弥漫大B细胞淋巴瘤治疗新进展汇编

1、 概述概述 流行病学流行病学 基于分子基于分子生物学生物学改变改变的的预后评价预后评价 治疗进展治疗进展 初治的初治的DLBCL 难治复发的难治复发的DLBCL 新药临床试验新药临床试验 概述 流行病学流行病学 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及及NHL的发病率的发病率 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,33

2、28,48% 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最常见的非霍奇金淋巴瘤: 31% 发病高峰发病高峰:60岁岁 临床表现及分子生物学特征临床表现及分子生物学特征: 高度异质性高度异质性 大细胞大细胞 无淋巴滤泡结构无淋巴滤泡结构 中位生存期

3、中位生存期: 数周数周/月月(若不治疗若不治疗) 30% 到到 40% 伴有伴有B 症状症状 可能伴有结外病变可能伴有结外病变(胃肠道胃肠道, 中枢神经系统中枢神经系统, 睾丸睾丸, 皮肤皮肤) Michallet AS, et al. Blood Rev. 2009;23:11-23. 2010年年NCCN指南指南: Essential Diagnostic Assessments for DLBCL 对所有切片进行血液病理学检查对所有切片进行血液病理学检查(至少至少1个为含有肿瘤组织的石蜡块个为含有肿瘤组织的石蜡块) 淋巴结切检淋巴结切检 当淋巴结难以切除或切取活检时当淋巴结难以切除或切取

4、活检时,联合联合FNA和空心针活检并结合辅助检查和空心针活检并结合辅助检查 时免疫表型时免疫表型:(DLBCL typically CD20+, CD45+, CD3-) 免疫组化免疫组化(石蜡切片石蜡切片):CD20, CD3, CD4, CD10, CD45, BCL2, BCL6, Ki-67, IRF-4/MUM1 流式细胞学流式细胞学:CD45, CD3, CD5, CD19, CD10, CD20, kappa/lambda NCCN Practice Guidelines in Oncology. 2010. 弥漫大弥漫大B细胞淋巴瘤的细胞淋巴瘤的 预后因素预后因素 不良预后因素

5、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. 1993;329:987-994. Yrs Percent Survival Very good Good Poor P .0001 基于修正基于修正IPI评分的总生存率评分的总生存率 1.0 0.9 0.8 0.7 0.6 0.5 0.4

6、 0.3 0.2 0.1 0 012345 Sehn LH, et al. Blood. 2007;109:1857-1861. 与弥漫大与弥漫大B细胞淋巴瘤相关的分子遗传学改细胞淋巴瘤相关的分子遗传学改 变变 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 基因表达谱基因表达谱-分子水平将分子水平将DLBCL分为不同的临床分为不同的临床 亚型亚型 1.0 0.8 0.6 0.4 0.2 0 0246810 Rosenwald A, et al. J Exp Med.

7、 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 1.0 048 Probability of Survival 6102 P 10 yrs 经过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基于基因表达的风险评

8、分- 预测预测DLBCL临床结果临床结果 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. ASH 2011. Abstract 87. 基于基因表达的风险评分基于基因表达的风险评分- 预测预测DLBCL临床结果临床结果 CHOPR-CHOP

9、 Winter JN, et al. ASH 2011. Abstract 87. Probability 1.0 0.8 0.6 0.4 0.2 0 1202468 10 Yrs FFS P = .003 Median Median 1.0 0.8 0.6 0.4 0.2 0 1202468 10 Yrs OS P = .001 Median Median 1.0 0.8 0.6 0.4 0.2 0 1202468 10 Yrs FFS P = .001 1.0 0.8 0.6 0.4 0.2 0 1202468 10 Yrs OS P = .0015 基于基因表达的风险评分基于基因表达的风

10、险评分- 预测预测DLBCL临床结果临床结果 High- vs low-gene risk scores significantly predicted OS CHOP (median follow-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基于基因表达的风险评分- 预测预测DLBCL临床结果临床结果 该预测模型也可区分一些不同 来源的细胞的差异 C

11、HOP: significant difference among nongerminal center B-cell (GCB) cases (P = .0002) R-CHOP: significant difference among GCB cases (P = .03) Molecular predictors largely independent of IPI in both CHOP, R-CHOP patients Winter JN, et al. ASH 2011. Abstract 87. 弥漫大弥漫大B细胞淋巴瘤的细胞淋巴瘤的 治疗进展治疗进展 初治初治DLBCL C

12、HOP Rituximab in DLBCL: GELA LNH-98.5 Phase III Study Primary endpoint: EFS Secondary endpoints: OS, RR R-CHOP every 3 wks for 8 cycles (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 Coi

13、ffier 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 CHOP 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. Un

14、treated 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) 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) Stratif

15、ied by IPI score, CR/PR, induction Cunningham D, et al. ASCO 2009. Abstract 8506. Newly diagnosed CD20+ DLBCL patients (N = 1080) R-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-C

