惰性淋巴瘤規(guī)范化治療08年NCCN治療指南解讀課件

1、惰性淋巴瘤規(guī)范化治療08年NCCN治療指南解讀 黃 慧 強(qiáng)中山大學(xué)附屬腫瘤醫(yī)院 淋巴瘤治療研究中心 Hungary ,Budapest 20192019 Lugano ICML,International Conference Maglinant LympphomaWHO Lymphoma ClassificationB cellB cell chronic lymphocyticMantle cellFollicular lymphomaMarginal B cell lymphoma, MALT typePlasma cell myeloma/plasmocytomaDiffuse lar

2、ge B cell lymphomaBurkitts lymphomaPrecursor B lymphoblastic leukemia/lymphomaT cellMycosis fungoidesPeripheral T cell lymphoma, unspecifiedAngioimmunoblastic T cell lymphomaExtranodal NK/T cell lymphomaAdult T cell leukemia/lymphoma (HTLV1+)Anaplastic large cell lymphoma, primary systemicPrecursor

3、T cell lymphoblastic leukemia/lymphomaDistribution of NHL subtypesIn the UK (population 60m), there are 8,450 new NHL cases/year1Across the EU (population 490m) this equates to an incidence of 69,000 new NHL cases/yearALBCLOtherDLBCLFLMALT lymphomaMature T-celllymphomaCLL/SLLMCLPMLBCLBurkitts lympho

4、maLiu Q, et al. Blood. 2019;102. Abstract 1446. Regimen生 存Treatment PeriodNo. of Patients5 yr (%)10 yr (%)15 yr (%)CHOP BleoCHOP Bleo-IFNATT-IFNATT-IFN vs. FND-IFNFND-R vs. FND-R(+IFN)1977 19821982 19881988 19921992 20192019 2019961311361422006475828290375260-2942-IFN: interferon; ATT: alternating t

5、riple therapy with CHOD-B/ESHAP/NOPP; FND: fludarabine, mitoxantrone, and dexamethasone; Bleo: bleomycin; CHOP: cyclophosphamide, doxorubicin, vincristine, prednisoneYes, Survival Has Improved!過去25年惰性淋巴瘤的生存是否有改善?Years% 存活率0510152025020406080100CHOP-BleoCHOP-Bleo+IFNATTIFNATTIFN vs FNDIFNR-FND+IFN vs

6、 FNDR+IFNP .0001IV期濾泡性淋巴瘤:不同治療方案的OS 1972-2019 Liu et al, JCO 2019; 24: 1582-1589Years% Alive0510152025020406080100CHOP-BleoCHOP-Bleo+IFNATTIFNATTIFN vs FNDIFNR-FND+IFN vs FNDR+IFNP .01IV期濾泡性淋巴瘤:不同治療方案的生存, FLIPI評分3Liu et al, JCO 2019; 24: 1582-1589Years %Failure-Free0510152025020406080100CHOP-BleoCHO

7、P-Bleo+IFNATTIFNATTIFN vs FNDIFNR-FND+IFN vs FNDR+IFNP Leukeran 一線 - 濾泡性淋巴瘤治療: RandomizedHiddemann et al.CHOPR-CHOPp可評估患者205223反應(yīng)率90%96%0.011TTF31 mNot reached 0.0001OS (estimated 2-y OS)90%95%0.016Marcus et al.CVPR-CVPp可評估患者159162反應(yīng)率57%81% 0.0001PFS15 m34 m 0.0001OS ( 隨訪 53 m)71%81% 0.03Herold et a

8、l.MCPR-MCPp可評估患者96105反應(yīng)率75%92% 0.001EFS19 mNot reached 0.0001OS 62 mNot reached0.016Foussard et al.CHVP/IFN-R-CHVP/IFN-p可評估患者183175反應(yīng)率 (CR/CRu)85% (49%)94% (76%) 0.0001EFS36 mNot reached 0.0001OS ( 隨訪 42 m)84%91% Ob1線FL4.Anton Hagenbeek (Holland)R-CHOP/ CHOP觀 察q3m 8M: Ob 51.6 Vs 15 (m) R-CHOP/CHOP,C

9、R M Ob, PFVFF) (FL)1線FL/MCL6.Martin DreylingFCM/R-FCM觀 察q4m2R-m better (FL, MCL)R-matainence better1線FL/MCLIndolent NHL: induction and Maintenanced8after ASCTRituximab before and after ASCTfor relapsed aggressive B-NHLCyclophosphamide 47 g/m2 G-CSF 10 g/kg/dBEAM /ASCTRituximab1 g/m2Rituximab 1 g/m2R

