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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 triple hit 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 Steve
2、n H. Swerdlow 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BC
3、L6重排检测 GCB型和/或形态学高侵袭性伴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 Bous
4、ka et al. Blood 2017;130:1819-1831 NGS found to be recurrently mutated 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
5、一个子集携带BCL2异位和突变，上调BCL2 mRNA和蛋白质表达 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
6、-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+/- ，Bcl-2+/- ，分裂指数80-100% 。TdT-，CD34-，cyclin D1-。 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治疗疗DLBCL患者OS MYC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)
7、0.2 P10X10 /L 9 Ann Arbor III-IV期 LDH 3x ULN, 中枢侵犯 Adam M. Petrich et al. Blood 2014;124:2354-2361 Clinical risk according to MYC and BCL2 status in DLBCL Pierre Sesques, and Nathalie A. Johnson Blood 2017;129:280-288 Translocation partner：对EFS无影响 patients receiving ID all patients patients achievin
8、g CR Cancer. 2016 February 15; 122(4): 559564. 多中心回顾性分析：DHL R-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PFS 80 60 40 20 0 R-CHOP (N=63)：mPFS 7.8月 R-CHOP (n=63) 100 80 R-Hyper CVAD (n=38) ：P=0.001 DA-EPOCH-R (n=57) ：P=0.0463 R-CODOX-M/IVAC (n=41) ：P=0.036 其他 (
9、n=24) P=0.00 0 1 1224364860 时间 (月) 100 80 60 40 20 0 强化诱导 (N=171) R-CHOP (N=100) 60 40 20 0 P=0.0016 25 P=0.56 05075100125 4 012 2436 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-C
10、HOP治疗EFS 和OS更长（持续输注） RCHOP (n=57) 100 80 60 40 20 0 10 0 REPOCH R ( n H = C 2 V 8 A ) D / M A (n=34) 80 其他 (n=10) 3y： 76% 60 3y： 67%3y： 40% 3y： 35% 40 20 0 3y： 32% 3y： 12% P=0.057 3y： 60 7(31.8%) 15(68.2%) 30(65.2%) 16(34.8%) 6(37.5%) 10(62.5%) 0.02 0.8 0.6 0.4 0.2 BM- + 12(68.2%) 10(45.5%) 41(89.1%
11、) 5(10.9%) 14(93.3%) 1(6.7%) 0.002 0.73 0.21 DHL (E/N=4/22) DEL (E/N=3/16) DLBCL (E/N=4/46) P=0.2617 ki6780% 80% 4(21.1%) 15(78.9%) 7(16.3%) 36(83.7%) 4(25%) 12(75%) 结结外部位0/1 2 11(50%) 11(50%) 31(68.9%) 14(31.1%) 8(50%) 8(50%) 0.0 1.0 012243648 ) 607284 时间 月( 低 0-1 中 2 高 3-5 5(22.7%) 2(9.1%) 15(68.2
12、%) 21(45.7%) 9(19.6%) 16(34.8%) 2(12.5%) 4(25%) 10(62.5%) IPI0.03 0.8 0.6 0.4 DA-EPOCH-R 治疗应疗应 答 CR CR 6(27.3%) 16(72.7%) 5(10.9%) 41(89.1%) 4(26.7%) 11(73.3%) NS 0.31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) 0.2 0.0
13、 0.72 (0.56-0.94) 0.87 (0.78-0.97) 0.65 (0.44-0.95) 0.08 0 122436486 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治疗的新诊断高危DLBCL Sathyanarayanan V, et al. 2016 ASH 106. CR后给给予ASCT一线线巩固治疗疗：并没 有提高EFS/OS P=0.17P=0.56 Oki et al. Br J Haematol. 2014 Sep;166(6):891-901 复发发/难难治DHL: ASCT二线线治疗疗疗疗
14、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
15、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; 研发发中的新药药和新方法 分类 BTK 抑制剂剂 PI3K 抑制剂剂 Ibrutinib Idelalisib BCL-2 抑制剂剂 MYC 抑制剂 ABT-199 BET 结构域蛋白 BCL-6 抑制剂 Aurora 酶 抑制剂 CART细胞免疫治疗疗 1555 Objective Response
16、s Achieved in Patients with MYC-Altered Relapsed/Refractory Diffuse Large B-Cell Lymphoma Treated with the Dual PI3K and HDAC Inhibitor CUDC-907 (NCT02674750) Daniel J. Landsburg, MD, et al. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA Contents CUDC-907, a first-in-class oral
17、 dual inhibitor of HDAC and PI3K enzymes, has demonstrated downregulation of MYC mRNA and protein levels Phase 2 study is designed to further explore the efficacy of CUDC-907 in DHL and DEL patients Patients with confirmed MYC-altered disease by central immunohistochemistry (IHC) testing Patients re
18、ceive 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, and vomiting 4035 Assessment of CD52 Expression in Double-Hit and Double- Expressor Lymphomas: Implicat
19、ions for Clinical Trial Eligibility (ID: NCT03132584) Jeffrey W. Craig, et al. Department of Pathology, Brigham and Womens Hospital, Boston, MA Contents Phase I trial investigating the use of alemtuzumab and low-dose CTX for the treatment of DHL/THL and DEL Study included 35 DHL, 5 THL, 7 HGBCL, NOS
20、, 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 validation must be performed on a case-by-case basis 577 JULIET: Phase II Primary Analysis of CA
