Rituximab治療復發(fā)淋巴瘤臨床研究進展PPT學習教案

1、會計學1Rituximab治療復發(fā)淋巴瘤臨床研究進展治療復發(fā)淋巴瘤臨床研究進展 常常 規(guī)規(guī) 化化 療療 +/-RT 造血干細胞造血干細胞移移 植植單克隆單克隆抗體抗體,RIT干擾素新治療方法新治療方法烷化劑，蒽環(huán)類，烷化劑，蒽環(huán)類，F(xiàn)LUVP-16,DDP,Taxanes美 羅 華第1頁/共64頁 復發(fā)難治淋巴瘤復發(fā)難治淋巴瘤臨床研究臨床研究其他治療其他治療第2頁/共64頁第3頁/共64頁第4頁/共64頁第5頁/共64頁方案疾病患者數(shù)量ORR/CRASCT performedSurvival in ASCT R-ICEDLBCL3678%/53%70%67% OS at 2 yearsR-IC

2、EAggressive B NHL875%/ 50%100%R-various (mostly ICE) DLBCL59 Not given100%81% OS at 2 yearsR-ICEAggressiveR-DHAPAggressive B NHL5362%/32%38%Median 20.4 months OSDHAP/VIM/DHAP RAggressive B NHL22575%/46% versus63% versusAt 2 years FFS54%/35% R, 46% R, 50%versus 24% respectively respectively in favour

3、 of R (p.001)R-ESHAPDLBCL/MCL/HD24 (15 =Not given79%DFS = 53% DLBCL)R-ESHAPDLBCL/MCL6100%/67%Not doneR-ESHAPAggressive B NHL2692 %/46%88%R-ESHAPAggressive B NHL1856%/28%38%R-ICE or R-DHAPDLBCL1060%/10%Not doneR-ASHAPAggressive B NHL2075%/45%25%R-DHAOXNHL33 (10 were 70%/27%Not stated HIV+)R-ICE or R-

4、DHAPRelapsed DLBCL 39663%/38%52% (n= 204)49% OS at 3 yearsfollowed by HDT(BEAM) and ASCT R maintenance第6頁/共64頁第7頁/共64頁R-DHAPDHAPP valueCR+PR75%54%P=0.01FFS50%24%P 0.001PFS52%31%P = 12 monthsFailure from diagnosis 12 monthsFailure from diagnosis = 12 monthsStandard salvage regimen does not overcome p

5、oor prognosis of early relapse第18頁/共64頁Salvage with rituximab (n=22)Salvage without rituximab (n=87)Salvage with rituximab (n=9)Salvage without rituximab (n=64)Feugier, P. et al. J Clin Oncol; 23:4117-4126 2005Effect of rituximab-containing chemotherapy as salvage treatment at time of first progress

6、ion on overallsurvival after progression: (A) in patients previously treated with cyclophosphamide, doxorubicin,vincristine, and prednisone (CHOP; log-rank test, P = .00043); (B) in patients previously treated withrituximab plus CHOP (log-rank test, P = .076)JOURNAL OF CLINICAL ONCOLOGYCumulative Pr

7、oportion SurvivingCumulative Proportion Survivingwith rituximab Without rituximab with rituximab Without rituximab 第19頁/共64頁RegimenDisease statusnORR/CRSurvivalReferenceR-GEMHigh grade B-NHL771%/29%median PFS and OS,(Wenger et al, 2005)(6478 years)10 and 11 months,R-GEMOXAggressive NHL4674%/72%2-yea

8、r EFS 43%,(El Gnaoui et al, 2007)2-year OS 66%R-GIFOX(Corazzelli et al, 2006)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) monthsR-CMDDLBCL3074%/57%2-year OS

