精准治疗时代DLBCL免疫化疗的地位.ppt

1、精准治疗时代DLBCL免疫化疗的地位,广东省人民医院肿瘤中心 淋巴瘤科 李文瑜,WHO 2008 Diffuse Aggressive BCLs,Diffuse large B-cell lymphoma, nos Morphologic variants Immunophenotpic and genetic subgroups (activated B-cell vs germinal center B- cell) Diffuse large B-cell lymphoma subtypes T-cell histiocyte-rich large B-cell lymphoma Pri

2、mary DLBCL of the central nervous system Primary cutaneous DLBCL, leg type EBV-positive DLBCL of the elderly Other types of large B-cell lymphoma Primary mediastinal large B-cell lymphoma Intravascular large B-cell lymphoma DLBLC associated with chronic inflammation Lymphomatoid granulomatosis ALK-p

3、ositive large B-cell lymphoma Plasmablastic lymphoma Large B-cell lymphoma arising from HHV-8 associated multicentric Castleman disease Primary effusion lymphoma Borderline cases B-cell lymphoma, unclassifiable with features intermediate between DLBCL and HL B-cell lymphoma, unclassifiable with feat

4、ures intermediate between DLBCL and BL,5年前如何诊断DLBCL,“.弥漫增生的大淋巴细胞，核仁突出，染色质分散. 免疫组化 CD20 ，CD79a 弥漫阳性 B-cell 诊断:DLBCL,R-CHOP是DLBCL一线标准治疗,Sehn,L et al J Clin Oncol 2005,病理报告 一线治疗,NCCN IPI Clinical risk and outcome in DLBCL,Zhou Z et al Blood. 2014,所有DLBCL用R-CHOP不合适 我们正在迅速转向精准诊断，治疗DLBCL,DLBCL应该知道的,细胞起源 G

5、CB vs ABC MYC表达： Double hit , Double expressor 信号通路 BCR, NF-KB, FLR/interleukin 受体信号-MYD88, FOXO pathway,代谢改变(磷酸化) 遗传学/表观遗传学改变 易位：BCL2, BCL6, MYC 突变：CD79a, MYD88, p53, EZH2, 甲基化,根据细胞来源，ABC/GCB治疗,COO in DLBCL:Gene expression vs. immunohistochemistry,Meyer et al,JCO 29：200，2011 Scott et al，Blood 123.1

6、214，2014 Scott et al，JCO 33：2848 ，2015,GCB nonGCB,怎样应用到临床实践中？,免疫组化的方法区别 GCB vs. non-GC,Hans CP et al Blood 2004,Sensitivity for GC 71% Sensitivity for non-GC 88%,ABC/GCB不同发病机制,Germinal Center,Post-Germinal Center,BCL-6,NF-kB,p21,p27Kip1,P53/ATR,Bcl-2,A1,DNA Damage Response Proliferation,Anti-Apoptot

7、ic Proteins,Wilson et al. Haematologica 2012,DA-EPOCH-R in Untreated DLBCL PFS in Molecular Subtypes,GCB DLBCL (100%),Non-GCB(ABC) DLBCL(67%),Probability,Enrolled-68 patients HI/H IPI: 40% Median follow-up 5.4 years),P = 0.008,BCL-6 Expression,Etoposide Topo II Modulates BCL-6 Through Transcriptiona

8、l Inhibition and Proteasome degradation,Ryan et al. Nature Immunology 2007, 8: 1132,The CORAL Study: R-ICE vs. R-DHAP 复发DLBCL,R-DHAP 在GCB 组获益更多,Thieblemont et al, J Clin Oncol 29: 4079, 2011,R-DHAP,R-ICE,GCB组：表观遗传学改变,DNA甲基化 组蛋白去乙酰化 相应的靶点 1，EZH2，20%GCB病例表达。GSK126新药 2，CREBBP:30%,回顾性分析：根据IHC分为GCB/non-G

9、CB,GCB亚组，与R-CHOP相比，R-ACVBP未获益,回顾性分析：根据IHC分为GCB/non-GCB,Non-GCB亚组，与R-CHOP相比，R-ACVBP获益,BiomarkerGCB VS ABC，BCR不同,ABC组,GCB及Burkitt组,ABC-DLBCL通路示意图,单药lenalidomide 在复发/难治性DLBCL: Non-GCB 组获益,CR+PR = 28% 中位持续时间10 months 主要毒副作用: 神经毒性 血小板减少,Hernandez et al, Cancer 117: 5058, 2011 Witzig et al, Ann Oncol 22:1

