套细胞淋巴瘤治疗现状及进展

套细胞淋巴瘤治疗现状及新进展中山大学肿瘤防治中心姜文奇Fisher RI . Ann Oncol . 1996;7(suppl 6):S 35-S 39.Armitage JO . Management of Mantle Cell Lymphoma . Oncology (Willston Park ). 1998.Romaguera JE , et al . Cancer . 2003;97:586-591.•占NHL 的3.0% -8.0%；•中老年人(中位＞60岁)，男∶女= 2-4∶1；•诊断时多为晚期：• 90%结外受累，常累及GI , BM , blood , • Spleen ,liver , CNS•兼具惰性和侵袭性淋巴瘤的特点•预后差，常规化疗5年生存率＜30%套细胞淋巴瘤（MCL ）过去曾命名为中心细胞性淋巴瘤，由非典型小淋巴细胞组成，广泛围绕正常生发中心，套区增宽，故称为套细胞淋巴瘤概 述MCL ：M antel C ELL L ymphoma /Most ChallengeLymphoma最具临床侵袭性、对目前治疗缓解期短、复发率高、中位生存期较短。

5-yr Overall Survival3Blood 1997 Jun 1;89(11):3909-18T -ALCL MALT FL Marginal zone , nodal Lymphoplasmacytoid SLL Burkitts DLBCMCL (27%)T -lymphoblastic PTCL30-49%>70%50-70%<30%1. Dreyling et al. Ann Oncol. 2014. 25(Suppl3): ii83–92.MCL 治疗挑战•MCL 具有侵袭性，病情进展迅速，治疗后复发率高，标准治疗难以治愈1•大部分患者在确诊时已到晚期1 •不存在金标准治疗方法1•较年轻的合适患者会给予强化治疗方案，但对大部分患者而言，这些方案并不适用1•已有治疗方法中极少有明显优越的方法。

ML的病理类型分布抗癌协会淋巴瘤病理专家组统计2008年5月至2010年4月全国52家医院的资料，n=21127 Non‐Hodgkin lymphoma subtypedistribution, geodemographic patterns, andsurvival in the US: A longitudinal analysis ofthe National Cancer Data Base from 1998 to2011There were 596,476 patients diagnosed withNHL，covers 70% of US cancer casesAmerican Journal of HematologyVolume 90, Issue 9, pages 790-795, 27 JUL 2015遗传学异常在MCL发生发展中的作用Semin Cancer Biol.2011 Sep 18.多种基因异常共同参与MCL发病机制•除了t（11,14）， cyclin D1过表达导致细胞周期调节机制异常, 还存在DNA损伤修复及凋亡机制异常7Cell cycleDNA damage response (> 80% MCL have secondaryalterations )INK 4/ARFDNA repairApoptosisDeletion 11q 22-23Mutations ATM locus ATM ATR p 21G 1/S arrest Deletion 17q /mutation p 53G 1SG 2MRB 1RB 1 Pcdk 4/cyclin D 1p 16p 14Stabilization of p 53Deletion 9q 21G 1/S arrest p 53p 27MDM 2CHK 1-2MCL 诊断•CD 19/20/22+ •CD 5+ •FMC 7+, HLA -DR ++, •sIg ++, λ > k•CD 10-, CD 23- and Bcl -6-•特征性的染色体易位t (11;14)(q 13;q 32)•Cyclin D 1+•FISH > 95%•Cytogenetics 70%•PCR 40%Small subset cyclin D 1-ve overexpress cyclin D 2, D 3 or E /translocations with other Ig lociWlodarska I , et al . Blood . 2008;111:5683-5690.MCL 诊断注意事项–对MCL患者应进行全面检查，准确分期，包括颈胸腹盆CT或PET-CT，骨髓活检或穿刺–对于拟诊为I～II期的患者，进行内镜检查除外胃肠道侵犯。

