惰性淋巴瘤治疗进展

nullnullB细胞惰性淋巴瘤治疗进展 nullnull工作分类 Working Formulation低度恶性 小淋巴细胞性淋巴瘤 滤泡性淋巴瘤，小核裂细胞为主 滤泡性淋巴瘤，大小细胞混合 中度恶性 滤泡性淋巴瘤，大细胞为主 弥漫性淋巴瘤，小核裂细胞 弥漫性，大小细胞混合淋巴瘤 弥漫性大细胞淋巴瘤 高度恶性 免疫母细胞淋巴瘤 淋巴母细胞淋巴瘤 小无裂细胞(Burkitt或非Burkitt)其他 毛细胞型 皮肤T细胞型 组织细胞性 髓外浆细胞瘤 不能分类 null惰性淋巴瘤的判定 临床症状较不明显、疾病进展缓慢 自然病程相对较长 对化疗敏感性差、难以治愈 Ardeshna KM, Smith P, Norton A, et al. Long-term effect of a watch and wait policy versus immediate systemic treatment for asymptomatic advanced-stage non-Hodgkin lymphoma: a randomised controlled trial. Lancet. 2003;362:516-522.null B-Cell Small lymphocytic lymphoma / CLL Follicular, Lymphoplasmacytic lymphoma any type Marginal Zone MALT nodal(monocytoid) splenic 惰性淋巴瘤 T-Cell Mycosis fungoides Anaplastic large cell,cutaneous …… Weisenburger DD ,Armitage JO. New approach to classifying non-Hodgkin’s lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin’s Lymphoma Classification Project. J Clin Oncol. 1998;16:2780-2795.nullFrom Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin. 2006;56:106-130.惰性淋巴瘤（B细胞）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 findingsIndolent 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 ＜5Indolent Lymphoma: Immuno-phenotypeIndolent 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惰性淋巴瘤生存率回顾 斯坦福大学(1970-2006)Semin Oncol. 2006;20(suppl 5):75. (%)年1997-2006 1986-1996 1970-1985100604020080051015202530惰性淋巴瘤生存率回顾 斯坦福大学(1970-2006)生存率 惰性淋巴瘤的治疗中的难题 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 1Horning S, et al. Semin Oncol 1993;20(5 suppl 5):7588; 2Rambaldi et al. Blood 2002;99:856862; 3Apostolidis J, et al. J Clin Oncol 1999;17:216–221; 4Hosing C, et al. Ann Oncol 2003 14(5):737744 the goal of therapy the goal of therapy提高生活质量，（缓解、消除临床症状 ） 延长生存时间nullHow I treat indolent lymphoma From www.bloodjournal.org on October 7, 2008. 治疗策略一：“wait and watch” 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? 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。A randomized prospective comparison of chemotherapy to total body irradiation as initial treatment for the indolent lymphoproliferative diseases Blood, Vol 69, No 6 (June), 2005: pp 1642-1646 A randomized prospective comparison of chemotherapy to total body irradiation as initial treatment for the indolent lymphoproliferative diseases Blood, Vol 69, No 6 (June), 2005: pp 1642-1646 A randomized prospective comparison of chemotherapy to total body irradiation as initial treatment for the indolent lymphoproliferative diseases Blood, Vol 69, No 6 (June), 2007: pp 1642-1646 A randomized prospective comparison of chemotherapy to total body irradiation as initial treatment for the indolent lymphoproliferative diseases Blood, Vol 69, No 6 (June), 2007: pp 1642-1646 治疗策略三：姑息性化疗 ------单药化疗治疗策略三：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 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美罗华清除淋巴细胞的机制恶性B细胞2. 补体 系统1. ADCC3. 