套细胞淋巴瘤MCL诊治进展

套细胞淋巴瘤诊治进展,套细胞淋巴瘤（Mantle Cell Lymphoma）,起自滤泡套层中未受抗原刺激的CD5+CD23-的B细胞肿瘤细胞由单一中小B细胞组成，缺乏母细胞原属惰性淋巴瘤，最具侵袭性,组织学分类,国际淋巴瘤分类研究组：对1403例分类研究DLBCL 31%滤泡性 22%小淋巴细胞（CLL型） 6%套细胞型 6%周围T细胞 6%边缘区B细胞MALT型 5%余下各亚型均 2%,3%-10%,625例分型统计(全国29家医院),MCL临床特点,中老年人，中位年龄60岁男：女=24：1大多数患者诊断时即处于疾病晚期(/)，常伴随结外播散病灶(90%：GI、骨髓)，80%外周血存在MCL细胞(FCM检测比例更高，92%)；CNS受累(复发)：4-22%；B症状5109/L，Hb10%Coombs试验阳性FCM免疫分型：CD19+CD5+，CD19+CD23+，CD22+dim，Lambda+dim,FISH检测t(11;14),t(11;14)阳性，R1G1Y2,t(11;14)(q13;q32)染色体易位,意义t(11;14)易位后形成IGH/CCND1基因，IgH基因附近的增强子使 cyclin D1过表达套细胞淋巴瘤的诊断性指标,CCND1,ExcessCCND1,IGH/CCND1 Dual Color, Dual Fusion Probe,11q13 region,14q32 region,探针杂交示意图,10,40,IHC:CyclinD1,男，40y； 肘部肿物； IHC：CyclinD1弱阳性；,所示箭头为染色体易位产生的融合信号(100)FISH:21%的细胞可见融合信号；诊断：MCL,10,CyclinD1,40,女，67y 扁桃体活检2块，直径0.3CM IHC：CyclinD1弱阳性；,所示箭头为染色体易位产生的融合信号(100)FISH:45%的细胞可见融合信号；诊断：MCL,Cyclin D1 表达是MCL敏感而特异的标记吗？,Cyclin D1 表达对MCL并非完全特异20-30%的MM多数毛细胞白血病阳性微阵列研究表明Cyclin D1在7%MCL中阴性，所以Cyclin D1表达并非诊断MCL必不可少的条件,这些病例极难诊断!,Cyclin D基因有3个亚型，包括D1、D2、D3，在部分Cyclin D1阴性的MCL中，可表达Cyclin D2或Cyclin D3，推测Cyclin D2和Cyclin D3的高表达在某种程度上替代了Cyclin D1的功能Cyclin D1的编码基因位于11q13上，功能主要是促进细胞增殖，是G1期细胞增殖信号的关键蛋白质，被视为癌基因，其过度表达可致细胞增殖失控而恶性化Cyclin D2的编码基因位于12p13，是细胞从G1期向S期转移所必须的Cyclin D3的编码基因位于染色体6p21，正常和恶性组织中未见CyclinD3基因异常及其蛋白的过度表达，前认为cyclinD3似乎不直接反映恶性度，而是肿瘤发展到晚期的结果,Cyclin D基因,CCND1-/t(11;14)- MCL,Siebert R,et al. Blood,2006,108:1109,IGK/CCND2,IGH/CCND3,细胞核SOX11表达在MCL诊断中的价值？,Haematologica,2009,94:1555,MCL细胞核表达SOX11蛋白,SOX11核蛋白表达,对传统MCL和惰性MCL组进一步研究，发现两者在13个基因的表达上有明显差异，SOX11为其中之一，并发现SOX11核蛋白表达缺失者大多无淋巴结肿大、低白细胞计数并且长生存，相反，SOX11阳性的MCL预后较差,关于SOX11和生存有异议,诊断预后治疗,3个SWOG临床试验(CHOP) 低度恶性淋巴瘤MCL：36/376MCL预后较其他低度恶性淋巴瘤差,Fisher RI,et al.Blood,1995,85:1075,10年FFS,10年OS,Ghielmini M, Zucca M. Blood,2009,114:1469,MCL,DLBCL,FL,MZL,FLIPI,International prognostic index (IPI),MCL ?,结外受累分期年龄体能状态LDH母细胞变异型Ki-67,MCL预后因素,好的预后因素:65岁好的体能状态临床分期I、II正常LDH、2-MG水平低IPI积分差的预后因素:母细胞变异型高Ki-67B症状脾肿大，骨髓浸润，低白蛋白水平,Analysis of Ki67 indices from 134 MCL pts showed correlation between Ki67 indices and survival,Analysis of 304 biopsy specimens showed Ki-67 index was significantly associated with OS(P0.0001) but IPI was not,Ki-67与预后,1. Tiemann M, et al. Br J Haematol. 