彌漫大B細胞淋巴瘤治療新進展48課件

1、彌漫大B細胞淋巴瘤治療新進展 張翼鷟天津醫(yī)科大學(xué)附屬腫瘤醫(yī)院血液科天津市腫瘤防治重點實驗室aprilzyzyahoo 概述 流行病學(xué) 基于分子生物學(xué)改變的預(yù)后評價 治療進展 初治的DLBCL 難治復(fù)發(fā)的DLBCL 新藥臨床試驗概述流行病學(xué)彌漫大B細胞淋巴瘤: 31%濾泡性淋巴瘤:22%邊緣區(qū)淋巴瘤:8%套細胞淋巴瘤:6%小細胞淋巴瘤 7%外周T細胞淋巴瘤:7%HL及NHL的發(fā)病率B-NHL 6632,66%UC 378,4%HL 854,9%T/NK-NHL 2138,21%病例總數(shù)：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%病例總數(shù)：6638B-NHL亞型的發(fā)病率DLBCL FL MALTL MCL CLL/SLL BL SMZL NMZL彌漫大B細胞淋巴瘤最常見的非霍奇金淋巴瘤: 31%發(fā)病高峰:60歲臨床表現(xiàn)及分子生物學(xué)特征: 高度異質(zhì)性 大細胞 無淋巴濾泡結(jié)構(gòu)中位生存期: 數(shù)周/月(若不治療)30% 到 40% 伴有B 癥狀可能伴有結(jié)外病變(胃腸道, 中樞神經(jīng)系統(tǒng), 睪丸, 皮膚)Michallet AS, et

3、 al. Blood Rev. 2009;23:11-23.2019年NCCN指南: Essential Diagnostic Assessments for DLBCL對所有切片進行血液病理學(xué)檢查(至少1個為含有腫瘤組織的石蠟塊)淋巴結(jié)切檢當淋巴結(jié)難以切除或切取活檢時,聯(lián)合FNA和空心針活檢并結(jié)合輔助檢查時免疫表型:(DLBCL typically CD20+, CD45+, CD3-)免疫組化(石蠟切片):CD20, CD3, CD4, CD10, CD45, BCL2, BCL6, Ki-67, IRF-4/MUM1流式細胞學(xué):CD45, CD3, CD5, CD19, CD10, CD

4、20, kappa/lambdaNCCN Practice Guidelines in Oncology. 2019.彌漫大B細胞淋巴瘤的預(yù)后因素不良預(yù)后因素影響化療效果與生存期年齡60歲LDH 正常值一般狀態(tài)評分 2Ann Arbor 分期 III/IV結(jié)外受累區(qū) 1 個*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評分的總生存率1.00012345Sehn LH, et al. Blood. 2019;109:1857-1861.與彌漫大B細胞淋巴瘤相關(guān)的分子遺傳學(xué)改變遺傳學(xué)異常較常見染色體異位: 50%DNA 失衡: 高達67%Abramson JS, et al. Blood. 2019;106:1164-1174.YrsOS基因表達譜-分子水平將DLBCL分為不同的臨床亞型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 經(jīng)過微陣列處理的相關(guān)性研究指標:比例風險模式 (FFS, OS)Winter JN, et al. ASH 2019. Abstract 87.基于基因表達的風險評分- 預(yù)測DLBCL臨床結(jié)果N = 183合格者, 可評估案例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.基于基因表達的風險評分- 預(yù)測DLBCL臨床結(jié)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基于基因表達的風險評分- 預(yù)測DLBCL臨床結(jié)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)基因風險評分對調(diào)整后的IPI多元分析具有預(yù)測意義Winter JN, et al. ASH 2019. Abstract 87.基于基因表達的風險評分- 預(yù)測DLBCL臨床結(jié)果該預(yù)測模型也可區(qū)分一些不同來源的細胞的差異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.彌漫大B細胞淋巴瘤的治療進展初治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復(fù)發(fā)難治 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.治療DLBCL的新藥臨床試驗DLBCL研究中的藥物 (Off-Label Use)Bevacizumab 貝伐單抗 recombinant, humanized, monoclonal VEGF antibodyBortezomib 硼替佐米proteasome inhibitorEnzastaurin PKC-selective inhibitorEpratuzuma

28、b 依帕珠單抗recombinant, humanized, monoclonal CD22 antibodyEverolimus 依維莫司mTOR inhibitorLenalidomide 雷利度胺immunomodulator, antiangiogenicRadioimmunotherapy Fostamatinib specific inhibitor of Syk in B-cell signaling pathway治療DLBCL的研究中的藥物: 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作為DLBCL的一線治療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 (苯達莫司汀) + 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(