利妥昔单抗体内净化造血干细胞移植治疗非霍奇金淋巴瘤

 目的 探讨利妥昔单抗（商品名：美罗华）体内净化造血干细胞移植治疗非霍奇金淋巴瘤（NHL）的疗效。方法 自体造血干细胞移植（AHSCT）-1、+8天运用利妥昔单抗375 mg／m2的体内净化。结果 7例患者移植后造血功能恢复,未观察到利妥昔单抗的严重毒副反应,移植后随访1～28个月（中位随访时间15个月）,均未见疾病进展或复发。结论 利妥昔单抗净化造血干细胞移植能提高CD+20 NHL的疗效,有助于清除微小残留病灶,延长NHL的生存期。     

抗CD20单克隆抗体联合自体外周血干细胞移植治疗非霍奇金淋巴瘤的临床研究

 目的　探讨抗CD20单克隆抗体（利妥昔单抗,商品名：美罗华）联合自体外周血干细胞移植（APBSCT）治疗B细胞非霍奇金淋巴瘤（NHL）的疗效。方法　21例CD20阳性的NHL患者,经过前期治疗,5例达完全缓解（CR）,难治性病例为16例,包括11例部分缓解（PR）和5例疾病进展（PD）。在自体造血干细胞动员的第1、8天及预处理的-1、＋7天每天应用利妥昔单抗375 mg／m2。结果　移植前疾病达到CR的5例患者,无一例复发;移植前处于PR的11例患者,仅1例在移植后6个月疾病复发,其余均无病生存;移植前处于PD的5例患者,2例无病生存。21例患者中位随访24（1～68）个月,复发、死亡4例（19 %）,其余17例均无病生存,2年无病生存（EFS）和总生存（OS）率均为81.0 %。未观察到利妥昔单抗对采集所得干细胞的质量和数量以及移植后造血恢复有不良影响。结论　APBSCT联合利妥昔单抗做体内净化治疗B细胞NHL疗效与移植前状态有关,作为巩固治疗,能使移植前达CR的患者获得长期生存,提高治愈率;作为强化治疗,可提高缓解率,延长PR患者的EFS及OS。利妥昔单抗的加入不影响造血干细胞采集和移植后造血重建。     

利妥昔单抗治疗非霍奇金淋巴瘤20例

目的 探讨利妥昔单抗治疗B细胞非霍奇金淋巴瘤(NHL)的疗效、安全性.方法 共20例患者,初治18例,复治2例.利妥昔单抗单用1例;应用利妥昔单抗联合化疗19例,其中用于自体造血干细胞移植(APBSCT)体内净化治疗8例,维持治疗4例.结果 初治者单药治疗完全缓解1例,利妥昔单抗联合化疗完全缓解(CR)率82.4%(14/17),2例部分缓解(PR),总有效率94.1%;复治组中1例CR,1例PR;移植组中未观察到利妥昔单抗对采集的干细胞质量和数量以及移植后造血恢复有不良影响;维持治疗组4例全部生存,最长随访57个月.结论利妥昔单抗治疗NHL安全、有效,不论单用还是联合化疗对B细胞NHL均有良好疗效,可作为APBSCT的体内净化药物.     

自体造血干细胞移植联合利妥昔单抗治疗CD+20B细胞淋巴瘤

 采用自体造血干细胞移植（AHSCT）治疗中,高危侵袭性淋巴瘤已获得了较好疗效,但仍有部分移植患者因复发而死亡。复发的根源主要为微小残留病变,包括体内残留的肿瘤细胞和移植物中的肿瘤细胞污染。利妥昔单抗可靶向性清除CD+20 B细胞,因此,对CD+20 B细胞淋巴瘤患者,移植前后应用利妥昔单抗可起到体内净化和清除残留病灶作用,AHSCT联合利妥昔单抗有望进一步提高CD+20 B细胞淋巴瘤的疗效。     

