高级别B细胞淋巴瘤.ppt

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1、高级别B细胞淋巴瘤,Definition：High Grade B Cell,Lymphoma by 2016 WHO,High-grade B-cell lymphoma,with MYC and,BCL2 and/or BCL6 rearrangements,伴MYC和BCL2和(或)BCL6重排的“double or triplehit lymphoma，但需要除外FL和LBL,High-grade B-cell lymphoma,NOS,没有MYC和BCL2和(或)BCL6重排，但形态学介于DLBCL和BL之间，具有原始细胞样特征,HGBL Categories,Steven H.Sw

2、erdlow et al.Blood 2016;127:2375-2390,Cytologic spectrum of HGBL,Steven H.Swerdlow et al.Blood 2016;127:2375-2390,Double-Hit and Double-expressor,Blood Rev.2017 March;31(2):3742.,DH和TH细胞来源比例,诊断建议,HGBL-DHL病理诊断主要依赖于FISH检测，需要同时检测出Myc和BCL-2或BCL-6重排阳性,关于FISH检测，两种看法：,所有DLBCL均应进行MYC、BCL2和BCL6重排检测,GCB型和/或形态

3、学高侵袭性伴MYC+细胞40%的患者中进行FISH检测,HGBL-NOS丌能简单地依靠Ki67来进行诊断，其细胞形态学必须符合HGBL的特征,HGBL-NOS异质性强，存在很多未知因素，后续可能对,这一分类进一步细化分层,Mechanisms：Double-Hit and Double-,expressor,Mechanisms：MYC deregulation in,aggressive lymphomas,Pierre Sesques,and Nathalie A.Johnson Blood 2017;129:280-288,Alyssa Bouska et al.Blood 2017;1

4、30:1819-1831,NGS found to be recurrentlymutated in 52 mBL cases,Alyssa Bouska et al.Blood 2017;130:1819-1831,HGBL与Burkitt淋巴瘤比较：基因组特征和潜在的治疗靶点,成人高级别B细胞淋巴瘤不伯基特淋巴瘤(BL)分子特征相,似,不儿童-mBL相比，成人-mBL携带明显而又高频的基因异常(del13q14，del17p，gain8q24和gain18q21)基因组分析揭示MYC-ARF-p53轴是主要的信号通路 成人-mBL的一个子集携带BCL2异位和突变，上调BCL2mRNA和蛋白

5、质表达 在50%的成人-mBL患者中观察到MIR17HG和它的旁系同源位点的获得/扩增。miR-1792在BCR信号通路的活性和对依鲁替尼的敏感性中发挥作用,Alyssa Bouska et al.Blood 2017;130:1819-1831,HGBL 的临床特征,中老年发病(51-65 years),高LDH,疾病呈进展状态,高IPI评分 BM/CNS 受累(9-50%),细胞遗传学,Double Hit/Triple Hit(MYC、BCL2、BCL6 rearrangements)可同时伴有 IG-MYC,或 Non-IG-MYC（常见于HBCL，NOS）,免疫表型表达全B抗原（CD

6、20、PAX5、CD79a），Bcl-6+，CD10+/-，Bcl-2+/-，分裂指数80-100%。TdT-，CD34-，cyclinD1-。,预后很差，中位 OS 2 年，不DHL相比，HGBL-NOS预后可能相对,较好,DLBCL：双打击(DHL)和双表达(DEL)患者预后更差,R-CHOP治疗DLBCL患者OSMYC和BCL2易位或MYC和BCL2蛋白表达1.0,0.8,其他DLBCL(n=236),0.6,MYC+/BCL2+(n=55),0.4,DHL(n=14),0.2,P0.001,*P=0.014(MYC+/BCL2+vs.其它),3,5,8,10,0,时间(年),通过对2个

