单克隆抗体治疗B细胞淋巴瘤的临床应用

利妥昔单抗作为首个获FDA批准用于肿瘤治疗的单克隆抗体,近十年来活跃在低度或滤泡型非霍奇金恶性淋巴瘤(NHL)、侵袭型淋巴瘤以及骨髓移植等治疗领域,成为人类抗击恶性淋巴瘤的有力武器之一.但临床治疗中,利妥昔单抗耐药问题提示,B细胞淋巴瘤的免疫治疗尚存在明显障碍.     

利妥昔单抗在血液系统临床应用研究新进展

利妥昔单抗为人鼠嵌合型单克隆抗体,已被FDA批准用于复发或难治性的CD20阳性的B细胞低度恶性或滤泡型非霍奇金淋巴瘤(NHL)的治疗.它能特异性结合B淋巴细胞表面CD20抗原,杀伤体内的B淋巴细胞.临床主要用于治疗各种一线或二线B细胞NHL,可以单独应用,亦可与化疗药物联合应用,目前还尝试用于慢性淋巴细胞白血病、多发性骨髓瘤、特发行血小板减少性紫癜等的治疗.     

1例美罗华过敏的护理体会

非霍杰金淋巴瘤（NHL）是常见的淋巴系统恶性肿瘤，其中绝大多数为B细胞来源。利妥昔单抗（美罗华）是一种嵌合鼠／人的单克隆抗体，该抗体与纵贯细胞膜的CD20抗原特异性结合，诱导B细胞凋亡，抑制细胞增殖。治疗CD20阳性对化疗抗拒的低度恶性滤泡性淋巴瘤，单药有效率60％，     

利妥昔单抗治疗B细胞淋巴瘤现状

抗CD20单抗利妥昔单抗（rituximab）是治疗B细胞非霍奇金淋巴瘤（B-NHL）的单克隆抗体药物。文章介绍利妥昔单抗单药治疗、联合其他化疗药物治疗以及靶向放射免疫治疗B细胞非霍奇金淋巴瘤的疗效，研究提示，利妥昔单抗与其他化疗药物联合应用治疗B-NHL具有增效或协同作用，可显著提高疗效，延长缓解期。     

利妥昔单抗在皮肤病中的治疗应用

利妥昔单抗是针对正常和恶性B淋巴细胞表面CD20抗原的鼠/人嵌合型单克隆抗体(mAb).它适用于治疗复发性或难治性、低度恶性或滤泡性、CD20阳性B细胞非霍奇金淋巴瘤,还常用于治疗慢性淋巴细胞白血病、原发性巨球蛋白血症和免疫性或特发性血小板减少性紫癜(ITP).利妥昔单抗能有效治疗原发性皮肤B细胞淋巴瘤和其他皮肤淋巴瘤以及混合型冷球蛋白血症,还可望用于治疗系统性红斑狼疮、皮肌炎、天疱疮、脉管炎和多种血液病.通常引起轻微皮肤不良反应,偶可引起副瘤天疱疮、Stevens-Johnson综合征、苔藓样皮炎、大疱性皮炎和中毒性表皮坏死松解症.     

人源化抗CD20单克隆抗体Obinutuzumab

虽然在过去的10年里,抗CD20单克隆抗体,特别是利妥昔单抗（rituximab）的出现,极大地改善了B细胞恶性淋巴瘤的治疗效果,但该病的短期复发率仍然很高。Obinutuzumab（曾用名：afutuzumab;     