利妥昔单抗联合化疗治疗弥漫大B细胞淋巴瘤临床分析

 目的　观察利妥昔单抗（商品名：美罗华）联合化疗治疗弥漫大B细胞淋巴瘤（DLBCL）的临床疗效及淋巴瘤国际预后指数（IPI）评分对预后的影响;探讨利妥昔单抗在DLBCL自体外周血干细胞移植（APBSCT）中的应用。方法　DLBCL 患者21例,IPI评分低危和中低危（0～2分）14例,中高危和高危（3～5分）7例。采用利妥昔单抗联合CHOP（环磷酰胺、多柔比星、长春新碱、泼尼松）方案4～8个疗程,其中有5例接受APBSCT,动员方案为利妥昔单抗联合环磷酰胺加依托泊苷,预处理方案为CBV （环磷酰胺、卡莫司汀、依托泊苷）方案。结果　21例患者中CR 13例（61.9 %）,总有效率90.5 %（19／21）;2年疾病无进展生存率为（69.74±10.43）%,2年总生存率为（84.44±8.35）%。IPI评分0～2分患者CR率92.9 %,总有效率100 %,3～5分患者CR率0,总有效率71.4 %,IPI 0～2分患者CR率高于3～5分患者（P＜0.01）;5例接受APBSCT的患者采集的中位单个核细胞（MNC）为7.34×108／kg,中位CD+34细胞为8.82×106／kg,造血恢复中性粒细胞＞0.5×109／L的中位时间＋9天,血小板＞20×109／L的中位时间＋12天;主要不良反应是输注相关的不良反应（14.3 %）以及化疗相关的血液学不良反应。结论　利妥昔单抗联合化疗治疗DLBCL疗效满意,IPI 0～2分患者的完全缓解率明显高于3～5分患者;利妥昔单抗不影响外周造血干细胞的采集及造血重建;利妥昔单抗应用安全性较好。     

自体干细胞移植联合利妥昔单抗治疗弥漫大B细胞淋巴瘤八例

目的观察自体干细胞移植（Auto—SCT）联合利妥昔单抗治疗弥漫大B细胞淋巴瘤（DLBCL）疗效。方法对Auto—SCT联合利妥昔单抗治疗DLBCL患者的疗效进行分析。8例CD;0DLBCL患者,化疗达CR后经巩固治疗,用环磷酰胺＋G—CSF动员后进行Auto—SCT,造血功能重建后予利妥昔单抗500mg静脉滴注,每周1次,连续2次,2个月后重复一次。出院后定期随访,用Karnosky评分标准评价生活质量。结果8例患者造血功能完全重建。予利妥昔单抗后除2例白细胞及1例血小板减少外,均无其他不良反应。随访2～6年,8例患者均无病生存,Karnosky评分100分。结论Auto—SCT联合利妥昔单抗是治疗DLBCL的有效方法,可降低移植后复发,提高长期生存率。     

弥漫性大B细胞淋巴瘤经利妥昔单抗联合化疗后进展伴CD20抗原表达丢失1例报道并文献复习

目的探讨B细胞恶性肿瘤利妥昔单抗（rituximab）治疗后进展伴CD20抗原表达丢失患者的生物学特性。方法分析1例弥漫大B细胞淋巴瘤利妥昔单抗联合化疗进展伴CD20抗原表达丢失及文献复习。结果1例45岁男性弥漫大B细胞淋巴瘤患者,初治时病理免疫组化（IHC）：CD5-、CD20＋、CD45RO-、CD10-、CycinD1弱表达。染色体46,XY。利妥昔单抗联合化疗达CR。利妥昔单抗维持治疗出现进展及白血病转化。流式细胞仪（FCAS）检测：CD19＋、CD79a＋、CD22＋而CD20-;免疫组化（IHC）染色CD20个别阳性细胞;核型为46,XY。结论B细胞恶性肿瘤经利妥昔单抗治疗后进展可能与CD20抗原表达丢失有关,应重新进行病理组织学、免疫表型和细胞分子遗传学检测。     

