弥漫大B细胞淋巴瘤治疗新进展48课件

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aprilzyzyahoo 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：10002SMZL,41,1%B-LBL,172,3%UC,387,6%DLBCL,NOS,3328,48%M

2、CL,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：6638B-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, 中枢神经系统, 睾丸, 皮肤)Michallet AS, et

3、 al. Blood Rev. 2009;23:11-23.2019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流式细胞学:CD45, CD3, CD5, CD19, CD10, CD

4、20, kappa/lambdaNCCN Practice Guidelines in Oncology. 2019.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 2Ann 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.YrsPercent SurvivalVery goodGood

5、PoorP .0001基于修正IPI评分的总生存率1.00012345Sehn LH, et al. Blood. 2019;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. 2019;106:1164-1174.YrsOS基因表达谱-分子水平将DLBCL分为不同的临床亚型1.00.200246810Rosenwald A, et al. J Exp Med. 2019;198:851-86

6、2.Rosenwald A, et al. N Engl J Med. 2019;346:1937-1947. Copyright 2019 Massachusetts Medical Society. All rights reserved.00.81.0048Probability of Survival6102P 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 2019. 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 fo

7、r R-CHOP5 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 2019. Abstract 87.基于基因表达的风险评分- 预测DLBCL临床结果CHOPR-CHOPWinter JN, et al. ASH 2019. Abstract 87.Probability1.00.201202

8、46810YrsFFSP = .003 Median Median1.00.20120246810YrsOSP = .001 Median Median1.00.20120246810YrsFFSP = .0011.00.20120246810YrsOSP = .0015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 OSCHOP (median follow-up: 7.6 yrs; P .0001)R-CHOP (median f

9、ollow-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 2019. 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 among GCB cases (P = .03)Molecular predictors l

10、argely independent of IPI in both CHOP, R-CHOP patientsWinter JN, et al. ASH 2019. Abstract 87.弥漫大B细胞淋巴瘤的治疗进展初治DLBCLCHOP Rituximab in DLBCL: GELA LNH-98.5 Phase III StudyPrimary endpoint: EFSSecondary endpoints: OS, RRR-CHOPevery 3 wks for 8 cycles(n = 202)CHOPevery 3 wks for 8 cycles(n = 197)Untrea

11、ted elderly patients with stage II-IV DLBCL(N = 399)Stratified by risk factors (0-1 vs 2-3)AssessmentCoiffier B, et al. N Engl J Med. 2019;346:235-242. Feugier P, et al. J Clin Oncol. 2019;23:4117-4126.Maint. Ritux. After R-CHOP or CHOP in Older DLBCL (E4494/C9793 Ph III Study)Primary endpoint: FFSM

12、orrison VA, et al. ASCO 2019. Abstract 8011.Habermann TM, et al. J Clin Oncol. 2019;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)Stratified by IPI score (0-1 vs 2-4)Responders(n = 415)Maintenance Rituxi

13、mabq6mos x 2 yrs, starting 4 wks after last cycle(n = 207)Observation(n = 208)Stratified by IPI score, CR/PR, inductionCunningham D, et al. ASCO 2009. Abstract 8506.Newly diagnosed CD20+ DLBCLpatients(N = 1080)R-CHOP-14 x 6 cycles +Rituximab x 8 cycles +Lenograstim on Days 4-12(n = 540)R-CHOP-21 x 8

14、 cycles +Rituximab x 8 cycles(n = 540)Stratified by IPI score and ageR-CHOP-14 vs R-CHOP-21 in Newly Diagnosed DLBCL (Phase III Study)Primary endpoint: OSSecondary endpoint: FFS, toxicity, response ratesCunningham D, et al. ASCO 2009. Abstract 8506.*249 patients not evaluable or data missing.R-CHOP-

15、14 vs R-CHOP-21 in Newly Diagnosed DLBCL: ResponsesLNH03-6B GELA: R-CHOP-14 vs R-CHOP-21 in Elderly DLBCL PatientsPrimary endpoint: EFSSecondary endpoints: CR or CRu, ORR, PFS , DFS, OS, dose intensity, toxicityDelarue R, et al. ASH 2009. Abstract 406.R-CHOP every 14 days for 8 cycles + IT MTX for 4

16、 cycles (n = 103)R-CHOP every 21 days for 8 cycles + IT MTX for 4 cycles (n = 99)DLBCL patients60-80 yrs of age(N = 202)ProphylacticDarbepoetin alfaConventional treatmentfor chemotherapy-induced anemiaProphylacticDarbepoetin alfaConventional treatmentfor chemotherapy-induced anemiaLNH03-6B GELA Tria

17、l: Results Delarue R, et al. ASH 2009. Abstract 406.Hematologic toxicities greater for R-CHOP-14Patients on R-CHOP-14 had higher rates of febrile neutropenia, hospitalization, and death due to toxicityLNH03-6B GELA Trial: ToxicitiesR-CHOP-14R-CHOP-21111522213650222669837383Patients (%)10090807060504

