惰性淋巴瘤规范化治疗08年nccn治疗指南解读

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 2008,2008 Lugano ICML,International Conference Maglinant Lympphoma,WHO Lymphoma Classification,B cell B cell chronic lymphocytic Mantle cell Follicular lymphoma Marginal B cell lymphoma, MALT type Plasma cell myeloma/plasmocytoma Diffuse large B cell lymphoma Burkitts lymphoma Precursor B lymphoblastic leukemia/lymphoma,T cell Mycosis fungoides Peripheral T cell lymphoma, unspecified Angioimmunoblastic T cell lymphoma Extranodal NK/T cell lymphoma Adult T cell leukemia/lymphoma (HTLV1+) Anaplastic large cell lymphoma, primary systemic Precursor T cell lymphoblastic leukemia/lymphoma,Distribution of NHL subtypes,In the UK (population 60m), there are 8,450 new NHL cases/year1 Across the EU (population 490m) this equates to an incidence of 69,000 new NHL cases/year,ALBCL,Other,DLBCL,FL,MALT lymphoma,Mature T-cell lymphoma,CLL/SLL,MCL,PMLBCL,Burkitts lymphoma,Liu Q, et al. Blood. 2003;102. Abstract 1446.,Regimen,生 存,Treatment Period,No. of Patients,5 yr (%),10 yr (%),15 yr (%),CHOP Bleo CHOP Bleo-IFN ATT-IFN ATT-IFN vs. FND-IFN FND-R vs. FND-R(+IFN),1977 1982 1982 1988 1988 1992 1992 1997 1997 2002,96 131 136 142 200,64 75 82 82 90,37 52 60 - -,29 42 - - -,IFN: interferon; ATT: alternating triple therapy with CHOD-B/ESHAP/NOPP; FND: fludarabine, mitoxantrone, and dexamethasone; Bleo: bleomycin; CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone,Yes, Survival Has Improved!,过去25年惰性淋巴瘤的生存是否有改善?,Years,% 存活率,0,5,10,15,20,25,0,20,40,60,80,100,CHOP-Bleo,CHOP-Bleo+IFN,ATTIFN,ATTIFN vs FNDIFN,R-FND+IFN vs FNDR+IFN,P .0001,IV期滤泡性淋巴瘤: 不同治疗方案的OS 1972-2002,Liu et al, JCO 2006; 24: 1582-1589,Years,% Alive,0,5,10,15,20,25,0,20,40,60,80,100,CHOP-Bleo,CHOP-Bleo+IFN,ATTIFN,ATTIFN vs FNDIFN,R-FND+IFN vs FNDR+IFN,P .01,IV期滤泡性淋巴瘤: 不同治疗方案的生存, FLIPI评分3,Liu et al, JCO 2006; 24: 1582-1589,Years,% Failure- Free,0,5,10,15,20,25,0,20,40,60,80,100,P .0001,IV期滤泡性淋巴瘤: 不同治疗方案的FFS 1972-2002,Liu et al, JCO 2006; 24: 1582-1589,惰性淋巴瘤治疗效果提高,常规化疗的改进 Rituximab，CD 20 RIT, Radio-immuno-therapy AHSCT/ Allo-HSCT,Rituximab:惰性 NHL(FL),单药治疗结论 单药：复发和难治的低度恶性NHL (RR 48%) 单药：初发的低度恶性NHL ( RR 73%) 联合化疗结论 (期临床研究) R-CVP 疗效明显优于CVP 方案 R-CHOP明显优于CHOP方案(TTF PFS OS) CVP 后 + R维持治疗进一步增加疗效(PFS) FCM+R 明显优于FCM 方案(RR CR PFS OS) R + Leukeran Leukeran,一线 - 滤泡性淋巴瘤治疗: Randomized,Rituximab 维持治疗的进展,Indolent NHL: induction and Maintenance,d8 after ASCT,Rituximab before and after ASCT for relapsed aggressive B-NHL,Cyclophosphamide 47 g/m2 G-CSF 10 g/kg/d,BEAM / ASCT,Rituximab 375 mg/m2,d1,d7,d1 after ASCT,Khouri IF, et al. J Clin Oncol 2005; 23:22402247.,Historical comparison N = 67,Rituximab significantly improves outcomes when combined with HDT and ASCT,Khouri IF, et al. J Clin Oncol 2005; 23:22402247.,Overall survival,Months post-transplant,0.0,1.0,6,3,0,9,12,15,18,21,24,27,30,p = 0.004,No rituximab (n = 30),Rituximab (n = 67),0.2,0.4,0.6,0.8,Months post-transplant,0.0,1.0,6,3,0,9,12,15,18,21,24,27,30,p = 0.002,0.2,0.4,0.6,0.8,Disease-free survival,No rituximab (n = 30),Rituximab (n = 67),Radio-Immuno-Therapy 单用,有效率： RIT 单用治疗复发耐药NHL,Response Duration: RIT on relapsed or refractory NHL,CD20 -I 131:FL and Transformed NHL: Long term outcome,11 studies ,1177 pts M age 57 ( 21-90), stage 90%, tumor 5cm 47%,BM + 44% 1st (141) 2rd (226) 3rd (228) 4th ( 540) Response R. 95 73 58 46 M.d. response - 35 16 12 CR (%) 78 46 32 23 M.d. CR - - 35 59 PFS1Y (%) 82 59 42 27 ASCO 2005,abstract 6561 USA multicenters,Zevalin巩固治疗FL,CUP trial: AHSCT欧洲多中心研究,Schouten H, et al. J Clin Oncol 2003;21:391827,Relapsed follicular NHL,Registration,3 cycles of chemotherapy,Restage,Randomisation,High dose therapy + unpurged stem cell support (n=33),High dose therapy + purged stem cell support (n=32),3 cycles of chemotherapy (n=24),Follow-up,CR or PR and 20% B-lymphocytes,NR or PD and 