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.     

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)     

Rituximab: an innovative therapy for non-Hodgkin's lymphoma.

The epidemiology, etiology, classification, and treatment of non-Hodgkin's lymphoma (NHL) are reviewed, and rituximab, a newly available therapy, is discussed. NHL comprises a group of lymphoproliferative disorders the frequency of which continues to rise. Although many classification systems exist for identifying specific histological subtypes, NHL is generally divided into indolent (low-grade) and aggressive (intermediate- and high-grade) forms. Low-grade NHL is characterized by a slowly progressive, continually relapsing course, with eventual transformation to a more rapidly progressive form that is usually fatal. Several options are available for the management of indolent NHL; none is curative. Rituximab, a human-mouse monoclonal antibody that targets the CD20 antigen expressed in over 90% of B-cell NHLs, provides an alternative to conventional chemotherapy that is relatively safe and effective. In a Phase III trial involving 166 patients with relapsed or refractory low-grade B-cell NHL, rituximab produced an overall response of 48%, with 20 of 80 responders still in remission more than 36 months after treatment. Study results in patients with bulky disease and those requiring retreatment have also been encouraging. Most adverse effects associated with rituximab are mild to moderate. Infusion-related reactions occur more commonly during initial infusions and in patients with evidence of increased tumor burden but can be effectively managed with premedication, supportive care, and adjusted infusion rates. Hematologic effects are generally mild and transient, and adverse immune responses are rare. Rituximab is an alternative to conventional chemotherapy for the treatment of relapsed or refractory low-grade or follicular CD20-positive B-cell NHL.     

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.     

利妥昔单抗治疗恶性淋巴瘤的进展

利妥昔单抗（人源化CD20单克隆抗体，商品名美罗华）是首个批准用于治疗表达CD20恶性淋巴省的单克隆抗体，广泛应用于低度恶性非雷奇金琳巴瘤（NHL）、侵袭性NHL，亦试用于霍奇金淋巴瘤（HL）及其他B细胞性恶性肿瘤。刊蚤昔单抗联合细胞毒性药物的疗效已在B细胞NHL的有关临床试验中得到证实。目前该药已被批准用于侵袭性淋巴瘤和惰性淋巴瘤的一线治疗，其维持治疗滤泡性淋巴瘤亦得出鼓舞人心的结果．利妥昔单抗已成为治疗B细胞性恶性淋巴瘤的重要手段之一。     

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.     

Rituximab and other emerging monoclonal antibody therapies for lymphoma

The recent approval of rituximab, gemtuzumab ozogamicin, alemtuzumab and ibritumomab tiuxetan by the FDA in the US revealed clear evidence that monoclonal antibodies (mAbs) have significant roles in the current treatment of haematologic malignancies. Among the mAbs under clinical development, anti-CD20 mAbs have been most extensively investigated and have shown definitive clinical efficacy. Rituximab is a genetically engineered chimeric anti-CD20 mAb, with mouse variable and human constant regions. Consecutive clinical trials conducted in the US, Europe and Japan have revealed that rituximab is a highly effective agent with acceptable toxicities against indolent and aggressive B cell non-Hodgkin’s lymphomas (B-NHLs) as a single agent and in combination with cytotoxic drugs. A recent French Phase III study in elderly patients with untreated aggressive B-NHL suggested that the addition of rituximab to standard CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy increases the complete response rate and prolongs event-free and overall survival. Lymphoma cells are inherently sensitive to radiation. The aim of radioimmunotherapy is to use the mAb to target radiation to lymphoma tissue while minimising toxicity to normal cells. The clinical trials of ⁹⁰Y ibritumomab tiuxetan and ¹³¹I tositumomab showed they have definitive efficacy in relapsed indolent B-NHL with acceptable toxicities. A recent comparative study in relapsed indolent B-NHL showed that ⁹⁰Y ibritumomab tiuxetan produces higher response rates than rituximab. In addition, BL22, a recombinant anti-CD22 immunotoxin, showed significant efficacy in patients with chemotherapy-resistant hairy cell leukaemia. MAbs will have significant roles in the treatment of lymphoid malignancies in the future.     

