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1、弥漫大B细胞淋巴瘤 治疗新进展,张翼鷟 天津医科大学附属肿瘤医院血液科 天津市肿瘤防治重点实验室 ,概述 流行病学 基于分子生物学改变的预后评价 治疗进展 初治的DLBCL 难治复发的DLBCL 新药临床试验,概述,流行病学,弥漫大B细胞淋巴瘤: 31%,滤泡性淋巴瘤:22%,边缘区淋巴瘤:8%,套细胞淋巴瘤:6%,小细胞淋巴瘤 7%,外周T细胞淋巴瘤:7%,HL及NHL的发病率,B-NHL 6632,66%,UC 378,4%,HL 854,9%,T/NK-NHL 2138,21%,病例总数：10002,SMZL,41,1%,B-LBL,172,3%,UC,387,6%,DLBCL,NOS,
2、3328,48%,MCL,307,5%,PCNs,221,3%,BL,107,2%,MMZL,99,1%,LPL,57,1%,DLBCL,SS,378,6%,MALTL,685,10%,FL,551,8%,CLL/SLL,424,6%,病例总数：6638,B-NHL亚型的发病率,DLBCL FL MALTL MCL CLL/SLL BL SMZL NMZL,弥漫大B细胞淋巴瘤,最常见的非霍奇金淋巴瘤: 31% 发病高峰:60岁 临床表现及分子生物学特征: 高度异质性 大细胞 无淋巴滤泡结构 中位生存期: 数周/月(若不治疗) 30% 到 40% 伴有B 症状 可能伴有结外病变(胃肠道, 中枢神
3、经系统, 睾丸, 皮肤) Michallet AS, et al. Blood Rev. 2009;23:11-23.,2010年NCCN指南: Essential Diagnostic Assessments for DLBCL,对所有切片进行血液病理学检查(至少1个为含有肿瘤组织的石蜡块) 淋巴结切检 当淋巴结难以切除或切取活检时,联合FNA和空心针活检并结合辅助检查 时免疫表型:(DLBCL typically CD20+, CD45+, CD3-) 免疫组化(石蜡切片):CD20, CD3, CD4, CD10, CD45, BCL2, BCL6, Ki-67, IRF-4/MUM1
4、流式细胞学:CD45, CD3, CD5, CD19, CD10, CD20, kappa/lambda NCCN Practice Guidelines in Oncology. 2010.,弥漫大B细胞淋巴瘤的预后因素 不良预后因素影响化疗效果与生存期 年龄60岁 LDH 正常值 一般状态评分 2 Ann Arbor 分期 III/IV 结外受累区 1 个*,Prognostic for patients older than 60 yrs of age only.,International NHL Prognosis Factors Project. N Engl J Med. 199
5、3;329:987-994.,Yrs,Percent Survival,Very good,Good,Poor,P .0001,基于修正IPI评分的总生存率,1.0,0.9,0.8,0.7,0.6,0.5,0.4,0.3,0.2,0.1,0,0,1,2,3,4,5,Sehn LH, et al. Blood. 2007;109:1857-1861.,与弥漫大B细胞淋巴瘤相关的分子遗传学改变,遗传学异常较常见 染色体异位: 50% DNA 失衡: 高达67%,Abramson JS, et al. Blood. 2005;106:1164-1174.,Yrs,OS,基因表达谱-分子水平将DLBC
6、L分为不同的临床亚型,1.0,0.8,0.6,0.4,0.2,0,0,2,4,6,8,10,Rosenwald A, et al. J Exp Med. 2003;198:851-862.,Rosenwald A, et al. N Engl J Med. 2002;346:1937-1947. Copyright 2002 Massachusetts Medical Society. All rights reserved.,0,0.2,0.4,0.6,0.8,1.0,0,4,8,Probability of Survival,6,10,2,P .001,Yrs,不同亚型的DLBCL的生存期
7、,Germinal-center B-cell like,Type 3,Activated B-cell like,基因表达谱-分子水平将DLBCL分为不同的临床亚型,Bea S, et al. Blood. 2005;106:3183-3190.,Lenz G, et al. N Engl J Med. 2008;359:2313-2323.,CHOP-R治疗方案对DLBCL亚型的预后具有价值,CHOP-Rituximab OS,1.0,0.8,0.6,0.4,0.2,0,Probability,0,1,2,3,4,5,6,Yrs,P = 4 x 10-3,CHOP-Rituximab PF
8、S,CHOP OS,1.0,0.8,0.6,0.4,0.2,0,0,1,2,3,4,5,6,Yrs,P = 1 x 10-4,1.0,0.8,0.6,0.4,0.2,0,0,1,2,3,4,5,Yrs,6,P = 8 x 10-6,GCB DLBCL,ABC DLBCL,基于基因表达的风险评分- 预测DLBCL临床结果,潜在的疾病生物学尚未确定 研究目的:CHOP- 及R-CHOP治疗后的DLBCL病人的基因表达特征 III 期随机实验,E4494存档的组织, (N = 632) CHOP vs R-CHOP rituximab 维持治疗老年DLBCL病人 石蜡包埋组织储存 10 yrs 经过
9、微阵列处理的相关性研究 指标:比例风险模式 (FFS, OS),Winter JN, et al. ASH 2011. Abstract 87.,基于基因表达的风险评分- 预测DLBCL临床结果,N = 183合格者, 可评估案例 6 genes for R-CHOP 5 genes for CHOP (single gene overlap LMO2) High- vs low-gene risk scores significantly predicted E4494 clinical outcome (median follow-up: 9.4 yrs),Winter JN, et al
