B-Cell Small lymphocytic lymphoma / CLL Follicular, Lymphoplasmacytic lymphoma any type Marginal Zone MALT nodal(monocytoid) splenic 惰性淋巴瘤（B细胞）1. 边缘带淋巴瘤：发生在淋巴滤泡及滤泡外套之间的淋巴瘤。免疫表型：CD5+,B 细胞型，表达BCL-2+ 。包括：淋巴结边缘区淋巴瘤:发生在淋巴结边缘区的淋巴瘤，其细胞形态类似于单核细胞，也称为“单核细胞样B细胞淋巴瘤脾边缘区淋巴瘤（SMZL): 发生于脾脏，和伴有绒毛状淋巴细胞粘膜相关性淋巴样组织结外边缘带B细胞淋巴瘤：发生在结外，可伴有t（11 ；18 ），包括：甲状腺桥本甲状腺炎相关性淋巴瘤干燥综合征相关性淋巴瘤幽门螺旋杆菌相关性胃淋巴瘤2. 滤泡性淋巴瘤：发生在生发中心，B细胞来源，CD5+ 、BCL-2+, 伴t（14 ；18 ）。3. 慢性淋巴细胞白血病/小细胞淋巴瘤：免疫标记：CD5+ CD23+ CD19+ CD+ Indolent Lymphoma: Clinical findings SLL FL LPL MZL Age (median,y) 65 59 63 60 M:F 2:1 1:1.7 1:1 1:1 Frequency(%) 5 33 1-2 5 Stage advanced(%) 90 90 100 25 Marrow positive(%) 95 40 95 20 IgM paraprotein(%) 1-2 0 80-90 ＜5 Indolent Lymphoma: Immuno-phenotype SLL FL LPL MZL MCL Surf Ig + +++ ++IgM +++ +++ Cyclin D1 - - - - +++ CD5 +++ - - - +++ CD10 - +++ - - - CD19 ++ +++ +++ +++ +++ CD20 + +++ ++ +++ +++ CD22 + +++ +++ CD23 +++ - ++ - + 惰性淋巴瘤的治疗惰性淋巴瘤的治疗中的难题传统化疗不能改善总生存1 传统化疗极少获得分子缓解2 大剂量化疗可以提高疗效但可承受的患者数量有限3, 且复发率高异体移植可能治愈, 但多数患者不适合, 且与移植相关的致死率很高4 the goal of therapy 治疗策略一：“wait and watch”惰性淋巴瘤的患者通常发病时年龄大，于诊断时常无临床症状、肿瘤负荷小的患者可以采取“watch and wait”（随访，暂不治疗）的策略。这一选择的主要依据是：常规放化疗无法彻底治愈惰性淋巴瘤,对患者的总体生存不产生较大的影响。Cancer waiting times: what is the value of a lymphoma waiting time? BACKGROUND AND AIM: Waiting times for patients with lymphoma have been reported across the United Kingdom since 2005. Lymphoma however, is not a single disease but a wide spectrum of lymphoid tumours that range from the most malignant to the most indolent, from highly curable to incurable. We now question the value of the current system that reports lymphoma waiting time on a quarterly basis and makes no allowance for the different types of lymphoma. METHOD: Four hundred and sixty nine cases of lymphoma were registered in the west of Scotland in 2004. Complete datasets were available on 428. Patient demographic data, subtypes of lymphoma, biopsy site and referral urgency data were linked to the waiting times analysis for 2004 for the three subtypes, Lymphoma (HL), Diffuse Large B Cell (DLBC) and follicular Non Hodgkin Lymp (NHL). RESULTS: Patients with HL were younger, more likely to receive urgent referral and have a diagnosis made from neck node biopsy than the other two groups. Patients with DLBC NHL however had the shortest interval between presentation and the start of treatment and were subsequently more likely to receive treatment within 62 days than patients with either follicular NHL (p < 0.001) or HL (p < 0.05). CONCLUSION: Lymphoma subtype is a major factor determining the rate of progress from presentation to the start of treatment, hence the waiting time. PMID: 18780517 [PubMed - in process] Savage SA, Wotherspoon HA, Pentland D, et al. Scott Med J. 2008 Aug;53(3):5-7 治疗策略二：姑息性放疗众多研究已经证实，Ⅰ或Ⅱ期的惰性淋巴瘤患者给予受累部位的放疗后，5年无病生存率可达35%-40% ，虽然仍有部分患者此后复发，但大部分患者可能疾病处于静止。