18、03020100Grade 3/4LeukocytesGrade 3/4NeutrophilsGrade 3/4HemoglobinRBCTransfusionGrade 3/4PlateletsPlateletTransfusionDelarue R, et al. ASH 2009. Abstract 406.Pfreundschuh M, et al. Lancet Oncol. 2019;7:379-391.MInT: Ph III Study of CHOP-like Chemo Rituximab in Adv DLBCL (Younger Pts)Patients with un

19、treated 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 (0-1 v

20、s 2-3), bulky disease, treatment center, and regimenMInT: 6-Yr Follow-up DataCurrent study presented 6-yr findings (N = 823)Multivariate analysis showed EFS influenced byRituximab (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 2019. A

21、bstract 111.R-EPOCH 方案Given every 21 days for 4-6 cyclesRegimen consists ofRituximab 375 mg/m2 on Day 1Etoposide 65 mg/m2 continuous IV on Days 2-4Prednisone 60 mg/m2 PO on Day 1-14Vincristine 0.5 mg continuous IV on Day 2-4Cyclophosphamide 750 mg/m2 IV on Day 5Doxorubicin 15 mg/m2 continuous IV on

22、Days 2-4Ph II Study of Dose-Adjusted EPOCH-R in DLBCL (CALGB 50103): PFS by IPI ScoreMedian potential follow-up: 54 mos5-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. 2019

23、;26:2717-2724.CALGB 50303: R-CHOP vs R-EPOCH in Newly Diagnosed DLBCLPrimary endpoints: EFS, molecular predictors of outcome for each regimenSecondary endpoints: RR, OS, toxicity, use of molecular profiling for pathological diagnosisR-CHOPevery 3 wks for 6 cyclesR-EPOCHDoxorubicin, etoposide, vincri

24、stine on Days 1-4, cyclophosphamide on Day 5,prednisone on Days 1-5Untreated patients with newly diagnosedDLBCL(N = 478)ClinicalT. NCT00118209. Primary endpoints: OS and PFSClosed: 12/15/07 with 276 randomized patientsPatients with bulky stage II-IV, high-int or high-risk CD20+ NHL(N = 276)

25、CHOP or R-CHOP for 5 cyclesPR or CRCHOP or R-CHOP for 3 coursesNo additional therapy until progressionCHOP or R-CHOP for 1 course + ASCTStratified by disease risk (int-high vs high)Off therapy if PRClinicalT. NCT00004031.Early vs Delayed HDT in High-Int/High-Risk DLBCL: Phase III S9704 Stud

26、y复发难治 DLBCLNCCN Guideline Recommendations for Treatment of Relapsed DLBCLSecond-line therapy in candidates for high-dose therapy + ASCTDHAP rituximabESHAP rituximabGDP rituximabGemOx rituximabICE rituximabminiBEAM rituximabMINE rituximabSecond-line therapy for patients who are not candidates for hig

27、h-dose therapyClinical trialRituximabCEPP rituximabPEPC EPOCH rituximabNCCN Practice Guidelines in Oncology. 2019.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 antibodyBortezomib 硼替佐米proteasome inhibitorEnzastaurin PKC-selective inhibitorEpratuzuma

28、b 依帕珠单抗recombinant, humanized, monoclonal CD22 antibodyEverolimus 依维莫司mTOR inhibitorLenalidomide 雷利度胺immunomodulator, antiangiogenicRadioimmunotherapy Fostamatinib specific inhibitor of Syk in B-cell signaling pathway治疗DLBCL的研究中的药物: Phase II Data1. Micallef IN, et al. ASCO 2019. Abstract 8500. 2. Zi

29、nzani PL, et al. Ann Oncol. 2019;19:769-773. 3. Haioun C, et al. ASCO 2019. Abstract 8069. 4. Friedberg JW, et al. Blood. 2019;115:2578-2585. 5. Wiernik PH, et al. J Clin Oncol. 2019;26:4952-4957.Bortezomib (硼替佐米)+ CHOP-R作为DLBCL的一线治疗Phase I/IIN = 40 patients with previously untreated DLBCLCHOP-21 +

30、rituximab 375 mg/m2 each cycle Bortezomib given at 3 different dosesArm 0 (n = 4): 0.7 mg/m2Arm 1 (n = 8): 1.0 mg/m2Arm 2 (n = 28): 1.3 mg/m2Median follow-up: 21 mos (range: 9-35)ORR resultsITT (n = 40): 90% (CR/CRu: 68%)Evaluable (n = 36): 100% (CR/CRu: 75%)Estimated 2-yr PFS: 72%Treatment generall

31、y well tolerated4 deaths prior to first response assessmentLeonard JP, et al. ASCO 2019. Abstract 8031.Bendamustine (苯达莫司汀) + Rituximab for Rel/Ref DLBCL: Phase II StudyDay 1: bendamustine 120 mg/m2 + rituximab 375 mg/m2 ; Day 2: bendamustine 120 mg/m2ORR of 60% required by study design Bendamustine + Rituximab28-day cycles for 6 cyclesPatients with relapsed/refractory DLBCL whofailed at least 1 previous therapy(