10、ituximab1 g/m2Rituximab375 mg/m2d1d7d1after ASCTKhouri IF, et al. J Clin Oncol 2019; 23:22402247.Historical comparisonN = 67Rituximab significantly improves outcomes when combined with HDT and ASCTKhouri IF, et al. J Clin Oncol 2019; 23:22402247.Overall survivalMonths post-transplant0.01.06309121518

11、21242730p = 0.004No rituximab (n = 30)Rituximab (n = 67)0.20.40.60.8Months post-transplant0.01.0630912151821242730p = 0.0020.20.40.60.8Disease-free survivalNo rituximab (n = 30)Rituximab (n = 67)Radio-Immuno-Therapy 單用有效率： RIT 單用治療復(fù)發(fā)耐藥NHLResponse Duration: RIT on relapsed or refractory NHLCD20 -I 13

12、1:FL and Transformed NHL:Long term outcome11 studies ,1177 ptsM age 57 ( 21-90), stage 90%, tumor 5cm 47%,BM + 44% 1st (141) 2rd (226) 3rd (228) 4th ( 540)Response R. 95 73 58 46M.d. response - 35 16 12CR (%) 78 46 32 23M.d. CR - - 35 59PFS1Y (%) 82 59 42 27 ASCO 2019,abstract 6561USA multicenters 方

13、 案 患者單一誘導(dǎo)后的CR率 (%) 鞏固后CR率 (%)ReferenceR-CHOP (3 ) + Zevalin consolidation II-IV FL; 60% stage IV2867Shipley et al.ASCO 2019FM (6 c) + 90Y-Ibritumomabtiuxetan consolidation IIIV FL;88% stage IIIIV73100(誘導(dǎo)后PR均轉(zhuǎn)為CR)Zinzani et al.ASH 2019R-CHOP +90Y-Ibritumomabtiuxetanconsolidation + Rmaintenance IIIV F

14、L;91% stage IIIIV; 40% high FLIPI4189Jankowitz et al.ASCO 2019Zevalin鞏固治療FLCUP trial: AHSCT歐洲多中心研究Schouten H, et al. J Clin Oncol 2019;21:391827Relapsed follicular NHLRegistration3 cycles of chemotherapyRestageRandomisationHigh dose therapy+ unpurged stemcell support(n=33)High dose therapy+ purged s

15、temcell support(n=32)3 cyclesof chemotherapy(n=24)Follow-upCR or PRand 20% B-lymphocytesn=140*Prior to randomisation clinicians must decide whetherbone marrow or periperal blood will be used as a stem cell support復(fù)發(fā)FL CUP trial: progression-free survival 1.00.80.60.40.20012 24 36 48 60 72 84MonthsPr

16、oportion progression-freeEventsTotalChemotherapy2024Unpurged 922Purged1124Schouten H, et al. J Clin Oncol 2019;21:391827復(fù)發(fā)LFAutoPBSCT in 1st Remission FLTrialInductionConditioningEFSOverall survivalLenz etal (GLSG)CHOP/MCPTBI/Cyclo (n=153)647% vs. 333%*(P00001)Not yet availableCHOP/MCP IFN (n=154)De

17、coninck etal(GOELAMS)VCAPTBI/Cyclo (n=86)60% vs. 48% (P0050)Median NRNo significant differenceCHVP/IFN-CHVP IFN- (n=80)Sebban etal (GELA)CHOPTBI/Cyclo (n=192)45% vs. 36% (P=05)86% vs. 74% (7-year OS)CHVP/IFNCHVP IFN- (n=209)After : Hiddemann ,W. Brit J Haem 2019AHSCT 1st-line :follicular lymphoma540

18、 pts, randomized trial 5-y estimated PFS 27% CHOP - IFN-alpha maintenance, 65% CHOP - ASCT, 68% R-CHOP - IFN-alpha maintenance 80% R-CHOP - ASCT.C. Buske1, M, 2019 Lugano abstract 028 Rituximab and/or High-Dose Therapy with Autotransplant at Time of Relapse in FL Improved supportive therapy and outc

19、ome after Auto vs. Allo transplantation?Allogeneic SCT over timeAutologous SCT over timeBut:- retrospective study with heterogenous patient population- TBI conditioning regimen significantly lower relapse rate (p=0.02)- no specific prognostic factors after autologous/allogeneic transplantationvan Be