诱导细胞调亡null 单克隆抗体治疗 联合化疗 造血干细胞移植 免疫毒素 (单抗联接毒素) 免疫放疗 (同位素标记单抗)++常见惰性淋巴瘤的治疗进展常见惰性淋巴瘤的治疗进展CLL/SLLCLL/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 目前各种治疗是不能治愈Ann Arbor分期 Cotswolds改良法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>10cm 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）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% Ⅰ 0期伴淋巴结肿大 中危 Ⅱ 0-Ⅰ期伴脾/肝或二者均肿大 中危 Ⅲ 0-Ⅱ期伴Hb<11.0g/d1或血压积<33% 高危 Ⅳ 0-Ⅲ期伴血小板<100000/l 高危CLL/SLL治疗指症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null方案的优化---clinical trails方案的优化---clinical trailsFludarabine AloneFludarabine 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 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 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 fludarabine with rituximabAddition 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 9011 BLOOD, 1 JANUARY 2005 VOLUME 105, 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 9011 BLOOD, 1 JANUARY 2005 VOLUME 105, NUMBER 1 fludarabine with rituximabFludarabine plus cyclophosphamide versus fludarabine alone BLOOD, 1 FEBRUARY 2006 _ VOLUME 107, NUMBER 3 Fludarabine plus cyclophosphamide versus fludarabine alone BLOOD, 1 FEBRUARY 2006 _ VOLUME 107, NUMBER 3 nullFollicular Lymphomanullnullnull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 :研究 (M39021)CVP±美罗华治疗初治滤泡性淋巴瘤 :研究设计 (M39021) 滤泡性 NHL (IWF B, C, D) III–IV期 18 岁 未接受过治疗 可测量病灶 组织学回顾随 机CVP x 4 周期 (每3周) 美罗华 + CVP x 4周期 (每3周)再 分 期CVP x 4 周期 (每3周) 美罗华 + CVP x 4 周期 (每3周)SD, PD退出CR, PR美罗华 375mg/m2 i.v. day 1 环磷酰胺 750mg/m2 i.v. day 1 长春新碱 1.4mg/m2 i.v. day 1 强的松40mg/m2 p.o. days 1–5 Marcus R, et al. Blood 2005;105:1417CVP±美罗华治疗初治滤泡性淋巴瘤 患者 (M39021)CVP±美罗华治疗初治滤泡性淋巴瘤 患者分析 (M39021)Marcus R, et al. Blood 2005;105:1417CVP±美罗华治疗初治滤泡性淋巴瘤 缓解率CVP±美罗华治疗初治滤泡性淋巴瘤 缓解率Solal-Celigny, et al. Blood 2005;106:Abs.350CVP±美罗华治疗初治滤泡性淋巴瘤 (随访42月)probabilityR-CVP: 中位 27 月CVP: 中位 7 月p<0.00011.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60月CVP±美罗华治疗初治滤泡性淋巴瘤 (随访42月)Solal-Celigny, et al. Blood 2005;106:Abs.350CVP±美罗华治疗初治滤泡性淋巴瘤 （疾病进展 ---随访42月）R-CVP: 中位 34 月CVP: 中位14 月probabilityp<0.00011.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60月CVP±美罗华治疗初治滤泡性淋巴瘤 （疾病进展 ---随访42月）Solal-Celigny, et al. Blood 2005;106:Abs.350CVP±美罗华治疗初治滤泡性淋巴瘤 总生存率 (OS) (随访42月)（预估3年）R-CVP: 89％CVP: 81％probabilityp=0.05531.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 6 12 18 24 30 36 42 48 54 60月CVP±美罗华治疗初治滤泡性淋巴瘤 总生存率 (OS) (随访42月)（预估3年）Solal-Celigny, et al. Blood 2005;106:Abs.350单药治疗复发、耐药的滤泡型淋巴瘤单药治疗复发、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） Journal of Clinical Oncology. Vol 16 No 8,1998; P2825 美罗华治疗初治/复发滤泡性淋巴瘤 美罗华治疗初治/复发滤泡性淋巴瘤 Hochster HS, et al. al.Blood 2005;106:Abs.349 van Oers al.Blood 2005;106:Abs.353Ghielmini M, et al. Blood 2004;103: 44164423 .null 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。 Neri N et al, J. Hematother Stem Cell Res. 2001(10):669-74 3.美罗华联合干扰素治疗滤泡型淋巴瘤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）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 Type of response Rituximab Rituximab+ Interferon α2aProlonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly*4 scheduleProlonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard weekly*4 scheduleMichele G, Shu-Fang , Schmitz H,et al. Blood, Jun 2007; 103: 4416 - 4423nullHow I treat indolent lymphoma From www.bloodjournal.org on October 7, 2008. 惰性淋巴瘤(FL)生存率回顾 安德森肿瘤中心(1977-2002)Liu Q, et al. Blood 2003;102:398a (Abs.1446)100 75 50 25 01997–2002 (R-FND)1992–97 (ATTIFN)1988–92 (ATTIFN)1982–88 (CHOP-BleoIFN)1977–82 (CHOP-Bleo)0 60 120 180 240 300 360生存率 %惰性淋巴瘤(FL)生存率回顾 安德森肿瘤中心(1977-2002)惰性淋巴瘤治疗的前景惰性淋巴瘤治疗的前景惰性淋巴瘤生存率回顾 斯坦福大学(1970-2006)Semin Oncol. 