治疗策略三：姑息性化疗------ 单药化疗苯丁酸氮芥：4-6mg/d ，服2-3 周，间歇2-3 周CXT ：150-200 mg/d ，服5-7 天，间歇2-3 周Pred ：①提高疗效②合并溶贫或血小板减少Fludarabine Alone 治疗策略四：常规剂量联合化疗CHOP/CHOPE/CHOP-B 组成ProMACE-CytoBOM 复发的一线治疗后耐药的治疗过程中病理类型转变的治疗策略五 大剂量放化疗结合造血干细胞移植Age≤65 years Relapsed disease ：2nd or 3rd relapse 1st relapse with response duration ≤1 years 1st relapse in failure after 3-4 salvage chemotherapy cycles Primary refractory disease 治疗策略六：生物治疗1. CD20 单克隆抗体(美罗华) 美罗华清除淋巴细胞的机制常见惰性淋巴瘤的治疗进展CLL/SLL 典型的免疫表型CD5+ CD19+ CD20 较模糊CD23+ 、CD10- ，周期素D1(-) 需与套细胞淋巴瘤鉴别，因都是CD5+B 细胞有白血病细胞负荷——流式（包括/ ）明确肿瘤克隆性目前各种标准治疗是不能治愈Ann Arbor 分期Cotswolds 改良法分期累及部位Ⅰ单一淋巴结组Ⅱ横隔同侧多个淋巴结组Ⅲ横隔二侧多个淋巴结组Ⅳ多个结外病灶或淋巴结与结外病灶X 包块>10 cm E 结外扩展或单个孤立性结外病灶A/B B 症状：体重丢失>10%，发热，夜间盗汗CLL/SLL 分类（Rai 系统）分期特征预后0 淋巴细胞增多，外周血L>15000/ l 好RM ：L >40% Ⅰ0 期伴淋巴结肿大中危Ⅱ0-Ⅰ期伴脾/肝或二者均肿大中危Ⅲ0-Ⅱ期伴Hb<11.0g/d1 或血压积<33% 高危Ⅳ0-Ⅲ期伴血小板<100000/ l 高危CLL/SLL 治疗指症希望治疗自身免疫性血细胞减少（AIHA 、ITP 、纯红AA ）反复发生感染有症状累及脏器功能就诊时肿瘤高负荷至少6个月疾病稳定进展方案的优化---clinical trails Fludarabine Alone 参考文献病例数先前治疗CR CR+PR Tondini, 2000 54 ≥1 48 68 Falkson,1996 21 1-2 33 62 Moskowitz,1994 32 2 6 50 Hiddermann,1993 38 3(1-11) 13 31 Pigaditou,1993 45 3(1-7) 9 44 Redman,1992 38 3(1-4) - 55 Leiby,1987 25 2.6 4 32 Fludarabine Combined 参考文献病例治疗方案先前CR CR+PR 数治疗Hochster, 1994 27 Flu 20mg/m2/d 5d 1/4w 无89 100 CTX 600-1000mg/m2 d1, 1/3-4W Lazzariono,1999 25 Flu 25mg/m2/d 3d 有32 72 CTX 350mg/m2/d 3d Dex 20mg/d 3d, 1/4W Bocchia,1999 30 Flu 15mg/m2/d 4d 无50 85 Epi 60mg/m2 d1 CTX 250mg/m2/d 4d 1/3-4W Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB -9712)John C. Byrd, Bercedis L. Peterson, Vicki A,et al. BLOOD, 1 JANUARY 2003 VOLUME 101, NUMBER 1 Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011BLOOD, 1 JANUARY 2005 VOLUME 105, NUMBER 1 Fludarabine plus cyclophosphamide versus fludarabine aloneBLOOD, 1 FEBRUARY 2006 _ VOLUME 107, NUMBER 3 单克隆抗体(美罗华) 用法：单用或联合用药（化疗、干扰素、生长因子）剂量：375mg/m2—500mg/m2 时机：早期诱导治疗、维持治疗：q6m×4 CVP± 美罗华治疗初治滤泡性淋巴瘤 患者分析(M39021) 单药治疗复发、耐药的滤泡型淋巴瘤166 例，CD20+ ，78% 为晚期病例（Ⅲ/Ⅳ）美罗华：375mg/m2 ，1/w （第1，8，15 ，22 天）美罗华治疗初治/复发滤泡性淋巴瘤2. 细胞因子(干扰素α) COPP COPP+IFN P 值例数27 28 总有效率20 （74% ）24 （86% ）CR 16 （59% ）20 （71% ）PR 4 （15% ）5 （18% ）7 年生存率74% 72% 0.2 CR 者7年EFS 70% 100% ＜0.01 IFN-α用法：第28 天起，5MU ，3/W×4W 患者均为滤泡性淋巴瘤，91% 为晚期病例。3. 美罗华联合干扰素治疗滤泡型淋巴瘤Cycle 1 Cycle 2 Observation CR Rituximab n=14 PR n=56 Randomization MR n=13 Rituximab + IFN-α2a NR n=13 Off study 美罗华联合干扰素治疗滤泡型淋巴瘤（additional 4 cycles of R or R + IFN-α）Complete 23% 48% Partial 59% 46% Minor 12% 6% Stable disease 3% 0 Progression 3% 0 p ＜0.05 Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly*4 schedule 惰性淋巴瘤治疗的前景How I treatindolent lymphoma ？Question ：Despite advances in treatment, there was little evidence until recently that this led to improvement in the survival of patients with indolent lymphoma, with patients continuing to have an unremitting course of relapse of disease. Is there still a role for a “watch-and-wait”approach in asymptomatic patients or should they be treated at diagnosis ？What are the optimal first-line and salvage treatments, what is the role of maintenance therapy ？John G. Gribben Institute of Cancer, Barts and The London, Queen Mary School of Medicine, London, United Kingdom From www.bloodjournal. org by on october 7, 2008. 新治疗策略----- 新药的研发新治疗策略----- 治疗方案优化新治疗策略：生物治疗----- 细胞免疫治疗Active Immunization for Cancer Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients C onclu sion ：Id-pulsed DC vaccination can induce T-cell and humoral anti-Id immune responses and durable tumor regression.Subsequent boosting with Id-KLH can lead to tumor regression despite