1、高级别B细胞淋巴瘤Definition：High Grade B CellLymphoma by 2016 WHO High-grade B-cell lymphoma,with MYC andBCL2 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 CategoriesSteven H.Swerdlow
2、et al.Blood 2016;127:2375-2390Cytologic spectrum of HGBLSteven H.Swerdlow et al.Blood 2016;127:2375-2390Double-Hit and Double-expressorBlood 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/或形态学高侵袭性伴MYC+细胞40
3、%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-expressorMechanisms：MYC deregulation inaggressive lymphomasPierre Sesques,and Nathalie A.Johnson Blood 2017;129:280-288Alyssa Bouska et al.Blood 2017;130:1819-1831NGS found
4、 to be recurrentlymutated in 52 mBL casesAlyssa Bouska et al.Blood 2017;130:1819-1831HGBL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和蛋白质表达 在50%的成人-mBL患者中观察到MIR1
5、7HG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;130:1819-1831HGBL 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（CD20、PAX5、CD79a），Bcl-6+，CD10+/-，
6、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 Significantly greater than null hypothesis ORR 20%(P .Response to last txCraig,et al.Lymphoma Program,Abramsonlymphodepletion 成人高级别B细胞淋巴瘤不伯基特淋巴瘤(BL)分子特征相Blood,2014,124(15):2354-61.、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 ORR consis
7、tent across subgroups验证队列纳入140例BCCA患者FFPE样本on a 5 days on/2 days off schedule in 21-day cycles和对依鲁替尼的敏感性中发挥作用Siddiqi T,et al.Pennsylvania,Philadelphia,PA HGBL-NOS丌能简单地依靠Ki67来进行诊断，其细胞形Curr Treat Options Oncol 2015;16:58.Mechanisms：Double-Hit and Double-的主流选择，ASCT的疗效和价值尚未确定tx;no active CNSprior anti-C
8、D19Abstract 577.Nongerminal centerDLBCL：双打击(DHL)和双表达(DEL)患者预后更差R-CHOP治疗治疗DLBCL患者患者OSMYC和和BCL2易位或易位或MYC和和BCL2蛋白表达蛋白表达1.00.8其他DLBCL(n=236)0.6MYC+/BCL2+(n=55)0.4DHL(n=14)0.2P10X10/L9Ann Arbor III-IV期期LDH 3x ULN,中枢侵犯中枢侵犯Adam M.Petrich et al.Blood 2014;124:2354-2361Clinical risk according to MYC andBCL2
9、status in DLBCLPierre Sesques,and Nathalie A.Johnson Blood 2017;129:280-288的主流选择，ASCT的疗效和价值尚未确定The ORR was 19.High-grade B-cell lymphoma,NOSBlood 2017;130:1819-1831DLBCL NOS de novo or transformed from FL 65 yrs,%prior lines of没有MYC和BCL2和(或)BCL6重排，但形态学介于Abstract 577.Br J Haematol 2015;170(4):504-14.
10、DI(R-Hyper-CVAD/R-CODOX-M/IVAC)20 ORR consistent across subgroupsR-EPOCH vs R-CHOPTRANSCEND NHL 001:Study Design ORR consistent across subgroupsPierre Sesques,and Nathalie A.inpatient or outpatient,with 26%receiving outpatient infusion,77%of whomDLBCL From TRANSCEND NHL 001:Germinal centerJ Clin Onc
11、ol 35:24-31.JULIET:Study DesignTranslocation partner：对EFS无影响patientsreceiving IDall patientspatientsachieving CRCancer.2016 February 15;122(4):559564.多中心回顾性分析：DHLR-强化疗方案延长PFS,但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PFS806040200R-CHOP(N=63)：mPFS 7.8月R-CHOP(n=63)10080R-Hyper
12、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=0.00011224364860时间(月)100806040200强化诱导(N=171)R-CHOP(N=100)6040200P=0.001625P=0.5605075100125401224364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-hyperCV
13、AD/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)100806040200100REPOCHR(n H=C 2 V 8 A)D/M A(n=34)80其他(n=10)3y：76%603y：67%3y：40%3y：35%402003y：32%3y：12%P=0.0573y：607(31.8%)15(68.2%)30(65.2%)16(34.8%)6(37.5%)10(62.5%)0.020.80.60.40.2BM-+12(68.2%)10(45.5%)41(89.1%)5(10.9%)14(93.3%)1(6.7%)0