10、. ASH 2011. Abstract 87.,基于基因表达的风险评分- 预测DLBCL临床结果,CHOP,R-CHOP,Winter JN, et al. ASH 2011. Abstract 87.,Probability, Median Median, Median Median,1.0,0.8,0.6,0.4,0.2,0,12,0,2,4,6,8,10,Yrs,FFS,P = .001,基于基因表达的风险评分- 预测DLBCL临床结果,High- vs low-gene risk scores significantly predicted OS CHOP (median follo
11、w-up: 7.6 yrs; P .0001) R-CHOP (median follow-up: 2.8 yrs; P = .0014) 基因风险评分对调整后的IPI多元分析具有预测意义,Winter JN, et al. ASH 2011. Abstract 87.,基于基因表达的风险评分- 预测DLBCL临床结果,该预测模型也可区分一些不同来源的细胞的差异 CHOP: significant difference among nongerminal center B-cell (GCB) cases (P = .0002) R-CHOP: significant difference a
12、mong GCB cases (P = .03) Molecular predictors largely independent of IPI in both CHOP, R-CHOP patients,Winter JN, et al. ASH 2011. Abstract 87.,弥漫大B细胞淋巴瘤的治疗进展,初治DLBCL,CHOP Rituximab in DLBCL: GELA LNH-98.5 Phase III Study,Primary endpoint: EFS Secondary endpoints: OS, RR,R-CHOP every 3 wks for 8 cyc
13、les (n = 202),CHOP every 3 wks for 8 cycles (n = 197),Untreated elderly patients with stage II-IV DLBCL (N = 399),Stratified by risk factors (0-1 vs 2-3),Assessment,Coiffier B, et al. N Engl J Med. 2002;346:235-242. Feugier P, et al. J Clin Oncol. 2005;23:4117-4126.,Maint. Ritux. After R-CHOP or CHO
14、P in Older DLBCL (E4494/C9793 Ph III Study),Primary endpoint: FFS,Morrison VA, et al. ASCO 2007. Abstract 8011. Habermann TM, et al. J Clin Oncol. 2006;24:3121-3127.,Untreated patients with CD20+ DLBCL, 60 yrs of age or older, PS 0-3 (N = 632),R-CHOP x 6-8 cycles (n = 318),CHOP x 6-8 cycles (n = 314
15、),Stratified by IPI score (0-1 vs 2-4),Responders (n = 415),Maintenance Rituximab q6mos x 2 yrs, starting 4 wks after last cycle (n = 207),Observation (n = 208),Stratified by IPI score, CR/PR, induction,Cunningham D, et al. ASCO 2009. Abstract 8506.,Newly diagnosed CD20+ DLBCL patients (N = 1080),R-
16、CHOP-14 x 6 cycles + Rituximab x 8 cycles + Lenograstim on Days 4-12 (n = 540),R-CHOP-21 x 8 cycles + Rituximab x 8 cycles (n = 540),Stratified by IPI score and age,R-CHOP-14 vs R-CHOP-21 in Newly Diagnosed DLBCL (Phase III Study),Primary endpoint: OS Secondary endpoint: FFS, toxicity, response rate
17、s,Cunningham D, et al. ASCO 2009. Abstract 8506.,*249 patients not evaluable or data missing.,R-CHOP-14 vs R-CHOP-21 in Newly Diagnosed DLBCL: Responses,LNH03-6B GELA: R-CHOP-14 vs R-CHOP-21 in Elderly DLBCL Patients,Primary endpoint: EFS Secondary endpoints: CR or CRu, ORR, PFS , DFS, OS, dose inte
18、nsity, toxicity,Delarue R, et al. ASH 2009. Abstract 406.,R-CHOP every 14 days for 8 cycles + IT MTX for 4 cycles (n = 103),R-CHOP every 21 days for 8 cycles + IT MTX for 4 cycles (n = 99),DLBCL patients 60-80 yrs of age (N = 202),Prophylactic Darbepoetin alfa,Conventional treatment for chemotherapy
19、- induced anemia,Prophylactic Darbepoetin alfa,Conventional treatment for chemotherapy- induced anemia,LNH03-6B GELA Trial: Results,Delarue R, et al. ASH 2009. Abstract 406.,Hematologic toxicities greater for R-CHOP-14 Patients on R-CHOP-14 had higher rates of febrile neutropenia, hospitalization, a