16、HOP-14 vs R-CHOP-21 in Newly Diagnosed DLBCL (Phase III Study) Primary endpoint: OS Secondary endpoint: FFS, toxicity, response rates 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:

17、R-CHOP-14 vs R-CHOP-21 in Elderly DLBCL Patients Primary endpoint: EFS Secondary endpoints: CR or CRu, ORR, PFS , DFS, OS, dose intensity, 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 f

18、or 4 cycles (n = 99) DLBCL patients 60-80 yrs of age (N = 202) Prophylactic Darbepoetin alfa Conventional treatment for chemotherapy- induced anemia Prophylactic Darbepoetin alfa Conventional treatment for chemotherapy- induced anemia LNH03-6B GELA Trial: Results Delarue R, et al. ASH 2009. Abstract

19、 406. Hematologic toxicities greater for R-CHOP-14 Patients on R-CHOP-14 had higher rates of febrile neutropenia, hospitalization, and death due to toxicity LNH03-6B GELA Trial: Toxicities R-CHOP-14 R-CHOP-21 11 15 2221 36 50 22 26 69 83 73 83 Patients (%) 100 90 80 70 60 50 40 30 20 10 0 Grade 3/4

20、Leukocytes Grade 3/4 Neutrophils Grade 3/4 Hemoglobin RBC Transfusion Grade 3/4 Platelets Platelet Transfusion Delarue R, et al. ASH 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 untre

21、ated 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 = 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

22、(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) 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

23、. ASH 2010. Abstract 111. R-EPOCH 方案方案 Given every 21 days for 4-6 cycles Regimen consists of Rituximab 375 mg/m2 on Day 1 Etoposide 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

24、 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 follow-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) Wil

25、son WH, et al. J Clin Oncol. 2008;26:2717-2724. CALGB 50303: R-CHOP vs R-EPOCH in Newly Diagnosed DLBCL Primary endpoints: EFS, molecular 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 cycle

26、s R-EPOCH Doxorubicin, etoposide, vincristine on Days 1-4, cyclophosphamide on Day 5, prednisone on Days 1-5 Untreated patients with newly diagnosed DLBCL (N = 478) ClinicalT. NCT00118209. Primary endpoints: OS and PFS Closed: 12/15/07 with 276 randomized patients Patients with bulky stage

27、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 therapy until progression CHOP or R-CHOP for 1 course + ASCT Stratified by disease risk (int-high vs high) Off therapy if PR ClinicalT. NCT00004031. Early vs Dela

28、yed HDT in High-Int/High-Risk DLBCL: Phase III S9704 Study 复发难治复发难治 DLBCL NCCN Guideline Recommendations for Treatment of Relapsed DLBCL Second-line therapy in candidates for high-dose therapy + ASCT DHAP rituximab ESHAP rituximab GDP rituximab GemOx rituximab ICE rituximab miniBEAM rituximab MINE r

29、ituximab Second-line therapy for patients who are not candidates for high-dose therapy Clinical trial Rituximab CEPP rituximab PEPC EPOCH rituximab NCCN Practice Guidelines in Oncology. 2010. 治疗治疗DLBCL的新药临床试验的新药临床试验 DLBCL研究中的药物研究中的药物 (Off-Label Use) Bevacizumab 贝伐单抗贝伐单抗 recombinant, humanized, monoc

30、lonal VEGF antibody Bortezomib 硼替佐米硼替佐米proteasome inhibitor Enzastaurin PKC-selective inhibitor Epratuzumab 依帕珠单抗依帕珠单抗recombinant, humanized, monoclonal CD22 antibody Everolimus 依维莫司依维莫司mTOR inhibitor Lenalidomide 雷利度胺雷利度胺immunomodulator, antiangiogenic Radioimmunotherapy Fostamatinib specific inhib

31、itor of Syk in B-cell signaling pathway Evolving Management Strategies in Non-Hodgkins Lymphoma 治疗治疗DLBCL的研究中的药物的研究中的药物: Phase II Data 1. Micallef IN, et al. ASCO 2008. Abstract 8500. 2. Zinzani PL, et al. Ann Oncol. 2008;19:769-773. 3. Haioun C, et al. ASCO 2010. Abstract 8069. 4. Friedberg JW, et

32、al. Blood. 2010;115:2578-2585. 5. Wiernik PH, et al. J Clin Oncol. 2008;26:4952-4957. Bortezomib (硼替佐米硼替佐米)+ CHOP-R作为作为 DLBCL的一线治疗的一线治疗 Phase I/II N = 40 patients with previously untreated DLBCL CHOP-21 + rituximab 375 mg/m2 each cycle Bortezomib given at 3 different doses Arm 0 (n = 4): 0.7 mg/m2 A

33、rm 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 first response assessment Leonard JP, et al. ASCO 2007. Abstract 8031. Bendamustine (苯达莫司汀苯达莫司汀) + 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 6 cycles Patients with rela