20、snien et al. Blood 2019How I treat indolent lymphomaJohn G. Gribben， Institute of Cancer, Barts and The London Queen Mary School of Medicine, London, United Kingdom;.Blood 2019 .3Years% 存活率0510152025020406080100CHOP-BleoCHOP-Bleo+IFNATTIFNATTIFN vs FNDIFNR-FND+IFN vs FNDR+IFNP .0001IV期濾泡性淋巴瘤:不同治療方案的

21、OS 1972-2019 Liu et al, JCO 2019; 24: 1582-1589 患者 (%)198720191976198619601975 年1008060402000510152025302000 2019?濾泡性淋巴瘤遠(yuǎn)期療效前瞻? 常 規(guī) 化 療RT造血細(xì)胞移植單克隆抗體,RIT干擾素新治療方法ADVANCES ON INDOLENT LYMPHOMA Fludarabine ( 單藥 )Untreated FLCR 14-47%RR 47-81%Treated FLCR 6-48%RR 31- 72%Fludarabine vs CVP ( phase III )CR

22、 9% vs 7%RR 64% vs 52%福達(dá)華 + 米托蒽琨初治初治福達(dá)華 + 環(huán)磷酰胺比較FCN +/- CD20單抗的療效49例患者進(jìn)行初步療效評價兩組的血液學(xué)和非血液學(xué)毒性相當(dāng)FCM=fludarabine/cyclophosphamide/mitoxantrone.Hiddemann W, et al. Semin Oncol. 2019;30(1 Suppl 2):16-20., Dreyling MH, et al. Blood. 2019;102 Abstract 351.40%FCN+CD20單抗n = 25CRFCNn = 2421%52%PR54%92%CR + PR7

23、5%福達(dá)華 / 環(huán)磷酰胺 / 米托蒽琨 +/- CD20單抗治療復(fù)發(fā)難治濾泡性淋巴瘤 FLU vs FLU-ID (FLU+Ida) (Bologna) FND vs ATT (MDACC) FC vs CVP Anti-20 (ECOG) FND followed by anti-CD20 vs FND plus anti-CD20 concurrenty (MDACC) FM vs CHOP anti-CD20 (Bologna)含福達(dá)華方案的III期隨機(jī)臨床研究FLU(%)FLU-ID (%)合計 (%)CR473943PR374239.5CR + PR848182.5CR濾泡性淋巴瘤小

24、淋巴細(xì)胞淋巴瘤淋巴漿細(xì)胞淋巴瘤套細(xì)胞淋巴瘤602923274043383350373131Zinzani et al. J Clin Oncol 2000FLU vs FLUIDRANDOMIZED PHASE III TRIAL初步臨床療效評價8個療程的FND方案與ATT(CHOD-Bleo, ESHAP, NOPP)治療IV期惰性淋巴瘤的隨機(jī)對照研究報道的5年OS內(nèi)分子學(xué)CR情況兩組沒有差異(bcl-2-): 84 % FND vs 82 % ATT; 5-year FFS: 41 % FND vs 50 % ATTFND vs ATTRANDOMIZED PHASE III TRIALT

25、SIMBERIDOU et al. Blood 2019RANDOMIZED PHASE III TRIALFND + R vs FND R 6個療程的FND方案同時使用或序貫使用CD20單抗治療IV期惰性淋巴瘤的隨機(jī)對照研究5年FFS: FND+R vs FND R 分別為 70%和44% (p=0.009)Jiang et al, ASH 2019 (# 1444)FM對比CHOP（CD20）初治濾泡性淋巴瘤隨機(jī)對照研究140例初治濾泡性NHL 入組標(biāo)準(zhǔn)：CD20+濾泡性I-II級Ann Arbor II-IV期ECOG 0-2CHOP (n=68)FM (n=72)隨機(jī)分組28天為一療程

26、共6個療程CR/PRSD/PD退出研究CD20單抗觀察 CR-CR+ PR+ PR-+:bcl2陽性-:bcl2陰性Zinzani et al. J Clin Oncol 2019;22(13):2654-2661RANDOMIZED PHASEFND + R vs FNDFM對比CHOP：完全緩解率和分子學(xué)完全緩解率顯著提高FM CHOPp值化療后cCR 68% 42%.003mCR 39% 19%.001對未達(dá)CR-用CD20單抗鞏固后cCR 90% 81%-mCR 71% 51%.01 cCR: 臨床完全緩解mCR: 分子學(xué)完全緩解 Zinzani et al. J Clin Oncol

