惰性淋巴瘤规范化治疗08年NCCN治疗指南解读课件

1、惰性淋巴瘤规范化治疗08年NCCN治疗指南解读 黄 慧 强中山大学附属肿瘤医院 淋巴瘤治疗研究中心 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!过去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期滤泡性淋巴瘤:不同治疗方案的OS 1972-2019 Liu et al, JCO 2019; 24: 1582-1589Years% Alive0510152025020406080100CHOP-BleoCHOP-Bleo+IFNATTIFNATTIFN vs FNDIFNR-FND+IFN vs FNDR+IFNP .01IV期滤泡性淋巴瘤:不同治疗方案的生存, FLIPI评分3Liu et al, JCO 2019; 24: 1582-1589Years %Failure-Free0510152025020406080100CHOP-BleoCHO

7、P-Bleo+IFNATTIFNATTIFN vs FNDIFNR-FND+IFN vs FNDR+IFNP Leukeran 一线 - 滤泡性淋巴瘤治疗: RandomizedHiddemann et al.CHOPR-CHOPp可评估患者205223反应率90%96%0.011TTF31 mNot reached 0.0001OS (estimated 2-y OS)90%95%0.016Marcus et al.CVPR-CVPp可评估患者159162反应率57%81% 0.0001PFS15 m34 m 0.0001OS ( 随访 53 m)71%81% 0.03Herold et a

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

9、R M Ob, PFVFF) (FL)1线FL/MCL6.Martin DreylingFCM/R-FCM观 察q4m2R-m better (FL, MCL)R-matainence better1线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 单用有效率： RIT 单用治疗复发耐药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 患者单一诱导后的CR率 (%) 巩固后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(诱导后PR均转为CR)Zinzani et al.ASH 2019R-CHOP +90Y-Ibritumomabtiuxetanconsolidation + Rmaintenance IIIV F

14、L;91% stage IIIIV; 40% high FLIPI4189Jankowitz et al.ASCO 2019Zevalin巩固治疗FLCUP trial: AHSCT欧洲多中心研究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复发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复发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期滤泡性淋巴瘤:不同治疗方案的

21、OS 1972-2019 Liu et al, JCO 2019; 24: 1582-1589 患者 (%)198720191976198619601975 年1008060402000510152025302000 2019?滤泡性淋巴瘤远期疗效前瞻? 常 规 化 疗RT造血细胞移植单克隆抗体,RIT干扰素新治疗方法ADVANCES ON INDOLENT LYMPHOMA Fludarabine ( 单药 )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%福达华 + 米托蒽琨初治初治福达华 + 环磷酰胺比较FCN +/- CD20单抗的疗效49例患者进行初步疗效评价两组的血液学和非血液学毒性相当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单抗n = 25CRFCNn = 2421%52%PR54%92%CR + PR7

23、5%福达华 / 环磷酰胺 / 米托蒽琨 +/- CD20单抗治疗复发难治滤泡性淋巴瘤 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)含福达华方案的III期随机临床研究FLU(%)FLU-ID (%)合计 (%)CR473943PR374239.5CR + PR848182.5CR滤泡性淋巴瘤小

24、淋巴细胞淋巴瘤淋巴浆细胞淋巴瘤套细胞淋巴瘤602923274043383350373131Zinzani et al. J Clin Oncol 2000FLU vs FLUIDRANDOMIZED PHASE III TRIAL初步临床疗效评价8个疗程的FND方案与ATT(CHOD-Bleo, ESHAP, NOPP)治疗IV期惰性淋巴瘤的随机对照研究报道的5年OS内分子学CR情况两组没有差异(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个疗程的FND方案同时使用或序贯使用CD20单抗治疗IV期惰性淋巴瘤的随机对照研究5年FFS: FND+R vs FND R 分别为 70%和44% (p=0.009)Jiang et al, ASH 2019 (# 1444)FM对比CHOP（CD20）初治滤泡性淋巴瘤随机对照研究140例初治滤泡性NHL 入组标准：CD20+滤泡性I-II级Ann Arbor II-IV期ECOG 0-2CHOP (n=68)FM (n=72)随机分组28天为一疗程