加拿大通报利妥昔单抗致肠梗阻和穿孔的不良事件

2006年11月10日,霍夫曼-罗氏有限公司与加拿大卫生部共同发布信息,通报了与利妥昔单抗(Rituximab,商品名:Rituxan)相关的肠梗阻和胃肠穿孔的不良事件。利妥昔单抗是一种嵌合型抗CD20单克隆抗体,用于治疗B细胞非霍奇金淋巴瘤(NHL)和类风湿性关节炎(RA)。基于上市后及临床研究数据,罗氏公司与加拿大卫生部强调以下事实和建议:(1)已观察到患者使用利妥昔单抗出现腹痛、肠梗阻和穿孔的病例,甚至导致一些患者死亡。大部分(包括所有死亡报告)发生于使用利妥昔单抗与化疗联合治疗NHL期间。(2)利妥昔单抗与这些病例间的因果关系尚未建立。(3)…     

抗CD20单克隆抗体治疗自身免疫病研究进展

抗CD20单克隆抗体即利妥昔单抗(rituximab,RTX),1997年被美国FDA批准用于治疗低度恶性B细胞非霍奇金淋巴瘤,是第一种获准用于治疗人类肿瘤的单克隆抗体.近年来,RTX在自身免疫病方面的应用受到广泛关注.鉴于RTX治疗类风湿关节炎、系统性红斑狼疮、特发性血小板减少性紫癜已有较多的论述,本文就RTX在其他自身免疫病中的治疗应用研究进行概述.     

利妥昔单抗治疗B细胞濑巴现状

抗CD20单抗利妥昔单抗(rituximab)是治疗B细胞非霍奇金淋巴瘤(B-NHL)的单克隆抗体药物.文章介绍利妥昔单抗单药治疗、联合其他化疗药物治疗以及靶向放射免疫治疗B细胞非霍奇金淋巴瘤的疗效,研究提示,利妥昔单抗与其他化疗药物联合应用治疗B-NHL具有增效或协同作用,可显著提高疗效,延长缓解期.     

利妥昔单抗致肠梗阻不良反应1例

利妥昔单抗(rituximab,RTx)是一种人-鼠嵌合性抗B淋巴细胞表面CD20抗原的单克隆抗体,是FDA批准的首个用于治疗肿瘤的单克隆抗体[1-2]。近年来,利妥昔单抗的应用范围不断扩大,在器官移植中的应用也越来越广泛,但利妥昔单抗导致的不良反应也逐渐增多[2-4]。我院1例肝移植患儿首次应用利妥昔单抗治疗时出现肠梗阻的严重不良反应,现报道如下。     

Rituxan immunotherapy and zevalin radioimmunotherapy in the treatment of non-Hodgkin's lymphoma

Immunotherapy with the anti-CD20 monoclonal antibody rituximab has been shown in clinical trials to be effective in the treatment of both indolent and aggressive non-Hodgkin's lymphomas (NHL). Recent studies have demonstrated improved clinical benefit with extended dose and maintenance therapies in patients with indolent lymphomas and chronic lymphocytic leukemia. Rituximab's label was recently expanded to include treatment of bulky disease, retreatment of patients previously treated with rituximab, and an eight-week extended treatment schedule. Rituximab has also been effectively combined with chemotherapy, resulting in higher response rates and longer response durations in randomized trials in patients with aggressive lymphoma. Studies continue to evaluate and expand the role of rituximab in the treatment of NHL, including its use in combined immunotherapy approaches and autologous stem cell transplant as well as in the treatment of autoimmune disorders. Radioimmunotherapy with the rituximab and ibritumomab tiuxetan (Zevalin) regimen was recently approved for the treatment of relapsed or refractory low-grade, follicular or CD20+ transformed NHL, including rituximab refractory follicular NHL. The regimen is delivered on an outpatient basis over the course of a week. Studies are currently exploring sequential dose therapy, radioimmunotherapy with rituximab maintenance, and ibritumomab tiuxetan radioimmunotherapy as part of autologous stem cell transplant. Current understanding of the mechanisms of action of rituximab and the use of rituximab and ibritumomab tiuxetan in patients with indolent and aggressive NHL will be discussed.     