7、R-CHOP治疗的DLBCL患者队列进行IHC检测分析MYC和BCL2蛋白表达不患者生先期纳入10个国际机构的167例患者的FFPET样本。验证队列纳入140例BCCA患者FFPE样本,Dunleavy K,et al.Curr Treat Options Oncol 2015;16:58.Johnson NA,et al.J Clin Oncol 2012;30(28):3452-9.,novel ECOG score,IPI,7%,R-IPI,ECOG DHL预后积分：,白细胞增多10X10/L,9,Ann Arbor III-IV期LDH 3x ULN,中枢侵犯,Adam M.Petri

8、ch et al.Blood 2014;124:2354-2361,Clinical risk according to MYC andBCL2 status in DLBCL,Pierre Sesques,and Nathalie A.Johnson Blood 2017;129:280-288,Translocation partner：对EFS无影响,patientsreceiving ID,all patients,patientsachieving CR,Cancer.2016 February 15;122(4):559564.,多中心回顾性分析：DHLR-强化疗方案延长PFS,但

9、OS未获益,100,强化诱导(N=136)：mPFS 21.6月,强诱导方案治疗DHL患者PFS显著优于R-CHOP，各方案都显著延长PFS,806040200,R-CHOP(N=63)：mPFS 7.8月,R-CHOP(n=63),10080,R-Hyper CVAD(n=38)：P=0.001DA-EPOCH-R(n=57)：P=0.0463R-CODOX-M/IVAC(n=41)：P=0.036其他(n=24),P=0.00,01,12,24,36,48,60,时间(月),100806040200,强化诱导(N=171)R-CHOP(N=100),60,40200,P=0.001625,

10、P=0.56,0,50,75,100,125,4,0,12,24,36,4,时间(月),时间(月),回顾性多中心研究入组311例DHL患者分析,Petrich AM et al.Blood,2014,124(15):2354-61.,MDACC：R-EPOCH方案治疗DHL疗效显著,MDACC经验结果：R-hyperCVAD/MA不R-CHOP治疗生存相似，而R-EPOCH治疗较R-CHOP治疗EFS和OS更长（持续输注）,RCHOP(n=57),100806040200,100,REPOCH,R(nH=C2V8A)D/M A(n=34)80其他(n=10),3y：76%,60,3y：,67%

11、,3y：40%3y：35%,40200,3y：,32%,3y：12%P=0.057,3y：10%,3y：20%,P=0.004,0 6 12 18 24 30,0 6 12 18 24 30 36 42 48,36 42 48,时间(月),时间(月),EFS,OS,多因素分析,95%CI,P值0.008,95%CI0.19-1.14 0.031,P值,HR0.37,HR0.47,R-EPOCH vs R-CHOP,R-HCVAD vs R-CHOP,0.611.92,0.0740.084,0.672.86,00,其他 vs R-CHOP,回顾性研究分析129例DHL患者的数据,Oki Y,et

12、 al.Br J Haematol 2014;166(6):891-901.,11项研究荟萃分析：R-EPOCH及剂量增强的免疫化疗方案是DHL一线有效治疗策略,首个DHL患者治疗结果荟萃分析结果表明：R-EPOCH较R-CHOP显著改善DHL患者PFS，降低进展风险，但OS相似,100806040200,10080,60,40,R-EPOCHDI(R-Hyper-CVAD/R-CODOX-M/IVAC)R-CHOP,R-EPOCH,DI(R-Hyper-CVAD/R-CODOX-M/IVAC)20,R-CHOP12,0,0,24,36 48,60,0,12,24,36,48,60,时间(月)

13、,时间(月),治疗,中位OS，月21.4,OS HR(95%CrI)参照,P值-,中位PFS，月12.1,PFS HR(95%CrI)参照,P值,R-CHOPR-EPOCHDI,-,31.4,0.77(0.51-1.13)0.89(0.62-1.27),0.1860.531,22.2,0.66(0.44-0.96)0.74(0.51-1.05),25.2,18.9,Howlett C,et al.Br J Haematol 2015;170(4):504-14.,MDACC:R-DA-EPOCH优化治疗DHL,DA-EPOCH-R治疗DHL(GCB)，无MYC和BCL2表达的DLBCL(GCB