–有母细胞变或高 Ki-67 表达或有中枢神经系统症状者应进行脑脊液检查惰性MCL的诊断•脾大而较少淋巴结肿大•Ki67较低，一般低于30%•70-90%IGVH突变，无其他染色体突变•少有P53突变•不/低表达SOX11•qRT-PCR检测SOX11、HDGFRP3、DBN1可助分辨惰性MCL。

惰性MCL：“观察与等待”优于立即治疗J Clin Oncol, 2009, 27: e189-190;J Clin Oncol, 2009, 27: 1209-1213MCL的预后因素-MIPI•由Hoster等于2008年提出，对来自 3 项随机临床试验的 455 例患者进行多因素分析，识别 4 个独立的生存预后因素。

（年龄、体力评分、LDH、白细胞计数），将患者分为低危、中危、高危组•分析还表明MCL中，Ann Arbor分期、骨髓受累、淋巴结外受累部位的数量与预后无关。

Hoster, Blood 2008MCL的预后因素- ki 67•ki67增值指数升高与预后差密切相关•NCCN要求初治应查ki67，＜30%预后好Blood 2008SOX11-positive MCL tumors have increased tumor angiogenesis network and PDGFAoverexpression.Jara Palomero et al. Blood 2014;124:2235-2247SOX11在MCL的预后价值Br J Haematol , 2008n =48; 1721 ± 230 dn =5; 501 ± 107 d5-year OS 78% vs 36%n =129n =12Blood . 2012iMcl 12例cMcl 15例Cancer Res , 20103.2 y vs 1.5 y P=0.014其他可预测MCL生存期的基因5-yearOS 78% vs 36%Blood . 2012iMcl12例cMcl 15例Cancer Res , 2010包括 TP53, RAN，MYC，TNFRSF10B，POLE2，SLC29A2等我院关于MCL预后指标新发现T abl e M ul t i vari at e anal ys i s of t hree-year P F S and O SPFS OS Clinical characteristicsHR 95%CI P HR 95%CI P Male (men) 0.258 0.031 - 2.126 0.208 20.094 0.693 - 582.869 0.081 Age (≤60) 0.295 0.051 - 1.702 0.172 0.149 0.008 - 2.776 0.202B symptoms (+) 1.223 0.321 - 4.660 0.768 0.285 0.018 - 4.538 0.374Serum LDH level (<245U/L) 0.053 0.004 - 0.683 0.024 0.023 0.001 - 0.434 0.012 IPI (high-intermediate risk) 0.430 0.112 - 1.657 0.220 0.891 0.186 - 4.262 0.885 MIPI (low risk) 56.728 6.050 - 531.908 0.000 135.128 4.084 - 4470.622 0.006 Spleen involvement (–) 5.994 1.163 - 30.887 0.032 307.707 2.103 - 45021.314 0.024 Extranodal involvement(+) 0.960 0.259 - 3.551 0.951 0.208 0.021 - 2.021 0.176 Bone marrow involvement(–) 0.098 0.012 - .817 0.032 0.021 0.000 - .972 0.048 Ann Arbor stage (IV) 0.164 0.026 - 1.040 0.055 0.003 0.000 - .274 0.012 MYC (≤ 8%) 0.171 0.041 - .715 0.016 0.122 0.021 - .716 0.020 Bcl-2 (≤ 80%) 0.352 0.087 - 1.425 0.143 0.000 0.000 - .082 0.004 20%的MCL高表达MYC和BCL-2，该群患者对常规治疗反应差，预后不佳Cai QQ et al oral presentation in Young Investigators Workshop of M.D. Anderson cancer center 2015MCL的一线诱导治疗MCL的一线诱导治疗不含HD -Ara -C 的一线诱导化疗含HD -Ara -C 的一线诱导化疗R -HyperCVAD /R -MACHOP and DHAP plus rituximab →ASCT 新的靶向治疗方案B -R R -BACiBrutinb , Vorinostat , and cladribine不含HD-Ara-C的一线诱导化疗Therapy ORR, %EFS, m 2y-OS, %CVP 60-8410-2045-65CHOP 75-887-2160-76R-CHOP 94-9617-2076MCP 63-7313-1585R-MCP7118mOS:56mMulticenter Evaluation of MCLAnnency Criteria fulfilled12345678910111213141516years00,250,50,751psingle