利妥昔单抗联合化疗治疗霍奇金淋巴瘤一例并文献复习

 【摘要】　目的　分析利妥昔单抗联合化疗方案治疗霍奇金淋巴瘤（HL）的疗效。方法　采用利妥昔单抗联合ABVD方案治疗1例经典型HL（cHL）并复习文献。结果　HL组织中有CD+20 表达,结节性淋巴细胞为主型表达率98 %～100 %,经典型表达率18 %～32 %。RS干细胞中亦有CD+20 表达。利妥昔单抗针对CD+20 细胞,清除RS细胞,抑制RS干细胞及反应性背景B细胞,阻断肿瘤细胞存活信号。利妥昔单抗单药治疗的临床反应率在结节性淋巴细胞为主型83 %～100 %,经典型22 %;与化疗联合应用,明显延长病情缓解期,提高治疗反应率。临床Ⅱ期观察利妥昔单抗联合ABVD方案治疗cHL患者,完全缓解率达81 %～93 %,5年无瘤生存率及总体生存率分别为83 %和96 %。该例患者治疗获得缓解,随访1年,健康生存。结论　利妥昔单抗联合化疗治疗HL安全有效。     

利妥昔单抗和挽救性自体造血干细胞移植治疗失败的原发性CD5+弥漫大B细胞淋巴瘤经验分享

目的 分析原发性CD5+弥漫大B细胞淋巴瘤(DLBCL)的特点及其特殊性.方法 对1例初诊时病理漏检CD5的原发性CD5+ DLBCL患者的诊疗过程进行总结,并复习相关文献.结果 本例初诊和复发均按照NCCN指南推荐进行,分别选用含有利妥昔单抗的标准剂量一线、二线化疗方案.并在二次复发时行挽救性自体造血干细胞移植,仍无法阻止病情进展,最终在移植后1 a内死亡.结论 原发性CD5+ DLBCL预后差,加入利妥昔单抗的化疗方案治疗不能改善其生存,挽救性自体造血干细胞移植亦无法改善其预后.     

利妥昔单抗联合高剂量治疗和自体外周血干细胞移植治疗侵袭性B细胞淋巴瘤的多中心前瞻性研究

目的 探讨在高剂量治疗联合自体外周血干细胞移植的基础上,加用利妥昔单抗治疗侵袭性B细胞淋巴瘤的可行性和疗效.方法 12个癌症研究中心共入组28例侵袭性B细胞淋巴瘤患者,其中22例为新诊断患者,6例为复发患者.每例患者共接受4次利妥昔单抗静脉输注,即在外周血干细胞动员化疗的前1天、动员化疗的第7天、干细胞回输的前1天和回输后的第8天各给予1次,每次375 mg/m2,共1500 mg/m2结果 高剂量治疗后,所有患者均达到完全缓解.中位随访37个月时,全组患者的4年总生存率和无进展生存率分别为75.0%和70.3%,新诊断患者的4年总生存率和无进展生存率均为72.7%.全组患者对利妥昔单抗治疗的耐受性较好,不良反应多为1、2度.结论 在高剂量治疗联合自体造血干细胞移植的基础上加入利妥昔单抗治疗侵袭性B细胞淋巴瘤是可行的,并且可能使患者的生存获益.     

High-dose rituximab does not negatively affect peripheral blood stem cell mobilization kinetics in patients with intermediate-grade non-Hodgkin's lymphoma

Rituximab, an anti-CD20 human-mouse chimeric monoclonal antibody has been shown to improve response rates when it is combined with standard salvage chemotherapy in patients with relapsed or refractory intermediate-grade B-cell non-Hodgkin's lymphoma. A vast majority of these patients subsequently undergo high-dose therapy followed by stem cell transplantation. However, the impact of rituximab on stem cell mobilization kinetics is not well characterized. The purpose of this study was to study the effect of high-dose rituximab given with chemotherapy on stem cell mobilization in patients with intermediate-grade B-cell non-Hodgkin's lymphoma. Thirty-six patients received ifosfamide, etoposide, and rituximab followed by filgrastim for stem cell mobilization. The chemotherapy regimen was well tolerated. Thirty-four of 36 patients (94%) were able to mobilize at least 2 × 10⁶ CD34+ cells/kg body weight after a median of 2 apheresis procedures. The median CD34+ cell dose collected per kilogram of recipient body weight was 6.5 × 10⁶ (range, 4.65-31.15). All patients who subsequently underwent high-dose chemotherapy and stem cell transplantation experienced sustained engraftment. In conclusion, high-dose rituximab given during stem cell mobilization does not negatively affect stem cell mobilization kinetics.     