Rituximab therapy for indolent non-Hodgkin's lymphoma

Indolent non-Hodgkin's lymphomas (NHLs) are essentially incurable with current treatments. Rituximab is a specific anti-CD20 chimeric monoclonal antibody against the CD20 antigen, which is stably expressed on most B-cells (from the pre-B-cell stage). Compared with chemotherapy, rituximab has an excellent tolerability profile, making it a good therapeutic option for patients with indolent NHL. In the pivotal study for rituximab, patients with relapsed or refractory indolent or follicular lymphoma (FL) had an overall response rate of 50%. There is evidence that first-line rituximab therapy may be associated with better response rates; in previously untreated FL with a low tumor burden, rituximab monotherapy has produced an overall response rate of 73%. Attempts to improve response rates to rituximab by increasing the dose or frequency of dosing showed that the addition of four extra infusions of rituximab (in addition to the standard treatment schedule) resulted in an overall response rate of 76% in patients with FL. Augmenting rituximab with cytokines is also an option for increasing response rates in patients with indolent NHL. In a trial by the Nordic Lymphoma Study Group in patients with previously untreated or first-relapse indolent NHL, who had stable disease or a partial response after four doses of rituximab, 48% of the patients treated with rituximab plus interferon-alpha2a achieved a complete response. A further option is to combine rituximab with chemotherapy. Interim analyses from the East German Study Group have shown that rituximab plus mitoxantrone, chlorambucil and prednisolone (MCP) resulted in overall response rates of 89% in patients with untreated indolent lymphoma. Rituximab is therefore an excellent treatment option both as first-line and as salvage therapy for patients with indolent NHL.     

利妥昔单抗治疗类风湿关节炎的临床研究进展

利妥昔单抗是一种特异性针对CD20分子的基因工程抗体,能与B淋巴细胞表面的CD20结合,并通过补体介导的细胞毒作用等机制对B淋巴细胞进行特异性清除,从而达到治疗作用.利妥昔单抗最初作为抗淋巴瘤药物首先获得美国FDA认证,近年来被应用于类风湿关节炎等自身免疫病的治疗,取得了较好的疗效.现对其治疗类风湿关节炎的作用机制、临床应用和研究进展做一综述.     

Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia

Rituximab (MabThera, Rituxan) is an anti-CD20 monoclonal antibody that induces lysis and apoptosis of normal and malignant human B cells, and sensitises malignant B cells to the cytotoxic effect of chemotherapy. In phase III trials in patients with indolent or aggressive B-cell non-Hodgkin's lymphoma (NHL), intravenous rituximab in combination with chemotherapy was more effective as first- or second-line therapy than chemotherapy alone in providing tumour remission and patient survival. Likewise, in patients with chronic lymphocytic leukaemia (CLL), rituximab in combination with chemotherapy appeared more effective than chemotherapy alone as either first- or second-line treatment. In addition, rituximab maintenance therapy was shown to significantly prolong tumour remission and patient survival in patients with indolent B-cell NHL or CLL. The combination of rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) was cost effective as first-line therapy for advanced-stage diffuse large B-cell NHL compared with CHOP alone. Rituximab, either alone or in combination with chemotherapy, was generally well tolerated in patients with NHL or CLL. Overall, rituximab in combination with chemotherapy, is a valuable option for first- and second-line therapy in patients with advanced-stage indolent or aggressive B-cell NHL, and possibly those with B-cell CLL, and is included in current treatment guidelines for these indications. The drug is also potentially useful as maintenance therapy in patients with indolent B-cell NHL or CLL.     