10、622-1627,2011,Non-GCB,GCB,2/3 期多中心随机对照研究: 复发/难治性DLBCL,Overall response rate: Lenalidomide: 27% IC: 12% Overall response rate, non GCB IHC: Lenalidomide: 28% IC: 11.5% Overall response rate, ABC GEP: Lenalidomide: 46% IC: 18%,Czuczman et al Abstract 628,来那度胺联合R-CHOP克服初治 non-GCB DLBCL的不良预后,试验设计,R2-CHO

11、P (6 个疗程，每个疗程 21天):* 来那度胺 25 mg PO，Day 1-10; 利妥昔单抗 (375 mg/m2)、环磷酰胺(750 mg/m2)、 多柔比星 (50 mg/m2)、长春新碱 (1.4 mg/m2) IV，Day 1; 泼尼松(100 mg/m2) PO，Day 1-5,*每个疗程的第2天给予乙二醇化非格司亭(6 mg SC) ，并且每天给予阿司匹林 (81 mg PO),单臂，2期，开放性性研究 主要研究终点：EFS 次要研究终点：PFS, OS, RR,Grzegorz S. Nowakowski. JCO, August 18, 2014,可评估患者 (n =

12、60) 4/64例患者无法进行评估 (3例拒绝进行治疗和评估，1例死亡),缓解率，% (PET 标准),18%,98%,2%,80%,ORR PD PR CR,总体缓解率高达98%,Grzegorz S. Nowakowski. JCO, August 18, 2014,R2-CHOP方案延长PFS和OS,R2-CHOP,R2-CHOP,R-CHOP,R-CHOP,Grzegorz S. Nowakowski. JCO, August 18, 2014,R2-CHOP方案能够改善non-GCB组的PFS,R-CHOP,R2-CHOP,Grzegorz S. Nowakowski. JCO, A

13、ugust 18, 2014,R2-CHOP方案能够更好改善non-GCB组的OS,R-CHOP,R2-CHOP,Grzegorz S. Nowakowski. JCO, August 18, 2014,不良事件可控,Grzegorz S. Nowakowski. JCO, August 18, 2014,Ibrutinib治疗DLBCL,Ranjana H. Advani, Joseph J. Buggy, Jeff P. JCO.2012.44.4281,ORR 22%,II期研究，ibrutinib 提高ABC DLBCL生存,Response rate,Wilson et al, AS

14、H 2012,Overall survival,Resistance: MyD88 mutant CD79B WT CARD 11 mutant,MYD 88+ CD79B 突变 Ibrutinib有效率 ABC DLBCL,%Response (CR+PR),5/7,10/29,4/5,CARD11 突变Ibrutinib ABC DLBCL 的疗效,%Response (CR+PR),5/7,10/29,4/5,0/5,0/4,ibrunitib 一线治疗: R-CHOP + ibrutinib,R-CHOP+ibrutinib耐受性好,Ib研究，non-GCB 2/2 CR 现在开展II

15、I期随机对照研究 nonGCB (Hans) R-CHOP vs. R-CHOP + ibrutinib 单药有效率40%ABC，提高有限 检测MYD88,CD79B,CARD11,Phase 2 Study of Everolimus in Relapsed Aggressive Lymphoma*,The median number of cycles at 10 mg daily was 2 (range, 112), with 87% (55/63) of patients receiving10mg daily at cycle 2,Median time to response f

16、or responders = 2.0 mos (range, 1.58.7 months). Median TTP = 3.4 mos (95% CI: 2.14.2) Median DR = 5.7 mos (95% CI: 3.612.3); 5 responders were progression free at 12 mos Median PFS = 3.0 mos (95% CI: 2.13.9) Median OS = 8.1 mos (95% CI: 5.312.5),Witzig et al. Leukemia 2011;25:341347.,*Results from e

17、ntire study population follow (MC048G; Witzig et al. EHA 2009),GCB/ABC(non-GCB)治疗方案,GCB组： 一线：R-EPOCH 二线：R-DHAP ABC(non-GCB) R-ACVBP 单药lenalidomide难治病例 Lenalidomide+R-CHOP 单药ibrunitib 单药Everolimus,MYC+ DLBCL,BCL 2 and MYC double expression,MYC /BCL2 共表达， DLBCL预后差标志 -MYC 重排，伯基特淋巴瘤的特征，也与DLBCL预后差相关. -BC

18、L2重排，有些报道中预后差相关 -同时存在这两种表达，预后极差；但这种表达，机理并不是因为异位,Johnson et al J Clin Oncol 2012 Hu et al Blood 2013 Green et al J Clin Oncol 2012,MYC/BCL2 Double Expression,Multivariable analysis: IPI,DE but not COO IPI,COO but not DE,BCL, unclassifiable with features intermediate between DLBCL and BL,不同的，一组疾病 生物学特

