Rituximab治疗复发淋巴瘤临床研究进展.ppt

1、中山大学肿瘤医院内科 黄 慧 强 淋巴瘤治疗研究中心 Tel:e-mail:huang_,Rituximab治疗复发淋巴瘤临床研究进展,Therapeutic Option of R/R NHL,常 规 化 疗 +/-RT,造血干细胞 移 植,单克隆 抗体,RIT,干扰素,新治疗方法,烷化剂，蒽环类，FLU VP-16,DDP,Taxanes,美 罗 华,挽救治疗的价值,复发难治淋巴瘤,临床研究,其他治疗,挽救方案的选择,治疗目的 病理类型 化疗敏感性 （过往化疗） 全身情况 年龄 经济,一，复发DLBCL,方案疾病患者数量ORR/CRASCT performedS

2、urvival in ASCT R-ICEDLBCL3678%/53%70%67% OS at 2 years R-ICEAggressive B NHL875%/ 50%100% R-various (mostly ICE) DLBCL59 Not given100%81% OS at 2 years R-ICEAggressive,R-DHAPAggressive B NHL5362%/32%38%Median 20.4 months OS DHAP/VIM/DHAP RAggressive B NHL22575%/46% versus63% versusAt 2 years FFS 54

3、%/35% R, 46% R, 50%versus 24% respectively respectively in favour of R (p.001) R-ESHAPDLBCL/MCL/HD24 (15 =Not given79%DFS = 53% DLBCL) R-ESHAPDLBCL/MCL6100%/67%Not done R-ESHAPAggressive B NHL2692 %/46%88% R-ESHAPAggressive B NHL1856%/28%38% R-ICE or R-DHAPDLBCL1060%/10%Not done R-ASHAPAggressive B

4、NHL2075%/45%25% R-DHAOXNHL33 (10 were 70%/27%Not stated HIV+) R-ICE or R-DHAPRelapsed DLBCL 39663%/38%52% (n= 204)49% OS at 3 years followed by HDT (BEAM) and ASCT R maintenance,Long expanding list,Rituximab + 挽救化疗,R-DHAP vs DHAP AHSCT,RR FFS DFS OS DHAP (n=101) 49% 21% 46% 48% R-DHAP (n=101) 77% 52

5、% 82% 62% p-value 0.01 0.001 0.003 0.03 2 years estimated 2006 ASH, Edo Vellenga et al.abstract 328,R + DHAP-VIM-DHAP and ASCT in R/R CD20 + NHL,FFS:failure free survival,Edo Vellenga et al, blood,2008 111: 537-543,Rituximab + DHAP-VIM-DHAP and ASCT in R/R CD20 + NHL,Edo Vellenga et al, blood,2008 1

6、11: 537-543,DHAP112 73 40 19 9 R-DHAP113 76 55 31 14,R-DHAP,DHAP,Cumulative percentage,Overall survival,R-ESHAP as salvage therapy for patients With R/R DLBCL:the influence of prior exposure to rituximabon outcome. A GEL/TAMO study,中山大学肿瘤医院 SUN YAT-SEN UNIVERSITY CANCER CENTER,N=163,中山大学肿瘤医院 SUN YAT

7、-SEN UNIVERSITY CANCER CENTER,R-ESHAP for R/R DLBCL: influence of prior exposure to rituximab on outcome,N=163 R-ESHAP n=94;ESHAP n=69. RR, refractory :R-ESHAP vs ESHAP 33% vs 8%; RR, relapsed :R-ESHAP vs ESHAP 75% vs 50%; PFS,R+ vs R- : 17% vs 57%; OS, R+ vs R- : 38% vs 67%.,Alejandro Martn et al,

8、haematologica,2008; 93(12):1829,Relapsed/refractory DLBCL:the CORAL trial,CD20+ DLBCL Relapsed/ refractory,R-ICE x 3,R-DHAP x 3,R A N D O M I S E,SD/PD Off study,PR/CR,A S C T,Rituximab 375 mg/m2 every 3 months for 2 years,Observation,480 patients needed Planned end of recruitment: summer 2008,R A N

9、 D O M I S E,Response including deaths COMPLETE RESPONSE UNCONFIRMED COMPLETE RESPONSE PARTIAL RESPONSE STABLE DISEASE23122212 PROGRESSIVE DISEASE DEATH PREMATURE WITHDRAWAL / NOT EVALUATED Total,RESPONSE AFTER INDUCTION TREATMENT INCLUDING DEATHS FOR ALL PATIENTS (INDUCTION ITT),R-ICE R-DHAP,N=197%