14、)以及DEL(GCB,和非GCB)患者OS相似,DA-EPOCH-R治疗高危患者疗效显著，可能克服R-CHOP治疗时的丌良预后因素,1.0,变量年龄,结果,DHL(GCB),DEL(GCB),DEL,P,6060,7(31.8%)15(68.2%),30(65.2%)16(34.8%),6(37.5%)10(62.5%),0.02,0.80.60.40.2,BM,-+,12(68.2%)10(45.5%),41(89.1%)5(10.9%),14(93.3%)1(6.7%),0.0020.730.21,DHL(E/N=4/22)DEL(E/N=3/16)DLBCL(E/N=4/46),P=0.

15、2617,ki67,80%80%,4(21.1%)15(78.9%),7(16.3%)36(83.7%),4(25%)12(75%),结外部位,0/12,11(50%)11(50%),31(68.9%)14(31.1%),8(50%)8(50%),0.01.0,0,12,24,36,48),60,72,84,时间 月,(,低 0-1中 2高 3-5,5(22.7%)2(9.1%)15(68.2%),21(45.7%)9(19.6%)16(34.8%),2(12.5%)4(25%)10(62.5%),IPI,0.03,0.80.60.4,DA-EPOCH-R治疗应答,CRCR,6(27.3%)1

16、6(72.7%),5(10.9%)41(89.1%),4(26.7%)11(73.3%),NS0.3,1年OS(95%CI)1年PFS(95%CI),DHL(E/N=6/22)DEL(E/N=6/16)DLBCL(E/N=7/46),P=0.0848,0.79(0.62-1),0.91(0.84-1),0.86(0.69-1),0.20.0,0.72(0.56-0.94),0.87(0.78-0.97),0.65(0.44-0.95),0.08,0,12,24,36,48,6,时间(月),回顾性分析纳入2010-2014年MD Anderson癌症中心233例接受DA-EPOCH-R治疗的新诊

17、断高危DLBCL,Sathyanarayanan V,et al.2016 ASH 106.,CR后给予ASCT一线巩固治疗：并没有提高EFS/OS,P=0.17,P=0.56,Oki et al.Br J Haematol.2014 Sep;166(6):891-901,复发/难治DHL:ASCT二线治疗疗效差,117 patients were included;44%had DEL and 10%had DHL.,J Clin Oncol 35:24-31.,Risk of CNS involvement,建议所有患者CR都应进行中枢神经系统预防治疗 尚无充足的研究结果证实全身CNS预防

18、比传统的鞘内注射对中枢侵犯的预防效果更好,Oki et al.Br J Haematol.2014 Sep;166(6):891-901,Adam M.Petrich et al.Blood 2014;124:2354-2361,Intensive Chemo+Allo-HSCT,DHL do very poorly with SD alone.DI strategies with allogeneic SCT lead to,significantly longer PFS and OS.,Christina Howlett,Blood 2013 122:2141;,研发中的新药和新方法,分

19、类,BTK 抑制剂PI3K 抑制剂,IbrutinibIdelalisib,BCL-2 抑制剂MYC 抑制剂,ABT-199,BET 结构域蛋白BCL-6 抑制剂,Aurora酶 抑制剂CART细胞免疫治疗,1555 Objective Responses Achieved inPatients with MYC-AlteredRelapsed/Refractory Diffuse Large B-CellLymphoma Treated with the Dual PI3K andHDAC Inhibitor CUDC-907,(NCT02674750),Daniel J.Landsburg

20、,MD,et al.,Abramson Cancer Center,University ofPennsylvania,Philadelphia,PA,Contents,CUDC-907,a first-in-class oral dual inhibitor of HDACand PI3K enzymes,has demonstrated downregulation ofMYC mRNA and protein levels,Phase 2 study is designed to further explore the efficacy,of CUDC-907 in DHL and DE