19、点介于DLBCL 与BL之间 - DLBCL or “高级别” BCL nos ， 伴有“molecular Burkitt” 基因表达特点 - 比BL更高年龄,常伴有 BCL2 and MYC 异位 - 预后差，OS 1 yr,Hummel M et al NEJM 2006 Dave SS et al I NEJM 2006 Swerdlow S Hematology 2014,BCLu,临床实际工作中确认 - 形态BL - 免疫表型/基因 表型不是BL 发生率？ -12%,Cook JR et al Am J Surg Pathol 2014 Swerdlow SH Hematology

20、 2014,Double Hit Lymphomas,在WHO 2008不是单独分型，高侵袭性，中位OS 1yr MYC-R 伴BCL2-R/BCL6-R -2-14% of DLBCL ,32-78% of BCLu -免疫表型常常GCB (80-90%) MYC/BCL6 DHL不同于MYC/BCL2 -MYC/BCL6 常不表达CD10 /BCL2,表达 MUM1,更少复杂的细胞遗传学改变 -预后真的非常差(DLBCL,nos /DHL)?,Pillai R et al Am J Surg Pathol 2013;Swerdlow S Hematology 2014; Ye Q et a

21、l Oncotarget 2015,Double Hit lymphoma-争议,MYC-R 如何确认？ -大部分研究用断裂探针 -但可能漏检10% 病例 IGH-MYC 探针 IGK-MYC,IGL-MYC探针没有商业化 需要解决的争议 -不同的 MYC partner ？ Non-IG异位预后不差，更多表现DLBCL形态 - MYC异位数量? 可能代表更差的预后,Tzankhov A et al Mod Pathol 2014,Pederson MO et al Eur J Haemotol 2014 Johnson N et al Blood 2009 Li S et al Mod pa

22、thol 2014,DHL : 病例特点,来源于回顾分析材料,Petrich AM et al Blood. 2014,回顾性分析:DHL强化方案好于RCHOP,Petrich AM et al Blood. 2014,MD Anderson回顾性分析,Oki et al Br J Haematol. 2014,回顾性研究:DHL,非随机性研究,经验性，但RCHOP疗效是最差的 强化方案,对比RCHOP，提高PFS，OS无影响 ASCT依然提高PFS，OS无影响 累及CNS :13% ，3years.,Petrich AM et al Blood. 2014 Oki et al Br J Ha

23、ematol. 2014,前瞻性研究DHL：PFS：DA-REPOCH for myc positive DLBCL,Kieron Dunleavy et al. ASH Annual Meeting. 2014,DE:DLBCL治疗挑战,MYC/BCL2, DE生存差, 即使强化化疗及 ASCT. -Takahasi et al,ASH 2015 abstract 3940 -Herrera et al，ASH 2015 abstract 522 Double Expressing (MYC/BCL2) and Double-Hit Diffuse Large B-Cell Lymphoma

24、s Have Inferior Survival Following Autologous Stem Cell Transplantation 25% of ABC ,17% of GCB -Punnoose et al，ASH 2015 abstract3,新方法：Myc+/Bcl-2+ DLBCL,双抑制剂myc（JQ1）/ bcl-2（Venetoclax）潜在的抑制剂 -Cinar et al,Leuk Res 39:730 2015 CUDC-907:双抑制剂HDAC/PI3K -DE,非常高的反应率 Younes et al,ASH 2015,abstract 257 SEL24-

25、B489 Pan-PIM kinase inhibitor -下调MYC蛋白表达 Jablonska et al,ASH 2015,abstract 706,Phase 1 Trial Testing Single Agent CUDC-907, a Novel, Oral Dual Inhibitor of Histone Deacetylase (HDAC) and PI3K: Initial Assessment of Patients with Relapsed or Refractory (RR) Diffuse Large B-Cell Lymphoma (DLBCL), Incl

26、uding Double Expressor (DE) Lymphoma,11例难治性DLBCL, 55%CR+PR,中位有效时间119天 3例DE,1CR,1PR,1SD,持续171天,In Vitro Efficacy in DLBCL Cells,CUDC-907 Decreases MYC Protein Levels in DLBCL Cells,In Vivo Efficacy in MYC+ Xenograft Models,Exploratory Biomarker Analysis in RR DLBCL: MYC, BCL-2 and COO,RR DLBCL Maximum Target Lesion Change,RR DLBC