20、nd death due to toxicity,LNH03-6B GELA Trial: Toxicities,R-CHOP-14,R-CHOP-21,11,15,22,21,36,50,22,26,69,83,73,83,Patients (%),100,90,80,70,60,50,40,30,20,10,0,Grade 3/4 Leukocytes,Grade 3/4 Neutrophils,Grade 3/4 Hemoglobin,RBC Transfusion,Grade 3/4 Platelets,Platelet Transfusion,Delarue R, et al. AS
21、H 2009. Abstract 406.,Pfreundschuh M, et al. Lancet Oncol. 2006;7:379-391.,MInT: Ph III Study of CHOP-like Chemo Rituximab in Adv DLBCL (Younger Pts),Patients with untreated CD20+ stage II-IV DLBCL (or bulky stage I), IPI 0-1, 18-60 yrs of age (N = 823),CHOP-like regimen* + 30-40 Gy radiotherapy (n
22、= 410),CHOP-like regimen* + Rituximab 375 mg/m2 + 30-40 Gy radiotherapy (n = 413),Cycle 6,*CHOP-21, CHOEP-21, MACOP-B, or PMitCEBO.,Stratified by age-adjusted IPI score (0-1 vs 2-3), bulky disease, treatment center, and regimen,MInT: 6-Yr Follow-up Data,Current study presented 6-yr findings (N = 823
23、),Multivariate analysis showed EFS influenced by Rituximab (HR: 0.49; P .001) Age-adjusted IPI (HR: 1.73; P .001) Bulky disease (HR: 1.43; P = .004),Pfreundshuh M, et al. ASH 2010. Abstract 111.,R-EPOCH 方案,Given every 21 days for 4-6 cycles Regimen consists of Rituximab 375 mg/m2 on Day 1 Etoposide
24、65 mg/m2 continuous IV on Days 2-4 Prednisone 60 mg/m2 PO on Day 1-14 Vincristine 0.5 mg continuous IV on Day 2-4 Cyclophosphamide 750 mg/m2 IV on Day 5 Doxorubicin 15 mg/m2 continuous IV on Days 2-4,Ph II Study of Dose-Adjusted EPOCH-R in DLBCL (CALGB 50103): PFS by IPI Score,Median potential follo
25、w-up: 54 mos 5-yr PFS: 79% Low risk IPI: 91% Low-int risk IPI: 90% High-int risk IPI: 67% High risk IPI: 47% IPI score significantly associated with PFS (P = .007),Wilson WH, et al. J Clin Oncol. 2008;26:2717-2724.,CALGB 50303: R-CHOP vs R-EPOCH in Newly Diagnosed DLBCL,Primary endpoints: EFS, molec
26、ular predictors of outcome for each regimen Secondary endpoints: RR, OS, toxicity, use of molecular profiling for pathological diagnosis,R-CHOP every 3 wks for 6 cycles,R-EPOCH Doxorubicin, etoposide, vincristine on Days 1-4, cyclophosphamide on Day 5, prednisone on Days 1-5,Untreated patients with
27、newly diagnosed DLBCL (N = 478),ClinicalTrials.gov. NCT00118209.,Primary endpoints: OS and PFS Closed: 12/15/07 with 276 randomized patients,Patients with bulky stage II-IV, high-int or high-risk CD20+ NHL (N = 276),CHOP or R-CHOP for 5 cycles,PR or CR,CHOP or R-CHOP for 3 courses No additional ther
28、apy until progression,CHOP or R-CHOP for 1 course + ASCT,Stratified by disease risk (int-high vs high),Off therapy if PR,ClinicalTrials.gov. NCT00004031.,Early vs Delayed HDT in High-Int/High-Risk DLBCL: Phase III S9704 Study,复发难治 DLBCL,NCCN Guideline Recommendations for Treatment of Relapsed DLBCL,