10、N=191%,63 .5 %62.8 %,Arm ofNb responders Treatment Nb patients with successful mobilization MARR (%) R-ICE19710352.3 R-DHAP19110454.5,Orlando ASCO May 2009 / Coral study C. Gisselbrecht,CORAL研究-毒性反应,R-ICER-DHAP,中性粒细胞减少相关感染 3-4级Yes33 (17%)31 (16%) 中性粒细胞减少无关感染 3-4级Yes11 (6%)15 (8%) 肾毒性 3-4级Yes2(1%)11

11、(6%) 血小板 输注 %pts35%57% 毒性致死 13,On induction safety population, a total of 90 SAEs in R-ICE arm and 120 in the R-DHAP arm were reported during the whole study, concerning respectively 58 patients (29%) and 69 patients (36%).,San Francisco December, 2008 / Coral study C. Gisselbrecht,OVERALL SURVIVAL

12、ACCORDING TO TREATMENT ARM (INDUCTION ITT),PROGRESSION-FREE SURVIVAL ACCORDING TO TREATMENT ARM (INDUCTION ITT),Orlando ASCO May 2009 / Coral study C. Gisselbrecht,56%,56%,45%,42%,曾用美罗华 挽救方案疗效： EFS,Failure from diagnosis = 12 months,Failure from diagnosis 12 months,Failure from diagnosis = 12 months

13、,Standard salvage regimen does not overcome poor prognosis of early relapse,Long-Term Results of the R-CHOP Study in the Treatment of ElderlyPatients With Diffuse Large B-Cell Lymphoma: A Studyby the Groupe dEtude des Lymphomes de lAdulte,Salvage with rituximab (n=22),Salvage without rituximab (n=87

14、),Salvage with rituximab (n=9),Salvage without rituximab (n=64),Feugier, P. et al. J Clin Oncol; 23:4117-4126 2005,Effect of rituximab-containing chemotherapy as salvage treatment at time of first progression on overall survival after progression: (A) in patients previously treated with cyclophospha

15、mide, doxorubicin, vincristine, and prednisone (CHOP; log-rank test, P = .00043); (B) in patients previously treated with rituximab plus CHOP (log-rank test, P = .076),JOURNAL OF CLINICAL ONCOLOGY,Cumulative Proportion Surviving,Cumulative Proportion Surviving,with rituximab,Without rituximab,with r

16、ituximab,Without rituximab,含利妥昔单抗的其他挽救治疗方案,RegimenDisease statusnORR/CRSurvivalReference R-GEMHigh grade B-NHL771%/29%median PFS and OS,(Wenger et al, 2005) (6478 years)10 and 11 months, R-GEMOXAggressive NHL4674%/72%2-year EFS 43%,(El Gnaoui et al, 2007) 2-year OS 66% R-GIFOX(Corazzelli et al, 2006

17、) GaRD (Cabanillas et al, 2006) GaRDAggressive B-NHL2255%/27% (Smith et al, 2006) (CR/CRu) R + EDLBCL667%/50%(Leonard et al, 2005) R + EDLBCL1547%/33%median PFS 6 (Strauss et al, 2006) (CR/CRu) months R-CMDDLBCL3074%/57%2-year OS 45%, (Niitsu et al, 2006) (6579 years)(CR/CRu) PFS 37% R-TTPAggressive

18、 NHL71 (32 70% 25%median DR 21 (Younes et al, 2005) primaryprimary months refractory) refractory R-TTPB-cell lymphoma1060%/30% (Canales et al, 2005) R-ADOXDLBCL (heavily 2070%/25%Median OS 11 mos Woehrer et al, 2005) pre-treated),Gisselbrecht C. B J H:2008 143, 607621,CMD: irinotecan, mitoxantrone,

19、dexamethasoneTTP: paclitaxel, topotecanE:epratuzumab,Another long list,Improving conditioning regimen before ASCT,DFS,J of Clin Oncol，2005，23：2240-2247,OS,67 patients with recurrent B-NHL 41 de novo DBLCL; 26 aggressive FL origin,Rituximab提高ASCT疗效,Cumulative Proportion Surviving,P=0.004,P=0.002,Mont

20、hs Post-Transplantation,Months Post-Transplantation,Rituximab (n=67),NO rituximab (n=30),Rituximab (n=67),NO rituximab (n=30),Concurrent Administration of High-Dose Rituximab Before and After AHSCT for Relapsed Aggressive B-Cell NHL,JOURNAL OF CLINICAL ONCOLOGY,R,PBPC collection,R 1000mg/m,R,R,d1d8,