20% B-lymphocytes,n=140,*,*Prior to randomisation clinicians must decide whether bone marrow or periperal blood will be used as a stem cell support,复发FL,CUP trial: progression-free survival,1.0 0.8 0.6 0.4 0.2 0,0 12 24 36 48 60 72 84,Months,Proportion progression-free,Events Total Chemotherapy 20 24 Unpurged 9 22 Purged 11 24,Schouten H, et al. J Clin Oncol 2003;21:391827,复发LF,AutoPBSCT in 1st Remission FL,After : Hiddemann ,W. Brit J Haem 2006,AHSCT 1st-line :follicular lymphoma,540 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, 2008 Lugano abstract 028,Rituximab and/or High-Dose Therapy with Autotransplant at Time of Relapse in FL,Improved supportive therapy and outcome after Auto vs. Allo transplantation?,Allogeneic SCT over time,Autologous SCT over time,But: - retrospective study with heterogenous patient population - TBI conditioning regimen significantly lower relapse rate (p=0.02) - no specific prognostic factors after autologous/allogeneic transplantation,van Besnien et al. Blood 2003,How I treat indolent lymphoma,John G. Gribben， Institute of Cancer, Barts and The London Queen Mary School of Medicine, London, United Kingdom;.,Blood 2008 .3,Years,% 存活率,0,5,10,15,20,25,0,20,40,60,80,100,CHOP-Bleo,CHOP-Bleo+IFN,ATTIFN,ATTIFN vs FNDIFN,R-FND+IFN vs FNDR+IFN,P .0001,IV期滤泡性淋巴瘤: 不同治疗方案的OS 1972-2002,Liu et al, JCO 2006; 24: 1582-1589,患者 (%),19871996 19761986 19601975,年,100 80 60 40 20 0,0 5 10 15 20 25 30,2000 2010?,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 FL CR 14-47% RR 47-81% Treated FL CR 6-48% RR 31- 72% Fludarabine vs CVP ( phase III ) CR 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. 2003;30(1 Suppl 2):16-20., Dreyling MH, et al. Blood. 2003;102 Abstract 351.,40%,FCN+CD20单抗 n = 25,CR,FCN n = 24,21%,52%,PR,54%,92%,CR + PR,75%,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,(%),CR,47,39,43,PR,37,42,39.5,CR + PR,84,81,82.5,CR,滤泡性淋巴瘤,小淋巴细胞淋巴瘤,淋巴浆细胞淋巴瘤,套细胞淋巴瘤,60,29,23,27,40,43,38,33,50,37,31,31,Zinzani et al. J Clin Oncol 2000,FLU vs FLUID,RANDOMIZED 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 % ATT,FND vs ATT,RANDOMIZED PHASE III TRIAL,TSIMBERIDOU et al. Blood 2002,RANDOMIZED PHASE III TRIAL,FND + 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 2003 (# 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 0-2,CHOP (n=68),FM (n=72),随 机 分 组,28天为一疗程 共6个疗程,CR/PR,SD/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 2004;22(13):2654-2661,RANDOMIZED PHASE,FND + R vs FND,FM对比CHOP： 完全缓解率和分子学完全缓解率显著提高,FM CHOP p值 化疗后 cCR 68% 42% .003 mCR 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 2004;22(13):2654-2661,RANDOMIZED PHASE,FND + R vs FND,FM对比CHOP：RFS,RFS: Relapse-free survive,Zinzani et al. J Clin Oncol 2004;22(13):2654-2661,RANDOMIZED PHASE,FND + R vs FND,FM对比CHOP：耐受性显著提高,Zinzani et al. J Clin Oncol 2004;22(13):2654-2661,两组无一例出现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 PHASE,FND + 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 % CR,ORR 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 (2003),Objective Response,Response Whole LG Intermediate 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 8 CR+PR 72 86 0 85 58,2.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,总体平均疗程：3.76(1-6)M 有效患者的平均疗程：4.22,滤泡性淋巴瘤治疗Meta分析,*化疗方案不含福达华 0106年,25篇临床文献、2421例,ASH 2006, Abstract 2754,10 mg 迅速释放的片剂 药代动力学研究 Foran et al., J Clin Oncol 1999 40-50 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 2001,福达华口服剂型方 便,口服 vs 静脉 : 疗效相当（单药CLL）,Boogaerts et al., JCO 2001,52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 days,Oral 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 2008.8.,Oral Fludarabine + CTX,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 d1-3 CTX 500-600mg/m2 d1,LQY , 59岁. CLL/SLL 17年,91.3 SLL IIIA，CHOP X6 ,CR 1998.3：WBC 38.6，BMCLL，成熟淋巴细胞占93.5%, CT X 6, PR 2005-6 至2006-1, R-FN 3 次，PR 2006-8200