利妥昔单抗联合DHAP方案治疗复发性非霍奇金淋巴瘤的临床疗效

 目的 探讨利妥昔单抗（商品名：美罗华）联合DHAP方案治疗复发性非霍奇金淋巴瘤（NHL）的疗效及安全性。方法 16例复发的B细胞NHL患者，其中8例接受美罗华联合DHAP方案治疗者为治疗组；8例接受联合化疗者为对照组；治疗组患者接受美罗华+DHAP方案治疗4 ~ 6周期，每周期21 d，于化疗开始前1天予美罗华（375 mg／m2）静脉滴注，然后每隔1周重复上述治疗，共4 ~ 6次。对照组予CHOP方案基础上加用甲氨蝶呤（MTX）、阿糖胞苷（Ara-C）、依托泊苷（VP16），治疗4 ~ 6周期，每周期21 d。结果 治疗组完全缓解（CR）率75 %，总有效（OR＝CR＋PR）率100 %，平均无进展生存期（PFS）（18.3±5.4）个月；对照组CR率37.5 %，OR率62.5 %，PFS（4.7±2.8）个月；治疗组平均PFS明显高于对照组（P＜0.05）。结论 美罗华联合DHAP方案对复发性NHL患者有较好疗效，且化疗药物的毒副作用未见增加。     

Rituximab

CHOP has been the standard chemotherapy for aggressive non-Hodgkin's lymphoma (NHL). However, indolent NHL remains largely an incurable diseases, with nearly static overall survival, and only 40% of patients with aggressive NHL are cured by CHOP. Monoclonal antibodies are an exciting advance in the treatment of lymphoma. Rituximab is a mouse/human chimeric monoclonal antibody that targets the CD20 antigen found on the surface of malignant and normal cells of the B-cell lineage, but not on primitive stem cells or mature plasma cells. Rituximab is safe and well-tolerated, and exhibit little cross-resistance with conventional chemotherapeutic agents. Clinical trials with rituximab indicate that the drug has broad application to NHL, although further clarification is needed to determine its optimal use in many of these clinical settings. In indolent NHL, rituximab has shown useful response rates, both as first-line therapy in relapsed disease. In aggressive lymphomas, diffuse large B-cell lymphoma is the most common form, the addition of rituximab to CHOP chemotherapy significantly lengthens disease-free and overall survival compared to CHOP alone as first line therapy, at least in elderly patients. These included combination with chemotherapy, prolonged or increased dosing regimens, and maintenance therapy, in which rituximab is administered to patients in remission to eliminate minimal residual disease and reduce the risk of relapse. Rituximab in vivo purging and maintenance is also being evaluated in autologous transplantation setting. Newer agents, including radiolabelled antibodies, Immunotoxin-linked antibodies and antibodies against novel target antigens are being tested in on-going clinical trial.     

An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab.

The chimeric anti-CD20 monoclonal antibody rituximab has become part of the standard therapy for patients with non-Hodgkin's lymphoma (NHL). To date, more than 300 000 patients have been treated with rituximab worldwide, including patients with indolent and aggressive NHL, Hodgkin's disease and other B-cell malignancies. Combination of rituximab with cytotoxic agents or cytokines has been explored in a number of different studies. Rituximab is now also approved for patients with diffuse large B-cell lymphoma when combined with standard CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone). The monoclonal antibody is generally well tolerated. Most adverse events are infusion-associated, including chills, fever and rigor related to the release of cytokines.     