21、BEAM + ASCT,C Y C,R-CHOP: 弥漫大B淋巴瘤,1999-2004年，N=80, 5年生存率76,中山大学肿瘤医院内科,我们的体会：1.美罗华 +化疗复发难治NHL,1999.7.-2004.7 共35例，102疗程， 32例可评价疗效， CR+PR 68.8, CR 40.6, SD 15.6，PD 15.6 1. 2和3 年OS 72.9、62.8、62.8。,黄慧强等癌症2006，25(4)：486489,Rituximab 联合挽救化疗治疗复发难治DLBCL长期随访结果,中山大学肿瘤医院内科 淋巴瘤治疗研究中心 王潇潇 黄慧强 等,不同方案的有效率,既往Rituxi

22、mab 对挽救化疗的影响,Overall survival GCB vs ABC,Side effects，不良反应,鞘 注： DepoCyte + 美罗华,3 例，DLBCL继发性中枢侵犯，SCNSL 复发/ 难治， 常规MTX, ARA-C, Dex,无效；全身尚有病灶 IT 化疗后（D+R）：均获CR AHSCT: 3, 6,1 月,2010 NCCN, DLBCL,Dense- R ICER-ICENew molecules DHAP.R-DHAP What Else?R- Other ASCT ASCT/ PET-evaluation ASCT/ RIC allo OS benefi

23、tProlonging OS? 更好的耐受性,复发 DLBCL的治疗选择,过去,现在,将来,提高治愈机会,(e.g. new anti CD 20, GA 101, CD40. anti-angiogenics lenalidomide),二. 复发Follicular lymphoma,复发滤泡型NHL,复发FL,滤泡型,R-化疗 R-单药 R-Thalidomide R-维持治疗 R- AHSCT?,Monotherapy for relapsed rituximab nave patients: overall response by relapse,McLaughlin J Clin

24、Oncol 1998;16:282533,1st relapse n =72,2nd relapse n =46,3rd relapse n =24,ORR %,0,10,20,30,60,40,50,57,46,38,Rituximab,CHOP every21 days(maximum 6 cycles),MabThera + CHOP every 21 days(maximum 6 cycles),Observation,MabThera maintenance*,CRPR,*375mg/m2 every 3 months for 2 years or until relapse,R A

25、 N D O M I SATION,MabThera maintenance in relapsed FL Study design,R A N D O M I SATION,van Oers M, et al. Blood 2008; 112:Abstract 836.,MabThera maintenance in relapsed FL improved PFS after CHOP R,van Oers M, et al. Blood 2008; 112:Abstract 836.,PFS (%),After response toCHOP induction,p 0.0001,80,

26、60,40,20,0,100,0,1,2,3,4,5,6,7,p = 0.043,8,O N Number of patients at risk,61,50,39,30,18,8,3,49,76,32,16,10,9,5,0,2,62,69,0,1,2,3,4,5,6,7,8,After response to MabThera-CHOP induction,80,60,40,20,0,100,O N Number of patients at risk,70,61,56,45,28,13,4,51,91,64,47,37,29,21,10,1,65,98,Years,MabThera,Ob

27、servation,MabThera,Observation,MabThera maintenance in relapsed FL improved PFS after CR/PR,van Oers M, et al. Blood 2008; 112:Abstract 836.,100,MabTheraMedian 52.7 mo,ObservationMedian 14.4 mo,After CR to MabThera plus CHOP,p = 0.003,80,60,40,20,0,100,0,1,2,3,4,5,6,7,p = 0.0006,8,O N Number of pati

28、ents at risk,30,16,13,11,6,3,0,38,48,40,35,31,24,17,9,2,29,49,MabTheraMedian 41.8 mo,ObservationMedian 15.6 mo,0,1,2,3,4,5,6,7,8,After non-CR to MabThera plus CHOP,80,60,40,20,0,O N Number of patients at risk,30,16,13,11,6,3,0,38,48,40,35,31,24,17,9,2,29,49,PFS (%),Years,MabThera maintenance therapy

29、 consistently improves overall survival vs observation,0.001,0.1,10,1000,Vidal L, et al. J Natl Cancer Inst 2009; 101:248255.,van Oers 2006,Forstpointner 2006,Ghielmini 2004,Hainsworth 2005,Hochster 2005,Hochster 2007,Subtotal (95% CI),HR (95% CI),HR (95% CI),Weight (%),15.2,29.1,8.1,20.7,25.3,1.5,1