21、L patients,Patients with confirmed MYC-altered disease by central,immunohistochemistry(IHC)testing,Patients receive 60 mg of CUDC-907 orally once a day,on a 5 days on/2 days off schedule in 21-day cycles,3 CR and 4 PR.The ORR was 19.4%(7/36),AE were diarrhea,nausea,fatigue,thrombocytopen,hypokalemia

22、,and vomiting,4035 Assessment of CD52 Expressionin Double-Hit and Double-Expressor Lymphomas:Implicationsfor Clinical Trial Eligibility,(ID:NCT03132584),Jeffrey W.Craig,et al.,Department of Pathology,Brigham andWomens Hospital,Boston,MA,Contents,Phase I trial investigating the use of alemtuzumab and

23、,low-dose CTX for the treatment of DHL/THL and DEL,Study included 35 DHL,5 THL,7 HGBCL,NOS,and 51,DLBCL,NOS,75%of DHL/THL and DEL exhibited convincing,cytoplasmic and/or membranous CD52 expression,Results suggesting that alemtuzumab-based therapy,may be appropriate for most patients,Target validatio

24、n must be performed on a case-by-case,basis,577 JULIET:Phase II Primary Analysisof CAR T-Cell TherapyTisagenlecleucel in Adult Patients WithRelapsed/Refractory DLBCL(NCT02631044),Stephen J.Schuster,MD,et al.Lymphoma Program,AbramsonCancer Center,University ofPennsylvania,Philadelphia,JULIET:Study De

25、sign,International,single-arm,open-label phase II trial,Tisagenlecleucel,infusion(0.6-6.0 x 108CAR+viable T-cells),Screening,apheresis,cryopreservation,Restaging,lymphodepletion,Adult DLBCL ptswith centrallyconfirmedhistology;2prior tx lines forDLBCL;PD,(n=99),PosttreatmentFollow-up(n=81,Tisagenlecl

26、euc,el,evaluable),manufacturing*,following or,ineligible forautoHSCT;noprior anti-CD19tx;no active CNSinvolvement(N=147),Day-2 toDay-14,Bridgingchemotherapy,*Centralized in US or Germany.Pts received US-made tisagenlecleucelinpatient or outpatient,with 26%receiving outpatient infusion,77%of whomrema

27、ined outpatient 3 days post infusion;1 pt infused with 0.6 x 108 CAR+viable T-cells;D/c before preinfusion:n=43(inability to manufacture,related to pt status,n=34);infusion pending for additional 5 pts.Ima3 mos.Data cutoff:March 2017.,Schuster SJ,et al.ASH 2017.Abstract 577.,JULIET Primary Analysis:

28、BaselinePt Characteristics,Pts(n=99),Pts(n=99),Baseline Characteristics,Baseline Characteristics,%,Median age,yrs(range).65 yrs,%,56(22-76)23,No.prior lines ofantineoplastic tx.2,443119,ECOG PS 0/1,%,55/45,.3.4-6,Histology,%.DLBCL.Transformed FL,8019,Response to last tx.Refractory.Relapsed,Double/tr

29、iple hits inCMYC/BCL2/BCL6,*%,5248,15,Cell of origin,%,Prior autoHSCT,47,.Germinal center B-cell type.Nongerminal center B-celltype,5242,90%of pts received bridging,chemotherapy,93%of pts receivedlymphodepleting chemotherapy,*CMYC/BCL2,n=4;CMYC/BCL6,n=3;CMYC/BCL2/BCL6,n=8.,Schuster SJ,et al.ASH 2017

30、.Abstract 577.,JULIET:Best ORR(Primary Endpoint),3-MoResponse(n=81),6-MoResponse(n=46),Best ORR(n=81),Response,%,ORR(CR+PR),53,38,37,.CR.PR,4014,326,307,Study met primary endpoint with ORR of 53%(95%CI:42%to 64%)Significantly greater than null hypothesis ORR 20%(P.0001),No relationship apparent betw