2005;131:29-38.2. Katzenberger T, et al. Blood. 2006;107:3407.,72,120,Mos,Percent Survival,192,144,24, 10%,P 40%,168,96,5,Yrs,Percent Survival,15,10,5% to 20%,P 1) + 1.367 log10 (LDH/ULN) + 0.9393 log10 (WBC count),LR：0.57 21%IR：0.57 score 1) + 1.367 log10 (LDH/ULN) + 0.9393 log10 (WBC count) + 0.2142 Ki-67 (%),LR：0.57 IR：0.57 score CHOP-IFN,PFS Dreyling et al. Blood. 2005.,CHOP-DHAP/ASCT,PFSLefrre et al. Leukemia. 2002.,R-HDS,PFSGianni et al. Blood. 2003.,R-HyperCVAD MTX/ARAC,PFSRomaguera et al. J Clin Oncol. 2005.,ASCT,IFN,R-HDS,CONTROLS, 65, 65,Standard Chemotherapy,High-Dose or Dose-Dense Therapies,单中心治疗MCL生存比较,MCL一线常规联合化疗大样本(30例)前瞻性研究,大剂量Ara-C一线治疗MCL的前瞻性研究,MCL一线治疗方案后PBSCT巩固的前瞻性研究,Tam CS, et al. Blood. 2009;113:4144-4152. This research was originally published in Blood. American Society of Hematology.,自体/异基因造血干细胞移植,Single institution/not very large numbers ASCT in first CR ASCT in relapseMini-allo about 50% at 5 yrs,PFS (Mos),Proportion Alive Without Progression,0.0,0.2,0.4,0.8,1.0,0,144,AUTO1 (n = 50),AUTO2 (n = 36),0.6,12,24,36,48,60,72,84,96,108,120,132,NST (n = 35),P = .01,P = .01,OS (Mos),Proportion Alive,0.0,0.2,0.4,0.8,1.0,0,144,AUTO1 (n = 50),AUTO2 (n = 36),0.6,12,24,36,48,60,72,84,96,108,120,132,NST (n = 35),P = .02,P = .10*,*P = .006 at 4 yrs landmark,Pts received COP, CHOP, or prednimustine and mitoxantrone followed by DexaBEAM, total body irradiation, cyclophosphamide, and ASCT All patients had a PCR-detectable clonal IgH gene rearrangement in the peripheral blood, bone marrow, or lymph nodesCR and MR observed in 14 pts,ASCT后MRD状态与预后,Pott C, et al. Blood. 2006;107:2271-2278.,0,100,0,60,80,Mos Since Auto-Tx,PFS,120,100,20,20,40,80,MRD negative (n = 14),P 0.001,60,MRD positive (n = 13),40,60,80,Mos Since Auto-Tx,OS,120,100,20,P 65岁患者改良HyperCVAD+美罗华维持一线巩固方案临床试验大剂量治疗联合自体干细胞解救,NCCN v.1. 2010,MCL建议治疗方案-2,二线方案苯达莫司汀美罗华硼替佐米美罗华克拉屈滨美罗华 FC 美罗华 FCMR FMR来那度胺PEPC美罗华Temsirolimus沙利度胺二线巩固方案大剂量治疗联合异基因干细胞移植（清髓或非清髓）,NCCN v.1. 2010,套细胞淋巴瘤治疗,2009 ASH Education Programe,R-CHOP vs. R-FCanti-CD20 vs. IFN,“Mini” transplant, 65 years,R-CHOP vs. R-CHOP/DHAPPBSCT,R-chemo +/- Bortezomib,1.