30、00,p 0.0003,0.51 (0.310.86),0.49 (0.181.30),0.50 (0.270.92),0.86 (0.491.49),0.51 (0.251.04),4.51 (0.4743.4),0.60 (0.450.79),Favours MabThera maintenance,Favours observation,Study,1,2010 NCCN, FL,2010 NCCN, 复发套细胞NHL,Antitumor activity ：rituximab plus thalidomide for R / R. mantle cell lymphoma.,Blood

31、. 2004 Oct 15;104(8):2269-71. Methods :16 pts, Rituximab t 375 mg/m(2) for 4 weekly doses thalidomide (200 mg /d, with a dose increment to 400 mg on day 15), Result: RR 81% CR 31% M PFS 20.4 m 3-y OS 75%.,四. 复发CLL, 慢淋,REACH: R-FC vs FC R-Bendamustine R-HDMP,1. 复发CLL,慢淋：REACH,随机化,R-FC q4wk 3,FC q4wk

32、3,再分期,R-FC q4wk 3,FC q4wk 3,SD 可以继续治疗PD 推出研究,CR, PR,复发/难治性 CLL 1次既往治疗 全部Binet 分期 ECOG PS 01 既往FC或美罗华治疗的病人排除 n = 552,招募期: 20032007.,Robak T, et al. Blood 2008; 112:Abstract LBA-1.,缓 解 率,与单用化疗比较，利妥昔单抗 500 mg/m2 + 化疗可使CR率加倍,R-FC FC,Robak T, et al. Blood 2008; 112:Abstract LBA-1.,80,60,40,20,0,100,CR,70

33、,58,PR/nPR,病人 (%),p = 0.0034,46,45,p = 0.8642,24,13,p = 0.0007,ORR,中位随访 25.3 月，REACH,利妥昔单抗 500 mg/m2 + 化疗用于既往治疗的CLL vs 单用化疗，PFS 改善了 50%,Robak T, et al. Blood 2008; 112:Abstract LBA-1.,年,0.5,0.0,2.0,2.5,3.0,3.5,4.0,4.5,5.0,PFS,0.8,0.6,0.4,0.2,0.0,1.0,p = 0.0002,R-FC: 中位 30.6 月,FC: 中位 20.6 月,1.0,1.5,2

34、. 美罗华 + 苯达莫司汀可用于治疗复发CLL,Fischer K, et al. Blood 2008; 112:Abstract 330.,15,63,ORR = 77%(n = 62),病人 (%),80,60,40,20,0,100,所有病人,PR/nPR,71,氟达拉滨-敏感,氟达拉滨-难治性,未突变IgVH,11q del,17p del,78,74,92,44,CR,n = 41,n = 9,n = 39,n = 13,n = 9,ORR,3. R-HDMP in relapsed CLL: Response,Percentage of patients,80,60,40,20,

35、100,57%,36%,ORR = 93%(n = 14),PR / nodular PR CR,Rai stage IIIIV: 86% Median TTP: 15 months Median TTNT: 22 months Median survival: not reached at 40 months,Castro JE, et al. Leukemia 2008; 22:20482053.,Rituximab + cladribine cyclophosphamidein relapsed/refractory CLL,Robak T, et al. Eur J Haematol

36、2007; 79:107113.,Median PFS 12 months (446),RC = rituximab + cladribine RCC = rituximab + cladribine + cyclophosphamide,五.其他分子靶向治疗进展,GA101: A new anti-CD20 antibody,First glycoengineered, humanised, type II CD20 antibody in clinical development Compared with MabThera, GA101 provides: Enhanced direct

37、 cell death induction1,2 Enhanced ADCC1,2,1. Umaa P, et al. Ann Oncol 2008; 19:Abstract 098. 2. Umaa P, et al. Blood 2006; 108:Abstract 229.,B cell,Increased direct cell death Unique type II epitope 110:Abstract 2338.,Tumour volume (x 1000 mm3)median IQR,Control,MabThera (30 mg/kg),GA101 (1 mg/kg),GA101 (10 mg/kg),GA101 (30 mg/kg),Time after cell transplantation (days),3.5,3.0,2.5,2.0,1.5,1.0,0.5,0.0,20,24,28,32,36,42,22,26,30,34,38,40,Start of therapy,Tumour-free animals,10/10,1/10,0/