9、45%, (Niitsu et al, 2006) (6579 years)(CR/CRu) PFS 37%R-TTPAggressive NHL71 (32 70% 25%median DR 21 (Younes et al, 2005)primaryprimary months refractory) refractoryR-TTPB-cell lymphoma1060%/30% (Canales et al, 2005)R-ADOXDLBCL (heavily 2070%/25%Median OS 11 mos Woehrer et al, 2005) pre-treated)Gisse

10、lbrecht C. B J H:2008 143, 607621CMD: irinotecan, mitoxantrone, dexamethasoneTTP: paclitaxel, topotecanE:epratuzumabAnother long list第20頁/共64頁第21頁/共64頁J of Clin Oncol，2005，23：2240-2247OS67 patients with recurrent B-NHL41 de novo DBLCL; 26 aggressive FL originRituximab提高提高ASCT療效療效Cumulative Proportio

11、n SurvivingP=0.004P=0.002Months Post-TransplantationMonths Post-TransplantationRituximab (n=67)NO rituximab (n=30)Rituximab (n=67)NO rituximab (n=30)第22頁/共64頁JOURNAL OF CLINICAL ONCOLOGYRPBPCcollectionR 1000mg/mRRd1d8BEAM + ASCTCYC第23頁/共64頁806040200總生存時間總生存時間100806040200生生存存率率% %MST 70月80例患者生存曲線80例患

12、者生存曲線1999-2004年，年，N=80, 5年生存率年生存率76中山大學腫瘤醫(yī)院內(nèi)科第24頁/共64頁黃慧強黃慧強等等癌癥癌癥2006，25(4)：486489第25頁/共64頁第26頁/共64頁NNRR (%)RR (%)CR (%)CR (%)SD (%)SD (%)PD (%)PD (%)R-CHOPR-CHOP2 2505050505050R-EPOCHR-EPOCH181877.877.861.161.15.65.616.616.6R-DHAPR-DHAP7 785.785.771.471.414.314.3R-GEMOXR-GEMOX6 666.666.633.333.333

13、.333.3R-DHAOXR-DHAOXR-IMVP16 R-IMVP16 R-ICER-ICER-GDPR-GDPOtherOther5 59 911112 24 4606066.666.663.663.6100100100100606022.222.236.336.32525202011.111.19 9202022.222.227.327.3Total646473.473.445.345.312.512.514.114.1第27頁/共64頁第28頁/共64頁第29頁/共64頁 第30頁/共64頁第31頁/共64頁第32頁/共64頁Dense- RICER-ICENew molecules

14、DHAP.R-DHAPWhat Else?R- Other ASCT ASCT/PET-evaluation ASCT/ RIC alloOS benefitProlonging OS?更好的耐受性過去現(xiàn)在將來提高治愈機會(e.g. new anti CD 20, GA 101, CD40. anti-angiogenics lenalidomide)第33頁/共64頁第34頁/共64頁第35頁/共64頁McLaughlin J Clin Oncol 1998;16:2825331st relapsen =722nd relapsen =463rd relapsen =24ORR %01020

15、30604050574638Rituximab第36頁/共64頁CHOP every21 days(maximum 6 cycles)MabThera + CHOP every 21 days(maximum 6 cycles) ObservationMabThera maintenance*CRPR*375mg/m2 every 3 months for 2 years or until relapseRANDOMISATION MabThera maintenance in relapsed FL Study designRANDOMISATIONvan Oers M, et al. Bl

16、ood 2008; 112:Abstract 836.第37頁/共64頁MabThera maintenance in relapsed FL improved PFS after CHOP Rvan Oers M, et al. Blood 2008; 112:Abstract 836.PFS (%)After response toCHOP inductionp 0.000180604020010001234567p = 0.0438O N Number of patients at risk61 50 39 30 18 8349 7632 16 10 950262 69012345678

17、After response to MabThera-CHOP induction806040200100O N Number of patients at risk70 61 56 45 28 13 451 9164 47 37 29 21 10 165 98YearsMabTheraObservationMabTheraObservation第38頁/共64頁MabThera maintenance in relapsed FL improved PFS after CR/PRvan Oers M, et al. Blood 2008; 112:Abstract 836.100MabThe