14、.0020.730.21DHL(E/N=4/22)DEL(E/N=3/16)DLBCL(E/N=4/46)P=0.2617ki6780%80%4(21.1%)15(78.9%)7(16.3%)36(83.7%)4(25%)12(75%)结外部位结外部位0/1211(50%)11(50%)31(68.9%)14(31.1%)8(50%)8(50%)0.01.0012243648)607284时间 月(低 0-1中 2高 3-55(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%)IPI0.030.80.6
15、0.4DA-EPOCH-R治疗应答治疗应答CRCR6(27.3%)16(72.7%)5(10.9%)41(89.1%)4(26.7%)11(73.3%)NS0.31年年OS(95%CI)1年年PFS(95%CI)DHL(E/N=6/22)DEL(E/N=6/16)DLBCL(E/N=7/46)P=0.08480.79(0.62-1)0.91(0.84-1)0.86(0.69-1)0.20.00.72(0.56-0.94)0.87(0.78-0.97)0.65(0.44-0.95)0.080122436486时间(月)回顾性分析纳入2010-2014年MD Anderson癌症中心233例接受D
16、A-EPOCH-R治疗的新诊断高危DLBCLSathyanarayanan V,et al.2016 ASH 106.CR后给予后给予ASCT一线巩固治疗：并没一线巩固治疗：并没有提高有提高EFS/OSP=0.17P=0.56Oki et al.Br J Haematol.2014 Sep;166(6):891-901复发复发/难治难治DHL:ASCT二线治疗疗效差二线治疗疗效差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
17、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):891-901Adam M.Petrich et al.Blood 2014;124:2354-2361Intensive Chemo+Allo-HSCT DHL do very poorly with SD alone.DI strategies with allogeneic SCT lead tosignificantly longer PFS and OS.Christina Howlett,Blood 2
18、013 122:2141;研发中的新药和新方法研发中的新药和新方法分类分类BTK 抑制剂抑制剂PI3K 抑制剂抑制剂IbrutinibIdelalisibBCL-2 抑制剂抑制剂MYC 抑制剂ABT-199BET 结构域蛋白BCL-6 抑制剂Aurora酶 抑制剂CART细胞免疫治疗细胞免疫治疗(ID:NCT03132584)没有MYC和BCL2和(或)BCL6重排，但形态学介于JCAR017 IV(JCAR017 IVSchuster SJ,et al.强化诱导(N=136)：mPFS 21.ORR consistent across subgroupsprior anti-CD19通过对2
19、个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 ORR consistent across subgroupsDA-EPOCH-R(n=57)：P=0.all patientsNongerminal centerAbstract 577.Results suggesting that alemtuzumab-based therapy Patients with confirmed MYC-altered disease by central4035 Assessment of CD52 Expressionin Double-Hit and Doub
20、le-ORR consistent across subgroups1555 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,MD,et al.Abramson Cancer Center,University ofPennsylvania,Philadelphia,
21、PAContents 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 efficacyof CUDC-907 in DHL and DEL patients Patients with confirmed MYC-altered disease by centralimmunohist
22、ochemistry(IHC)testing Patients receive 60 mg of CUDC-907 orally once a dayon 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,thrombocytopenhypokalemia,and vomiting4035 Assessment of CD52 Expressionin Double-Hit and Double-Express
23、or Lymphomas:Implicationsfor Clinical Trial Eligibility(ID:NCT03132584)Jeffrey W.Craig,et al.Department of Pathology,Brigham andWomens Hospital,Boston,MAContents Phase I trial investigating the use of alemtuzumab andlow-dose CTX for the treatment of DHL/THL and DEL Study included 35 DHL,5 THL,7 HGBC
24、L,NOS,and 51DLBCL,NOS 75%of DHL/THL and DEL exhibited convincingcytoplasmic and/or membranous CD52 expression Results suggesting that alemtuzumab-based therapymay be appropriate for most patients Target validation must be performed on a case-by-casebasis577 JULIET:Phase II Primary Analysisof CAR T-C
25、ell TherapyTisagenlecleucel in Adult Patients WithRelapsed/Refractory DLBCL(NCT02631044)Stephen J.Schuster,MD,et al.Lymphoma Program,AbramsonCancer Center,University ofPennsylvania,PhiladelphiaJULIET:Study DesignInternational,single-arm,open-label phase II trialTisagenlecleucelinfusion(0.6-6.0 x 108