2006;20(suppl 5):75. (%)年1997-2006 1986-1996 1970-1985100604020080051015202530惰性淋巴瘤生存率回顾 斯坦福大学(1970-2006)生存率How I treat indolent lymphoma ？How I treat indolent 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 -----新药的研发新治疗策略 -----治疗方案优化新治疗策略 -----治疗方案优化新治疗策略：生物治疗 -----细胞免疫治疗新治疗策略：生物治疗 -----细胞免疫治疗Active Immunization for CancerActive Immunization for CancerLoading DCEx vivo Directly in vivoGene Gene, Protein/peptide Cell fragments RNA Whole tumor cellKnown limited repertoire of TAALarge repertoire of unknown antigensDNA vaccinationNeeds adjuvant: plasmid sequences muscle injurynullVaccination with autologous tumor-loaded dendritic cells induces clinical and immunological responses in indolent B cell lymphoma patients with relapsed and measurable disease: a pilot study Eighteen relapsed patients with measurable indolent non-Hodgkin lymphoma (NHL) were vaccinated with dendritic cells (DCs) loaded with killed autologous tumor cells. Six patients had objective clinical responses including three continuous complete remissions (CR) and three partial responses (PR), with a median follow-up of 50.5 months. Eight patients had stable disease, while four had progressive disease. Clinical responses were significantly associated with a reduction in CD4(+)CD25(+)FOXP3(+) regulatory T cells, an increase in CD3(-)CD56(dim)CD16(+) NK cells and maturation of lymphocytes to the effector memory stage either in post-vaccine peripheral blood or tumor specimen samples. In partial responding patients, vaccination significantly boosted the IFN-gamma producing T cell response to autologous tumor challenge. In one HLA-A*0201(+) patient that achieved CR, IL-4 release by circulating T cells in response to tumor-specific IgH-encoded peptides was also documented. Immunohistochemical analysis of tumor biopsies using biotin-conjugated autologous serum samples revealed a tumor-restricted humoral response only in the post-vaccine serum from responding patients, whereas no autologous tumor-specific reactivity was detected in pre- or post-vaccine sera from non-responder patients. Collectively these results demonstrate that vaccination with tumor-loaded DCs may induce both T and B cell responses and produces clinical benefits in indolent NHL patients with measurable disease. Di Nicola M, Zappasodi R, Carlostella C, et al. Blood. 2008 Sep 22 Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients Idiotype-pulsed dendritic cell vaccination for B-cell lymphoma: clinical and immune responses in 35 patients Conclusion： 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 apparent resistance to the primary DC vaccine. John M , Debra K. Czerwinski, et,al. CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS nullTumor-specific, cytotoxic T-lymphocyte response after idiotype vaccination for B-cell, non-Hodgkin's lymphoma. Blood, Jul 1996; 88: 580 - 589. Andrea Anichini, Roberta Mortarini, Luca Romagnoli ，et al. Skewed T-cell differentiation in patients with indolent non-Hodgkin lymphoma reversed by ex vivo T-cell culture with c cytokines. Blood, Jan 2006; 107: 602 - 609. Humoral immune response and immunoglobulin G Fc receptor genotype are associated with better clinical outcome following idiotype vaccination in follicular lymphoma patients regardless of their response to induction chemotherapy.Blood, Feb 2007; 109: 951 - 953. …… nullThanks !