应较Thalidomide少，具有广阔的应用前景。少，具有广阔的应用前景。Lenalidomide 联合联合R-CHOPREAL07研究结果研究结果Lancet Oncol.2014 Jun;15(7):730-7Lenalidomide 联合联合R-CHOPREAL07研究结果研究结果Lancet Oncol.2014 Jun;15(7):730-7 Participants were to receive 15 mg oral lenalidomide on days 114 of six 21-day cycles.Standard doses of R-CHOP21 chemotherapy Lenalidomide 联合联合R-CHOPREAL07研究结果研究结果Lancet Oncol.2014 Jun;15(7):730-7Lenalidomide 联合联合R-CHOPREAL07研究结果研究结果Lancet Oncol.2014 Jun;15(7):730-7