Rituximab in B-cell disorders other than non-Hodgkin's lymphoma

Rituximab is a human/mouse chimeric monoclonal antibody that binds to the CD20 antigen and is expressed at all stages of B-cell development. Rituximab has demonstrated efficacy as monotherapy and in combination with chemotherapy in the treatment of both indolent and aggressive non-Hodgkin's lymphoma (NHL). Rituximab treatment results in rapid depletion of B-cells and this has led to the consideration of other B-cell disorders as candidates for rituximab therapy. Recent studies have demonstrated the efficacy of rituximab in a variety of such disorders, including chronic lymphocytic leukemia (CLL), post-transplant lymphoproliferative disorder (PTLD), Waldenstr?m's macroglobulinemia (WM), multiple myeloma (MM), idiopathic thrombocytopenic purpura (ITP), hairy-cell leukemia (HCL) and cold agglutinin disease (CAD). In patients with CLL, increasing the dose and/or frequency of rituximab treatment has given improved response rates compared with the standard dose schedule used in NHL, and combination immunochemotherapy has yielded an overall response rate of 92% (with a 60% complete response rate). Clinical trials have also demonstrated evidence of efficacy for rituximab in PTLD, WM and relapsed or refractory ITP. Efficacy of rituximab in CAD and relapsed or refractory HCL has also been demonstrated in small studies and case reports. Available data thus indicate that rituximab can be an effective therapy in a wide range of CD20+ lymphoid disorders.     

Ten years of rituximab in NHL

Background: Rituximab, a chimeric mouse/human monoclonal antibody targeting the pan-B-cell antigenic marker CD20, was the first monoclonal antibody licensed for use in the treatment of cancer. Objective: This review focuses on the impact of rituximab in the treatment of patients with B-cell non-Hodgkin lymphoma (NHL). Methods: Three key areas related to the use of rituximab in B-cell NHL are discussed: mechanism of action, clinical efficacy in both indolent and aggressive disease, and safety of its use as both monotherapy and in combination with chemotherapy. Results/conclusions: Rituximab has demonstrated significant clinical efficacy in the treatment of NHL, particularly in combination with chemotherapy, and its use has revolutionized the treatment of both indolent and aggressive B-cell NHL over the past decade. Furthermore, consistent toxicity data have been obtained with a safe and tolerable profile in most patients.     

Rituximab

Rituximab is a chimeric monoclonal antibody that targets the CD20 molecule on the B-cell surface. It is the first antibody of its kind to be licensed for the treatment of non-Hodgkin's lymphoma. Rituximab was found to be effective, well-tolerated and has a good safety profile, though its precise cellular effects are still not well understood. Rituximab has been shown to be of therapeutic benefit in various autoimmune diseases in which B lymphocytes play a role. This article summarizes the current literature regarding the use of rituximab in lymphoma, rheumatoid arthritis, systemic lupus erythematosus and other selected autoimmune diseases.     

The efficacy and safety of rituximab in refractory pemphigus: a review of case reports

Rituximab is a chimeric murine-human monoclonal antibody that targets the CD20 antigen found on B cells and results in rapid depletion of this cell population. It is indicated for patients with relapsed or refractory, low-grade or follicular, CD20-positive, B cell non-Hodgkin's lymphoma. In addition, rituximab has been used for many other diseases, including refractory pemphigus. In this study, 42 case reports of patients with refractory pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus treated with rituximab were reviewed for clinical efficacy and safety. Forty-one of the 42 patients had at least some improvement following the rituximab therapy, while 6 suffered infectious adverse events. Though rituximab appears to be effective in the treatment of refractory pemphigus diseases, further studies are warranted to clarify its overall safety, especially concerning the risk of infectious adverse events in this patient population.     

Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia

Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy in patients with various lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin's lymphoma (NHL) and B-cell chronic lymphocytic leukaemia (CLL). While the optimal use of the drug in many clinical settings has yet to be clarified, two pivotal trials have established rituximab as a viable treatment option in patients with relapsed or refractory indolent NHL, and as a standard first-line treatment option when combined with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (the most common type of aggressive NHL). The former was a noncomparative trial in relapsed indolent NHL (follicular and small lymphocytic subtypes) with clinical responses achieved in about half of patients treated with rituximab 375 mg/m(2) intravenously once weekly for 4 weeks, which was similar to some of the most encouraging results reported with traditional chemotherapeutic agents. The latter was a randomised comparison of eight cycles of CHOP plus rituximab 375 mg/m(2) intravenously (one dose per cycle) versus CHOP alone in previously untreated elderly patients (60 to 80 years of age) with diffuse large B-cell lymphoma. In this pivotal trial, 2-year event-free and overall survival were significantly higher with rituximab plus CHOP, and there was no increase in clinically significant adverse effects compared with CHOP alone. Treatment with rituximab is generally well tolerated, particularly in terms of adverse haematological effects and serious or opportunistic infections relative to standard chemotherapy. Infusion-related reactions occur in the majority of patients treated with rituximab; these are usually mild to moderate flu-like symptoms that decrease in frequency with subsequent infusions. In approximately 10% of patients, however, severe infusion-related reactions develop (e.g. bronchospasm, hypotension). These reactions are usually reversible with appropriate interventions and supportive care but there have been rare reports of fatalities. CONCLUSIONS: Clinical trials with rituximab indicate that the drug has broad application to B-cell malignancies, although further clarification is needed to determine its optimal use in many of these clinical settings. Importantly, rituximab in combination with CHOP chemotherapy has emerged as a new treatment standard for previously untreated diffuse large B-cell lymphoma, at least in elderly patients. Compared with conventional chemotherapy, rituximab is associated with markedly reduced haematological events such as severe neutropenia, as well as associated infections. Rituximab may be particularly suitable for elderly patients or those with poor performance status, and its tolerability profile facilitates its use in combination with cytotoxic drugs. PHARMACODYNAMIC PROPERTIES: Rituximab is a mouse/human chimaeric IgG(1)-kappa monoclonal antibody that targets the CD20 antigen found on the surface of malignant and normal B lymphocytes. Although treatment with rituximab induces lymphopenia in most patients, typically lasting about 6 months, a full recovery of B lymphocytes in the peripheral blood is usually seen 9-12 months after therapy, as CD20 is not expressed on haematopoietic stem cells. CD20 is, however, expressed on >90% of B-cell non-Hodgkin's lymphomas (NHL) and to a lesser degree on B-cell chronic lymphocytic leukaemia (CLL) cells.Although not fully elucidated, the cytotoxic effects of rituximab on CD20-positive malignant B cells appears to involve complement-dependent cytotoxicity, complement-dependent cellular cytotoxicity, antibody-dependent cellular cytotoxicity and induction of apoptosis. In addition, in vitro data indicate that rituximab sensitises tumour cells to the effects of conventional chemotherapeutic drugs. PHARMACOKINETIC PROPERTIES: Serum rituximab concentrations increased in proportion to dose across a wide range of single- and multiple-dose intravenous regimens in patients with B-cell NHL. When administll NHL. When administered at a dose of 375 mg/m(2) once weekly for 4 weeks in a pivotal trial in patients with relapsed or refractory indolent B-cell NHL (follicular or small lymphocytic subtypes), peak serum concentrations essentially doubled from the first (239.1 mg/L) to the fourth (460.7 mg/L) infusion, while elimination half-life (t(1/2)) increased from 76.3 to 205.8 hours (3.2 to 8.6 days). The concomitant increase in serum rituximab concentrations and t(1/2) with each successive infusion may be due, at least in part, to the elimination of circulating CD20-positive B cells and reduction or saturation of CD20-binding sites after the initial infusions of rituximab. The pharmacokinetic properties of rituximab are also characterised by wide inter-individual variability, and serum drug concentrations that are correlated with clinical