29、Second-line therapy in candidates for high-dose therapy + ASCT DHAP rituximab ESHAP rituximab GDP rituximab GemOx rituximab ICE rituximab miniBEAM rituximab MINE rituximab,Second-line therapy for patients who are not candidates for high-dose therapy Clinical trial Rituximab CEPP rituximab PEPC EPOCH
30、 rituximab,NCCN Practice Guidelines in Oncology. 2010.,治疗DLBCL的新药临床试验,DLBCL研究中的药物 (Off-Label Use),Bevacizumab 贝伐单抗 recombinant, humanized, monoclonal VEGF antibody Bortezomib 硼替佐米proteasome inhibitor Enzastaurin PKC-selective inhibitor Epratuzumab 依帕珠单抗recombinant, humanized, monoclonal CD22 antibod
31、y Everolimus 依维莫司mTOR inhibitor Lenalidomide 雷利度胺immunomodulator, antiangiogenic Radioimmunotherapy Fostamatinib specific inhibitor of Syk in B-cell signaling pathway,治疗DLBCL的研究中的药物: Phase II Data,1. Micallef IN, et al. ASCO 2008. Abstract 8500. 2. Zinzani PL, et al. Ann Oncol. 2008;19:769-773. 3. H
32、aioun C, et al. ASCO 2010. Abstract 8069. 4. Friedberg JW, et al. Blood. 2010;115:2578-2585. 5. Wiernik PH, et al. J Clin Oncol. 2008;26:4952-4957.,Bortezomib (硼替佐米)+ CHOP-R作为DLBCL的一线治疗,Phase I/II N = 40 patients with previously untreated DLBCL CHOP-21 + rituximab 375 mg/m2 each cycle Bortezomib giv
33、en at 3 different doses Arm 0 (n = 4): 0.7 mg/m2 Arm 1 (n = 8): 1.0 mg/m2 Arm 2 (n = 28): 1.3 mg/m2,Median follow-up: 21 mos (range: 9-35) ORR results ITT (n = 40): 90% (CR/CRu: 68%) Evaluable (n = 36): 100% (CR/CRu: 75%) Estimated 2-yr PFS: 72% Treatment generally well tolerated 4 deaths prior to f
34、irst response assessment,Leonard JP, et al. ASCO 2007. Abstract 8031.,Bendamustine (苯达莫司汀) + Rituximab for Rel/Ref DLBCL: Phase II Study,Day 1: bendamustine 120 mg/m2 + rituximab 375 mg/m2 ; Day 2: bendamustine 120 mg/m2 ORR of 60% required by study design,Bendamustine + Rituximab 28-day cycles for
35、6 cycles,Patients with relapsed/refractory DLBCL who failed at least 1 previous therapy (N = 25, ITT),Vacirca JL, et al. ASCO 2010. Abstract 8041.,Bendamustine+ Rituximab for Rel/Ref DLBCL: Preliminary Phase II Results,Vacirca JL, et al. ASCO 2010. Abstract 8041.,Everolimus(依维莫司): Ongoing Phase II a
36、nd III Studies in DLBCL,Phase II Everolimus plus rituximab in relapsed/refractory DLBCL1 Everolimus, panobinostat, or both in relapsed/refractory DLBCL2 Everolimus in relapsed/refractory lymphoma3 Phase III Everolimus as adjuvant therapy following CR to first-line rituximab-chemotherapy in patients
37、with poor-risk DLBCL4,1. ClinicalTrials.gov. NCT00869999. 2. ClinicalTrials.gov. NCT00978432. 3. ClinicalTrials.gov. NCT00436618. 4. ClinicalTrials.gov. NCT00790036.,Phase II R-CHOP plus bevacizumab for first-line treatment of DLBCL1 Bevacizumab plus R-CHOP for first-line treatment of stage II-IV DLBCL2 Phase III R-CHOP vs R-CHOP plus bevacizumab for first-line treatment of DLBCL3,Bevacizumab(贝伐单抗): Ongoing Phase II and III Studies in DLBCL,ClinicalTrials.gov. NCT00788606. ClinicalTrials.gov. NCT00121199. 3. ClinicalTrials.gov. NCT00486759,谢谢！,