18、raMedian 52.7 moObservationMedian 14.4 moAfter CR to MabThera plus CHOPp = 0.00380604020010001234567p = 0.00068O N Number of patients at risk30 16 13 1163038 4840 35 31 24 17 9229 49MabTheraMedian 41.8 moObservationMedian 15.6 mo012345678After non-CR to MabThera plus CHOP806040200O N Number of patie

19、nts at risk30 16 13 1163038 4840 35 31 24 17 9229 49PFS (%)Years第39頁/共64頁0.0010.1101000Vidal L, et al. J Natl Cancer Inst 2009; 101:248255.van Oers 2006Forstpointner 2006Ghielmini 2004 Hainsworth 2005 Hochster 2005 Hochster 2007Subtotal (95% CI)HR (95% CI)HR (95% CI)Weight (%)15.229.18.120.725.31.51

20、00p 0.00030.51 (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 observationStudy1第40頁/共64頁2010 NCCN, FL第41頁/共64頁第42頁/共64頁第43頁/共64頁第44頁/共64頁隨隨機機化化R-FC q4wk 3FC q4wk 3再再分分期期R-FC q4wk 3FC q4wk 3SD 可以繼續(xù)治療可以繼續(xù)治療PD 推出

21、研究推出研究CR, PRl 復發(fā)復發(fā)/難治性難治性 CLLl 1次既往治療次既往治療l 全部全部Binet 分期分期l ECOG PS 01l 既往既往FC或美羅華治或美羅華治療的病人排除療的病人排除l n = 552招募期招募期: 20032007.Robak T, et al. Blood 2008; 112:Abstract LBA-1.第45頁/共64頁R-FCFCRobak T, et al. Blood 2008; 112:Abstract LBA-1.806040200100CR7058PR/nPR病人病人 (%)p = 0.00344645p = 0.86422413p = 0

22、.0007ORR第46頁/共64頁Robak T, et al. Blood 2008; 112:Abstract LBA-1.年年0.50.02.02.53.03.54.04.55.0PFS0.80.60.40.20.01.0p = 0.0002R-FC: 中位中位 30.6 月月FC: 中位中位 20.6 月月1.01.5第47頁/共64頁Fischer K, et al. Blood 2008; 112:Abstract 330.1563ORR = 77%(n = 62)病人病人 (%)806040200100所有病人所有病人PR/nPR71氟達拉濱氟達拉濱-敏感敏感氟達拉濱氟達拉濱-難

23、治性難治性未突變未突變IgVH11q del17p del78749244CRn = 41n = 9n = 39n = 13n = 9ORR第48頁/共64頁Percentage of patients8060402010057%36%ORR = 93%(n = 14)PR / nodular PRCR Rai stage IIIIV: 86% Median TTP: 15 months Median TTNT: 22 months Median survival: not reached at 40 monthsCastro JE, et al. Leukemia 2008; 22:2048

24、2053.第49頁/共64頁ResponseTotaln = 46RCn = 18RCCn = 28 ORR CR PR34 (74%)3 (7%)31 (67%)12 (67%)1 (6%)11 (61%)22 (78%)2 (7%)20 (71%)Robak T, et al. Eur J Haematol 2007; 79:107113.Median PFS 12 months (446)RC = rituximab + cladribineRCC = rituximab + cladribine + cyclophosphamide第50頁/共64頁第51頁/共64頁1. Umaa P, et al. Ann Oncol 2008; 19:Abstract 098.2. Umaa P, et al. Blood 2006; 108:Abstract 229.第52頁/共64頁B cellEffectorcellIncreased direct cell deathUnique type II epitope & elbow-hinge modificationIncreased ADCC Higher affinity to the ADCC receptor FcgRIIIALower CDC activityRecognition of type II epi