21、R T-Cell Therapy Tisagenlecleucel in Adult Patients With Relapsed/Refractory DLBCL (NCT02631044) Stephen J. Schuster, MD, et al. Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia JULIET: Study Design International, single-arm, open-label phase II trial Tisagenlecleuc
22、el infusion (0.6-6.0 x 108 CAR+ viable T- cells) Screening, apheresis, cryopreservation Restaging, lymphodepletion Adult DLBCL pts with centrally confirmed histology; 2 prior tx lines for DLBCL; PD (n = 99) Posttreatment Follow-up (n = 81 Tisagenlecleuc el evaluable) manufacturing* following or inel
23、igible for autoHSCT; no prior anti-CD19 tx; no active CNS involvement (N = 147) Day -2 to Day -14 Bridging chemotherapy *Centralized in US or Germany. Pts received US-made tisagenlecleucel inpatient or outpatient, with 26% receiving outpatient infusion, 77% of whom remained outpatient 3 days post in
24、fusion; 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. Ima 3 mos. Data cutoff: March 2017. Schuster SJ, et al. ASH 2017. Abstract 577. JULIET Primary Analysis: Baseline P
25、t Characteristics Pts (n = 99) Pts (n = 99) Baseline Characteristics Baseline Characteristics, % Median age, yrs (range) . 65 yrs, % 56 (22-76) 23 No. prior lines of antineoplastic tx . 2 44 31 19 ECOG PS 0/1, %55/45 . 3 . 4-6 Histology, % . DLBCL . Transformed FL 80 19 Response to last tx . Refract
26、ory . Relapsed Double/triple hits in CMYC/BCL2/BCL6,* % 52 48 15 Cell of origin, % Prior autoHSCT47 . Germinal center B-cell type . Nongerminal center B-cell type 52 42 90% of pts received bridging chemotherapy, 93% of pts received lymphodepleting chemotherapy *CMYC/BCL2, n = 4; CMYC/BCL6, n = 3; CM
27、YC/BCL2/BCL6, n = 8. Schuster SJ, et al. ASH 2017. Abstract 577. JULIET: Best ORR (Primary Endpoint) 3-Mo Response (n = 81) 6-Mo Response (n = 46) Best ORR (n = 81) Response, % ORR (CR + PR) 533837 . CR . PR 40 14 32 6 30 7 Study met primary endpoint with ORR of 53% (95% CI: 42% to 64%) Significantl
28、y greater than null hypothesis ORR 20% (P .0001) No relationship apparent between 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 43/81 (53.1) 41.7-64
29、.3 All Pts Age, yrs 2 lines 22/41 (53.7) 37.4-69.3 21/40 (52.5) 36.1-68.5 Cell of origin* 19/34 (55.9) 37.9-72.8 19/41 (46.3) 30.7-62.6 Nongerminal center Germinal center Rearranged MYC/BCL2/BCL6 Double/triple hits Other 5/12 (41.7)15.2-72.3 38/69 (55.1) 42.6-67.1 0102030405060708090100 ORR (%)*Data
30、 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/R DLBCL From TRANSCEND NHL 001: Correlation Between Patient Characteristics and Clinical Outcomes (NCT02631044) Jeremy S. Abramson, MD, MMSc1,
31、 Massachusetts General Hospital Cancer 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 novo or transformed from FL DLBCL FULL (n = 91): CORE + pts with DLBCL transf
32、ormed from CLL/MZL, PMBCL, or FL3B Enrollment, apheresis, JCAR017 Pts with R/Rmanufacturing DLBCL Dose-FindingDLBCL Dose-Expansion CohortCohort JCAR017 IV DL1S: 5 x 107 cells single dose, D1; DL1D: 5 x 107 cells double dose, D1, D14; DL2S: 1 x 108 cells single dose, D1 DLBCL after 2 lines of tx or R
33、/R MCL after 1 line of tx * Pivotal DLBCL cohort enrollment ongoing (JCAR017 IV DL2S) JCAR017 IV DL1S, DL2S *Pts could receive low-dose CT for disease control during JCAR017 manufacturing. Pts received 1 cycle of JACR017 tx, with each cycle preceded by lymphodepletion (fludarabine 30 mg/m2 + cycloph
34、osp mg/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 Exploratory Analysis: Response* CORE DL1S FULL All Dose Levels Response,* n (%) All Dose Levels DL2S Best overall response . ORR . CR n = 68 51 (75)
35、38 (56) n = 49 41 (84) 30 (61) - Pts with 3-mo f/u . 3-mo ORR . 3-mo CR n = 55 27 (49) 22 (40) n = 40 26 (65) 21 (53) n = 21 11 (52) 7 (33) n = 15 12 (80) 11 (73) *Data cutoff: November 1, 2017. In CORE population, pts with durable responses (CR/PR) at 3 mos had generally lower baseline tumor burden
36、, inflammation mar and inflammatory cytokines Siddiqi 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/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 your Attention