agentcomb. no b. with anthra.event free interval after chemotherapy in stages III + IV含HD-Ara-C的诱导化疗Study Therapy N Age , Yrs ORR(CRR), %5-Yr EFS,%5-Yr OS,%Nordic MCL-2(R + Maxi-CHOP +HD Ara-C + MaintR)160< 6696 (54)6374 GITIL(R) HDS-ASCT77< 61CRR:866174MDACC R-HyperCVAD/R-MA 97Up to 80(1/3 > 65)CRR:8448 (FFS)65≤ 65CRR:8960 (FFS)76CALGB R-Maxi-CHOP-MTX/VP16-Ara-C/CBV7818-6988(69)56 (PFS)64EU younger patients R-CHOP/DHAP-TAM → ASCT208< 6597 (63)65 (TTF)781. ASH 20072. ASH 20073. J Clin Oncol. 20054. Clin Lymphoma Myeloma. 2007利妥昔单抗在MCL治疗地位•利妥昔单抗联合多种传统方案均可提高疗效Author N induction Consolidation Response rateOR（CR）MedianPFS/EFSMedianOSLenz 2005 Hoster 2003123CHOP INFmaintenancevsASCT75%(7%)14mo(TTF)46%(5y）RCHOP94%(34%)28mo(TTF)59% (5y)Herold 200890MCP INF63%(15%)18mo56mo R-MCP INF71%(32%)20mo50mo Dreyling200875CHOP/MCP Intensive ASCT78%(42%)43mo90mo Rummel200888R-CHOP-95%(35%)--R-bendamustine-89%(32%)--Delarue 200960R-CHOP/R-DHAP Intensive ASCT95%（96%）83mo75mo（5y）Geissler 2008159Intensive R-CHOP-HAIntensive ASCT96%（55%）63%（3y）81%（4y）R-CHOP vs CHOP一线治疗MCL•随机对照研究Blood 2008R-CHOP (n=63)CHOP (n=60)P Value ORR,%9475.005CR,%347.0002TTP, m 2114<0.05PFS, m 2019>0.052y-OS, m 7676>0.055y-OS, m5946>0.05Rituximab and intensive induction therapy for MCL•芬兰：maxiCHOP alternating with R high dose cytarabine with R -in vivo purged autologous stem cell support •美国：R -hyper -CVAD /R -MA•丹麦：3*R -CHOP responders continued with HD -Ara -C (2000 mg /m (2), bid . over 4 d ) and rituximab and stem cell harvest , followed by BEAM (carmustine , etoposide , Ara -C , melphalan ) and autologous stem cell rescue•法国:R -DHAP followed by intensive therapy with autologous stem -cell transplantation as first -line therapy for mantle cell lymphoma .Meta分析：与单纯化疗相比，利妥昔单抗联合化疗可为MCL患者带来OS获益Schulz H et al, J Natl Cancer Inst, 2007; 99: 706-714 Bendamustine plus rituximab versus CHOP plusrituximab as first-line treatment for patients withindolent and mantle-cell lymphomas-StiL trial Figure 3. Progression-free survival in histological subtypes of follicular lymphoma (A), mantle-cell lymphoma (B), marginal-zone lymphoma (C), and Waldenstrom's macroglobulinaemia (D)B-R=bendamustine plus rituximab. R-CHOP=CHOP plus rituximab.Mathias J Rummel,et al. Lancent l, Volume 381, Issue 9873, 2013, 1203–1210BR vs R-CHOP for iNHL and MCL STIL NHL1：PPF B-R优于R-CHOP•STIL研究确立了在不适合干细胞移植惰性BNHL及MCL患者中前线治疗地位；•与R-CHOP相比，BR疗效相当获更好，毒性更低。