27、 2019;22(13):2654-2661RANDOMIZED PHASEFND + R vs FNDFM對比CHOP：RFSRFS: Relapse-free surviveZinzani et al. J Clin Oncol 2019;22(13):2654-2661RANDOMIZED PHASEFND + R vs FNDFM對比CHOP：耐受性顯著提高Zinzani et al. J Clin Oncol 2019;22(13):2654-2661III/IV級毒性FM(n=72)CHOP(n=68)p值中性粒細(xì)胞減少30%39%差別不顯著惡心嘔吐 3%22%0.001脫發(fā)14%

28、85%0.001外周神經(jīng)系統(tǒng)毒性 026%0.001便秘 032%0.001兩組無一例出現(xiàn)III/IV級貧血或血小板減少兩組無一例因毒性或感染而死亡RANDOMIZED PHASEFND + R vs FND含福達(dá)華方案聯(lián)合環(huán)磷酰胺（FC）三藥聯(lián)合:FCM聯(lián)合米托蒽琨（FN）ORR 71-94 %，CR 20-47 %83 % ORR，66 % CRORR 72-88%，27-66% CR 1.含F(xiàn)ludarabine 聯(lián)合方案治 療 復(fù) 發(fā) 惡 性 NHL 中山大學(xué)腫瘤醫(yī)院內(nèi)科 黃慧強(qiáng)等(2019) Objective ResponseResponse Whole LG Intermedia

29、te untreated Relapse （ n=25） (n=21) （n=4） (n=13) (n=12) CR 32 38 0 39 25 PR 40 48 0 46 33 SD 24 14 75 15 33 PD 4 0 25 0 8CR+PR 72 86 0 85 582.含F(xiàn)ludarabine方案治療初治/復(fù)治惰性淋巴瘤廣東協(xié)作組初步報告南方醫(yī)院 中山 大學(xué)一附院 廣東省人民醫(yī)院 中山大學(xué)第二附屬醫(yī)院 廣州醫(yī)學(xué)院二附院 廣州軍區(qū)陸軍總醫(yī)院 中山大學(xué)腫瘤醫(yī)院療 效N%ORCR2141.18 78.43%PR1937.25 GPR11.96 SD23.92 總體平均療程：3.76(1

30、-6)M 有效患者的平均療程：4.22 濾泡性淋巴瘤治療Meta分析CR 率化療或聯(lián)合化療*37 %Rituximab化療53 %Fludarabine單藥/聯(lián)合68 %放射免疫治療,RIT79 %*化療方案不含福達(dá)華0106年,25篇臨床文獻(xiàn)、2421例ASH 2019, Abstract 275410 mg迅速釋放的片劑藥代動力學(xué)研究Foran et al., J Clin Oncol 201940-50 mg/m2 口服相當(dāng)于25 mg/m2 i.v.生物利用度不受食物影響Oscier et al., Hematol J 2019福達(dá)華口服劑型方 便口服 vs 靜脈 : 療效相當(dāng)（單藥C

31、LL）Boogaerts et al., JCO 201952例，F(xiàn)L有效率65%，CR率30%62%既往CD20單抗治療緩解者Oral Fludarabine + CTX :75 untreated CLL:Final response and F/U Duration of R.( CR/PR) 1085 daysOral fludarabine +CTX : 75 untreated CLLFinal response and F/U 口服 Fludarabine + CTX治療惰性淋巴瘤 初步結(jié)果報告中山大學(xué)附屬腫瘤醫(yī)院內(nèi)科 淋巴瘤治療和研究中心 2019.8. Oral Fludar

32、abine + CTXInitalAge GenderDiagnosisCyclesResponseSide effect 169650ZGM66FMALT AR-FC*3PR骨髓抑制1程,嘔吐第2程,胃腸反應(yīng)170962JYZ48FCLL R-FC *1無 168159LJM74MSLLR-FC*5CR 無 170581YQT55MMCL A R-FM*2 FM *2 GPR-骨髓抑制16980LCX 57F 鼻咽MALT A R-FC*1 無170581HMT 37 F 幼淋巴細(xì)胞白血病R-FC *1畏寒、發(fā)熱等輸注反應(yīng)C225816LRZ67M SLL A FC *2無C223385WHL35FSLL AFC*3 CRu-惡心、納差 Response Rate 聯(lián)合化療：Oral fludarabine + CTX 7 FC- Rituximab 6 Oral Fludarabie + Mitoxantrane 1共20療程，1-5療程有效率 ：100 ( 8 / 8 ) CR : 37 % ( 3/ 8 )Oral Fludarabine 30-40mg/m2 d1-3CTX 500-600mg