31、een tisagenlecleucel dose and 3-mo,response,Responses observed across entire dose range,Schuster SJ,et al.ASH 2017.Abstract 577.,JULIET:ORR by Subgroups,Null Hypothesis of ORR 20%,ORR,n/N(%),95%CI,All PtsAge,yrs 65,65,SexFemaleMale,Prior antineoplastic therapy 2 lines 2 lines,Cell of origin*,Nongerm

32、inal centerGerminal centerRearranged MYC/BCL2/BCL6Double/triple hitsOther,5/12(41.7),ORR(%),*Data missing for 6 pts,ORR consistent across subgroups,Schuster SJ,et al.ASH 2017.Abstract 577.Reprinted with permission.,193 CAR T-Cell Therapy JCAR017 in R/RDLBCL From TRANSCEND NHL 001:Correlation Between

33、 Patient Characteristicsand Clinical Outcomes,(NCT02631044),Jeremy S.Abramson,MD,MMSc1,Massachusetts General HospitalCancer Center,Boston,MA,TRANSCEND NHL 001:Study Design,Multicenter,multicohort,open-label phase I trial,DLBCL CORE(n=67):high-grade B-cell lymphoma(double/triple hit),DLBCL NOS de nov

34、o or transformed from FL,DLBCL FULL(n=91):CORE+pts with DLBCL transformed from,CLL/MZL,PMBCL,or FL3BEnrollment,apheresis,JCAR017Pts with R/Rmanufacturing,DLBCL Dose-Finding,DLBCL Dose-ExpansionCohort,CohortJCAR017 IV,DL1S:5 x 107 cells singledose,D1;DL1D:5 x 107 cells doubledose,D1,D14;DL2S:1 x 108

35、cells singledose,D1,DLBCL after2 lines of txor R/R MCLafter 1 lineof tx,*,Pivotal DLBCL cohortenrollment ongoing(JCAR017 IVDL2S),JCAR017 IVDL1S,DL2S,*Pts could receive low-dose CT for disease control during JCAR017 manufacturing.Pts received 1 cycle ofJACR017 tx,with each cycle preceded by lymphodep

36、letion(fludarabine 30 mg/m2+cyclophospmg/m2 x 3 days).Follow-up:PK,scans Q3M for 1 yr;safety,viral vector for 15 yrs.,Siddiqi T,et al.ASH 2017.Abstract 193.,TRANSCEND NHL 001 ExploratoryAnalysis:Response*,COREDL1S,FULLAll DoseLevels,Response,*n(%),All DoseLevels,DL2S,Best overall response.ORR.CR,n=6

37、851(75)38(56),n=4941(84)30(61),-,-,Pts with 3-mo f/u.3-mo ORR.3-mo CR,n=5527(49)22(40),n=4026(65)21(53),n=2111(52)7(33),n=1512(80)11(73),*Data cutoff:November 1,2017.,In CORE population,pts with durable responses(CR/PR)at 3 moshad generally lower baseline tumor burden,inflammation marand inflammator

38、y cytokines,Siddiqi T,et al.ASH 2017.Abstract 193.,总 结,WHO2016分类HGBL尚有很多未知因素，临床表现为一类侵袭性,、预后丌好的亚型，但觃范诊治下其中有少部分患者可能为低危,应当将MYC和BCL2/BCL6遗传学和免疫组化检查整合到诊断程序之中。Bcl-2/Myc的DHL大多为GCB亚型，增殖能力强，而BCL-6/Myc的DHL大多为ABC亚型,以R-CHOP为基础的化疗方案并丌适用，以R-DA-EPOCH、R-HyperCVAD、R-CODOX-M/IVAC为代表的强化方案仍然是目前的主流选择，ASCT的疗效和价值尚未确定,DHL患者有更多几率发生CNS进展，诊断时需要检查脑脊液且建,议进行鞘注预防,需要更深入研究这类疾病，探索新的治疗方法：如小分子靶向疗药物、细胞免疫治疗（CART）、异基因造血干细胞移植，,Thank You for yourAttention,