26、共6个疗程CR/PRSD/PD退出研究CD20单抗观察 CR-CR+ PR+ PR-+:bcl2阳性-:bcl2阴性Zinzani et al. J Clin Oncol 2019;22(13):2654-2661RANDOMIZED PHASEFND + R vs FNDFM对比CHOP：完全缓解率和分子学完全缓解率显著提高FM CHOPp值化疗后cCR 68% 42%.003mCR 39% 19%.001对未达CR-用CD20单抗巩固后cCR 90% 81%-mCR 71% 51%.01 cCR: 临床完全缓解mCR: 分子学完全缓解 Zinzani et al. J Clin Oncol

27、 2019;22(13):2654-2661RANDOMIZED PHASEFND + R vs FNDFM对比CHOP：RFSRFS: Relapse-free surviveZinzani et al. J Clin Oncol 2019;22(13):2654-2661RANDOMIZED PHASEFND + R vs FNDFM对比CHOP：耐受性显著提高Zinzani et al. J Clin Oncol 2019;22(13):2654-2661III/IV级毒性FM(n=72)CHOP(n=68)p值中性粒细胞减少30%39%差别不显著恶心呕吐 3%22%0.001脱发14%

28、85%0.001外周神经系统毒性 026%0.001便秘 032%0.001两组无一例出现III/IV级贫血或血小板减少两组无一例因毒性或感染而死亡RANDOMIZED PHASEFND + R vs FND含福达华方案联合环磷酰胺（FC）三药联合:FCM联合米托蒽琨（FN）ORR 71-94 %，CR 20-47 %83 % ORR，66 % CRORR 72-88%，27-66% CR 1.含Fludarabine 联合方案治 疗 复 发 恶 性 NHL 中山大学肿瘤医院内科 黄慧强等(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Fludarabine方案治疗初治/复治惰性淋巴瘤广东协作组初步报告南方医院 中山 大学一附院 广东省人民医院 中山大学第二附属医院 广州医学院二附院 广州军区陆军总医院 中山大学肿瘤医院疗 效N%ORCR2141.18 78.43%PR1937.25 GPR11.96 SD23.92 总体平均疗程：3.76(1

30、-6)M 有效患者的平均疗程：4.22 滤泡性淋巴瘤治疗Meta分析CR 率化疗或联合化疗*37 %Rituximab化疗53 %Fludarabine单药/联合68 %放射免疫治疗,RIT79 %*化疗方案不含福达华0106年,25篇临床文献、2421例ASH 2019, Abstract 275410 mg迅速释放的片剂药代动力学研究Foran et al., J Clin Oncol 201940-50 mg/m2 口服相当于25 mg/m2 i.v.生物利用度不受食物影响Oscier et al., Hematol J 2019福达华口服剂型方 便口服 vs 静脉 : 疗效相当（单药C

31、LL）Boogaerts et al., JCO 201952例，FL有效率65%，CR率30%62%既往CD20单抗治疗缓解者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治疗惰性淋巴瘤 初步结果报告中山大学附属肿瘤医院内科 淋巴瘤治疗和研究中心 2019.8. Oral Fludar

32、abine + CTXInitalAge GenderDiagnosisCyclesResponseSide effect 169650ZGM66FMALT AR-FC*3PR骨髓抑制1程,呕吐第2程,胃肠反应170962JYZ48FCLL R-FC *1无 168159LJM74MSLLR-FC*5CR 无 170581YQT55MMCL A R-FM*2 FM *2 GPR-骨髓抑制16980LCX 57F 鼻咽MALT A R-FC*1 无170581HMT 37 F 幼淋巴细胞白血病R-FC *1畏寒、发热等输注反应C225816LRZ67M SLL A FC *2无C223385WHL35FSLL AFC*3 CRu-恶心、纳差 Response Rate 联合化疗：Oral fludarabine + CTX 7 FC- Rituximab 6 Oral Fludarabie + Mitoxantrane 1共20疗程，1-5疗程有效率 ：100 ( 8 / 8 ) CR : 37 % ( 3/ 8 )Oral Fludarabine 30-40mg/m2 d1-3CTX 500-600mg