response. Although pharmacokinetic data are limited in patients with aggressive forms of NHL, such as diffuse large B-cell lymphoma, rituximab appears to have a similar pharmacokinetic profile in these patients to that in patients with indolent B-cell NHL. The pharmacokinetics of rituximab are also reported to be similar whether the drug is administered with or without cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy. THERAPEUTIC USE: A number of studies have demonstrated efficacy of intravenous rituximab in patients with various lymphoid malignancies of B-cell origin, including indolent (e.g. follicular lymphoma) and aggressive (e.g. diffuse large B-cell lymphoma) forms of NHL, and CLL, but the drug has not yet been approved for use in CLL, and approved indications in NHL vary between countries. In the US, for example, rituximab is available for the treatment of patients with low-grade or follicular, relapsed or refractory, CD20-positive B-cell NHL. In Europe, the drug has similar approval for relapsed or refractory follicular NHL as in the US, but has also been approved for use in combination with CHOP chemotherapy for the most common aggressive form of NHL (CD20-positive, diffuse large B-cell lymphoma). Rituximab was approved for these indications primarily on the basis of results from two pivotal trials. In Japan, rituximab has been approved for indolent B-cell NHL and mantle cell lymphoma (an aggressive form of B-cell NHL), primarily on the basis of results of a Japanese phase II trial. Indolent NHL: Results of several studies evaluating rituximab 375 mg/m(2) once weekly for 4 weeks in patients with indolent forms of B-cell NHL (primarily follicular and small lymphocytic lymphomas) showed objective response (OR) rates ranging from approximately 40-60% in those receiving the drug for relapsed or refractory indolent B-cell NHL, and slightly higher (50-70%) for those receiving rituximab as first-line therapy. In a pivotal trial in 166 patients with relapsed or refractory low-grade or follicular B-cell NHL, intent-to-treat (ITT) analysis showed an OR rate of 48%, and a projected median time to progression of 13 months.Encouraging data are also emerging on the use of rituximab in combination with chemotherapeutic agents (e.g. CHOP, fludarabine-containing regimens) or other drugs (e.g. interferon-alpha2a) in previously untreated patients with indolent forms of B-cell NHL (primarily follicular and small lymphocytic subtypes). Rates for OR were consistently around 95%, with the majority being complete responses (CRs). Follow-up data from a study in 40 patients with low-grade or follicular B-cell NHL treated with rituximab plus CHOP as first-line therapy showed that responses were durable with a progression-free survival and median duration of response >5 years.Bcl-2 gene rearrangement (t14;18) occurs in malignant cells in up to 85% of patients with follicular lymphoma, and minimal residual disease in peripheral blood and bone marrow can be monitored using polymerase chain reaction (PCR). In several studies assessing blood and/or bone marrow, rituximab has achieved molecular response (conversion from PCR-positive to PCR-negative bcl-2 status) in at least half of the patients. Aggressive NHL: Studies with rituximab as monotherapy in aggressive B-cell NHL, a potentially curable disorder, have generally been restricted to patients with relapsed or recurrent disease, since CHOP has traditionally been the standard first-line treatment regimen. However, promising results from phase II monotherapy studies prompted further clinical investigation of rituximab in conjunction with chemotherapy. Thus, most studies with rituximab in patients with aggressive forms of B-cell NHL have involved combination therapy, including a pivotal randomised trial comparing eight cycles of standard CHOP therapy plus rituximab 375 mg/m(2) (one dose per cycle) versus CHOP alone in 399 previously untreated elderly patients (60-80 years of age) with diffuse large B-cell lymphoma. Results of the pivotal trial showed a clear advantage for rituximab plus CHOP versus CHOP in terms of event-free survival (primary endpoint) at 2 years (57% vs 38%, p < 0.001). Overall survival at 2 years (70% vs 57%, p < 0.01) and CR rate (76% vs 63%, p < 0.01) were also higher with the rituximab-CHOP combination. Other, smaller trials with rituximab in combination with CHOP or other chemotherapeutic regimens, either as first-line therapy or for patients with relapsed or refractory aggressive B-cell NHL, have also shown promising results in terms of clinical response rates.CLL: In relatively small trials (n < 40) conducted primarily in patients with relapsed or refractory B-cell CLL, rituximab monotherapy (various regimens) achieved OR rates of 23-45%, with median duration of response ranging from approximately 3-10 months. (ABSTRACT TRUNCATED)