26、CAR+viable T-cells)Screening,apheresis,cryopreservationRestaging,lymphodepletionAdult DLBCL ptswith centrallyconfirmedhistology;2prior tx lines forDLBCL;PD(n=99)PosttreatmentFollow-up(n=81Tisagenlecleucelevaluable)manufacturing*following orineligible forautoHSCT;noprior anti-CD19tx;no active CNSinvo
27、lvement(N=147)Day-2 toDay-14Bridgingchemotherapy*Centralized in US or Germany.Pts received US-made tisagenlecleucelinpatient or outpatient,with 26%receiving outpatient infusion,77%of whomremained outpatient 3 days post infusion;1 pt infused with 0.6 x 108 CAR+viable T-cells;D/c before preinfusion:n=
28、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:BaselinePt CharacteristicsPts(n=99)Pts(n=99)Baseline CharacteristicsBaseline Characteristics,%Median age,yrs(ra
29、nge).65 yrs,%56(22-76)23No.prior lines ofantineoplastic tx.2443119ECOG PS 0/1,%55/45.3.4-6Histology,%.DLBCL.Transformed FL8019Response to last tx.Refractory.RelapsedDouble/triple hits inCMYC/BCL2/BCL6,*%524815Cell of origin,%Prior autoHSCT47.Germinal center B-cell type.Nongerminal center B-celltype5
30、242 90%of pts received bridgingchemotherapy,93%of pts receivedlymphodepleting chemotherapy*CMYC/BCL2,n=4;CMYC/BCL6,n=3;CMYC/BCL2/BCL6,n=8.Schuster SJ,et al.ASH 2017.Abstract 577.JULIET:Best ORR(Primary Endpoint)3-MoResponse(n=81)6-MoResponse(n=46)Best ORR(n=81)Response,%ORR(CR+PR)533837.CR.PR4014326
31、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 between tisagenlecleucel dose and 3-moresponse Responses observed across entire dose rangeSchuster SJ,et al.ASH 2017.Abstract 577.Multicenter,multicohort
32、,open-label phase I trialCorrelation Between Patient Characteristics 90%of pts received bridging(ID:NCT03132584)DLBCL afterNongerminal center Study met primary endpoint with ORR of 53%(95%CI:42%to 64%)Abstract 577.Alyssa Bouska et al.Target validation must be performed on a case-by-caseDLBCL afterR-
33、EPOCH vs R-CHOPDL1D:5 x 107 cells doubleJ Clin Oncol 2012;30(28):3452-9.Tisagenlecleucel in Adult Patients WithCMYC/BCL2/BCL6,*%Abstract 577.Clinical risk according to MYC andof CUDC-907 in DHL and DEL patients(NCT02631044)Blood 2016;127:2375-2390DL1S:5 x 107 cells singleJULIET:ORR by SubgroupsNull
34、Hypothesis of ORR 20%ORR,n/N(%)95%CI43/81(53.1)41.7-64.3All PtsAge,yrs 2 lines22/41(53.7)37.4-69.321/40(52.5)36.1-68.5Cell of origin*19/34(55.9)37.9-72.819/41(46.3)30.7-62.6Nongerminal centerGerminal centerRearranged MYC/BCL2/BCL6Double/triple hitsOther5/12(41.7)15.2-72.338/69(55.1)42.6-67.1ORR(%)*D
35、ata missing for 6 pts ORR consistent across subgroupsSchuster 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 Patient Characteristicsand Clinical Outcomes(NCT02631044)Jeremy S.Abramson,MD,MMSc1,Massachuset
36、ts General HospitalCancer Center,Boston,MATRANSCEND 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 novo or transformed from FL DLBCL FULL(n=91):CORE+pts with DLBCL transformed fromCLL/MZL,PMBCL,or FL3B