Clinical use of rituximab in haematological malignancies

Rituximab is a chimeric human/mouse monoclonal antibody that is approved for the treatment of relapsed and refractory non-Hodgkin's lymphoma (NHL) and in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy as first-line therapy for diffuse large B-cell NHL, where it has shown the first survival advantage over CHOP alone in more than 20 years. Strategies to help define the optimal therapeutic usage of rituximab are being assessed, including first-line and maintenance or extended therapy, and the combination of rituximab with chemotherapy in indolent NHL. Emerging data suggest that earlier use may yield higher response rates, extended therapy can prolong remission, and the addition of rituximab to chemotherapy can increase clinical and molecular remission rates when compared with those achieved using chemotherapy alone. Studies in the peritransplant setting suggest a role for rituximab in vivo purging prior to transplant and/or maintenance rituximab as a means of clearing minimal residual disease. Rituximab has also shown activity in other B-cell disorders such as chronic lymphocytic leukaemia. The full potential of this immunotherapeutic agent remains to be defined in ongoing and future clinical trials.     

Concurrent administration of high-dose rituximab before and after autologous stem-cell transplantation for relapsed aggressive B-cell non-Hodgkin's lymphomas.

PURPOSE: We investigated the efficacy and safety of administering high-dose rituximab (HD-R) in combination with high-dose carmustine, cytarabine, etoposide, and melphalan chemotherapy and autologous stem-cell transplantation (SCT) in patients with recurrent B-cell aggressive non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Sixty-seven consecutive patients were treated. Rituximab was administered during stem-cell mobilization (1 day before chemotherapy at 375 mg/m(2) and 7 days after chemotherapy at 1,000 mg/m(2)), together with granulocyte colony-stimulating factor 10 mug/kg and granulocyte-macrophage colony-stimulating factor 250 microg/m(2) administered subcutaneously daily. HD-R of 1,000 mg/m(2) was administered again days 1 and 8 after transplantation. The results of this treatment were retrospectively compared with those of a historical control group receiving the same preparative regimen without rituximab. RESULTS: With a median follow-up time for the study group of 20 months, the overall survival rate at 2-years was 80% (95% CI, 65% to 89%) for the study group and 53% (95% CI, 34% to 69%) for the control group (P = .002). Disease-free survival was 67% (95% CI, 51% to 79%) for the study group and 43% (95% CI, 26% to 60%) for the control group (P = .004). The median time to recovery of absolute neutrophil count to >/= 500 cells/microL was 11 days (range, 8 to 37 days) for the rituximab group and 10 days (range, 8 to 17 days) for the matched control group (P = .001). However, infections were not significantly increased in patients treated with rituximab. CONCLUSION: The results of this study suggest that using HD-R and autologous SCT is a feasible and promising treatment for patients with B-cell aggressive NHL.     

The role of complement in the mechanism of action of rituximab for B-cell lymphoma: implications for therapy

Rituximab, a genetically engineered chimeric monoclonal antibody specifically binding to CD20, was the first antibody approved by the U.S. Food and Drug Administration for the treatment of cancer. Rituximab significantly improves treatment outcome in relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL). However, there are also some challenges for us to overcome: why approximately 50% of patients are unresponsive to rituximab in spite of the expression of CD20, and why some responsive patients develop resistance to further treatment. Although the antitumor mechanisms of rituximab are not completely understood, several distinct antitumor activities of rituximab have been suspected, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), apoptosis, and direct growth arrest. To counteract resistance to rituximab therapy, several strategies have been developed to: (a) augment the CDC effect by increasing CD20 expression, heteroconjugating rituximab to cobra venom factor and C3b, and inhibiting membrane complement regulatory protein, especially CD59, function; (b) enhance the ADCC effect through some immunomodulatory cytokines and CR3-binding beta-glucan; and (c) reduce the apoptotic threshold or induce apoptotic signaling on the tumor. Extensive studies indicate that rituximab combined with these approaches is more effective than a single rituximab approach. Herein, the mechanism of action of and resistance to rituximab therapy in B-cell NHL, in particular, the involvement of the complement system, are extensively reviewed.