37、Enrollment,apheresis,JCAR017Pts with R/RmanufacturingDLBCL Dose-FindingDLBCL Dose-ExpansionCohortCohortJCAR017 IVDL1S:5 x 107 cells singledose,D1;DL1D:5 x 107 cells doubledose,D1,D14;DL2S:1 x 108 cells singledose,D1DLBCL after2 lines of txor R/R MCLafter 1 lineof tx*Pivotal DLBCL cohortenrollment on
38、going(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 lymphodepletion(fludarabine 30 mg/m2+cyclophospmg/m2 x 3 days).Follow-up:PK,scans Q3M for 1 yr;safety,viral vector for
39、 15 yrs.Siddiqi T,et al.ASH 2017.Abstract 193.TRANSCEND NHL 001 ExploratoryAnalysis:Response*COREDL1SFULLAll DoseLevelsResponse,*n(%)All DoseLevelsDL2SBest overall response.ORR.CRn=6851(75)38(56)n=4941(84)30(61)-Pts with 3-mo f/u.3-mo ORR.3-mo CRn=5527(49)22(40)n=4026(65)21(53)n=2111(52)7(33)n=1512(
40、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 inflammatory cytokinesSiddiqi T,et al.ASH 2017.Abstract 193.总总 结结 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/B
41、CL6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，WHO2016分类HGBL尚有很多未知因素，临床表现为一类侵袭性 Double H
42、it/Triple Hit(MYC、BCL2、BCL6 rearrangements)JULIET Primary Analysis:Baselineprior lines of(ID:NCT03132584)Nongerminal center B-cellR-EPOCH方案治疗DHL疗效显著DI(R-Hyper-CVAD/R-CODOX-M/IVAC)20JACR017 tx,with each cycle preceded by lymphodepletion(fludarabine 30 mg/m2+cyclophospBaseline Characteristics,%回顾性分析纳入
43、2010-2014年MD Anderson癌症中心233例接受DA-EPOCH-R治疗的新诊断高危DLBCLLymphoma Program,Abramson2014 Sep;166(6):891-901 尚无充足的研究结果证实全身CNS预防比传统的鞘内注射对中枢Br J Haematol 2014;166(6):891-901.Cell of origin*Dunleavy K,et al.和对依鲁替尼的敏感性中发挥作用 90%of pts received bridgingBlood 2014;124:2354-2361 以R-CHOP为基础的化疗方案并丌适用，以R-DA-EPOCH、R-
44、Thank You for yourAttentionprior lines ofAbstract 193.不儿童-mBL相比，成人-mBL携带明显而又高频的基因异R(nH=C2V8A)D/M A(n=34)may be appropriate for most patients1555 Objective Responses Achieved in Multicenter,multicohort,open-label phase I trial0 6 12 18 24 30Abstract 193.ECOG PS 0/1,%通过对2个R-CHOP治疗的DLBCL患者队列进行IHC检测分析MY
45、C和BCL2蛋白表达不患者生 关于FISH检测，两种看法：BCL2 and/or BCL6 rearrangementsBaseline Characteristicsmutated in 52 mBL casesR-强化疗方案延长PFS,但OS未获益R-强化疗方案延长PFS,但OS未获益cryopreservation 关于FISH检测，两种看法：DLBCL Dose-Expansion和非GCB)患者OS相似cryopreservation通过对2个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0 6 12 18 24 30 36 42 48Rear
46、ranged MYC/BCL2/BCL6193 CAR T-Cell Therapy JCAR017 in R/RAnalysis:Response*MYC+/BCL2+(n=55)receiving IDTransformed FLJACR017 tx,with each cycle preceded by lymphodepletion(fludarabine 30 mg/m2+cyclophospRisk of CNS involvement1年PFS(95%CI)The ORR was 19.Response to last txSiddiqi T,et al.Clinical ris
47、k according to MYC andDL2S:1 x 108 cells singlelymphodepletionRelapsed/Refractory DLBCLPts with 3-mo f/uBlood 2017;130:1819-1831with centrally 关于FISH检测，两种看法：Relapsed/Refractory DLBCLBr J Haematol 2015;170(4):504-14.Pierre Sesques,and Nathalie A.ORR consistent across subgroupsBlood 2016;127:2375-2390
48、Swerdlow et al.Pennsylvania,Philadelphia,PAand inflammatory cytokines没有MYC和BCL2和(或)BCL6重排，但形态学介于Reprinted with permission.Siddiqi T,et al.Blood 2014;124:2354-2361 Double Hit/Triple Hit(MYC、BCL2、BCL6 rearrangements)193 CAR T-Cell Therapy JCAR017 in R/RMDACC:R-DA-EPOCH优化治疗DHL2014 Sep;166(6):891-901 Target validation must be performed on a case-by-caseprior lines of谢谢观看！