Immunotherapeutic and immunoregulatory drugs in haematologic malignancies

A better understanding of the biology and pathogenesis of hematological malignancies has led to the development of immunotherapeutic and immunoregulatory drugs. Many of these agents have revolutionized the current treatment modalities, while others are under investigation. Rituximab (anti-CD20 antibody) has been established as the gold standard of treatment for aggressive B-cell lymphomas in combination with CHOP and has shown significant activity as monotherapy in the treatment of indolent B-cell lymphomas. In follicular lymphomas the combination of Rituximab with chemotherapy improves the outcome compared to chemotherapy alone. CD 20-based radioimmunotherapy, with the advantage of the bystander effect, represents an additional therapeutic alternative in B-cell lymphomas and may produce tumor regression in Rituximab resistant patients. The anti-CD52 monoclonal antibody, alemtuzumab, further expands the armamentarium against lymphoid malignancies producing high response rates in these entities. Antibody-targeted chemotherapy such as gemtuzumab ozogamicin, consisting of an anti-CD33 antibody combined to calicheamicin, has shown efficacy in the treatment of refractory acute myeloid leukemia; exact indications, timing and dosing schedule for optimized efficacy remain to be determined. Interferons have proven significant activity in cutaneous lymphomas, hairy cell leukemia and chronic myelogenous leukemia by mechanisms that are not fully elucidated. Thalidomide, by acting as an immunomodulatory and antiangiogenic agent can modulate neoplastic cells microenvironment and lead to disease control in multiple myeloma as well as in numerous other hematological malignancies. Bortezomib, a proteasome inhibitor, displays significant anti-tumor activity, especially in multiple myeloma and lymphoproliferative disorders. The addition of these agents in therapeutic regimens has improved considerably the treatment of hematological malignancies.     

Antibody therapy of lymphoma

The availability of rituximab and the possible imminent availability of two new radiolabelled monoclonal anti-CD20 antibodies (Yttrium-90 (⁹⁰Y)-ibritumomab and Iodine-131(¹³¹I)-tositumomab) have captured much attention in the treatment of lymphoma. The chimeric monoclonal anti-CD20 antibody, rituximab has truly heralded a new era for the treatment of lymphoma and human malignancies. The full potential of antibody-based therapy to improve the outcome in patients with B-cell non-Hodgkin’s lymphoma has yet to be defined, but recent data suggests that the combination of chemotherapy plus rituximab may significantly improve outcome for patients with aggressive lymphoma over chemotherapy alone. Highly promising data are also emerging for the use of rituximab in combination with chemotherapy in other types of lymphoma. New advances in antibody therapy, driven by new technologies and defining novel antigen targets, offer the promise of more effective tumour specific therapies. Combinations of antibodies, either conjugated with radioisotopes or unlabelled, used with chemotherapy are likely to provide definitive advances in the treatment of lymphoma in the immediate future.     

Mechanism of action of rituximab

Rituximab, the humanized chimeric anti-CD20 monoclonal antibody, represents a powerful tool for treating B-cell malignancies and is licensed for the treatment of relapsed or chemorefractory low-grade or follicular non-Hodgkin's lymphoma (NHL). It has a unique mode of action and can induce killing of CD20+ cells via multiple mechanisms. The direct effects of rituximab include complement-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity, and the indirect effects include structural changes, apoptosis, and sensitization of cancer cells to chemotherapy. In vitro studies have made a significant contribution to the understanding of these mechanisms of action and have led to the development of innovative and effective treatment strategies to optimize patient response. The most significant of these strategies is the combination of rituximab and CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone), which is proving a highly effective combination in the treatment of NHL. However, all patients do not respond equally well to rituximab, and in vitro studies have identified a possible mechanism of resistance involving the anti-complement inhibitors CD55 and CD59. Neutralizing antibodies to CD55 and CD59 can overcome resistance to rituximab-mediated complement-mediated cytotoxicity in vitro. This paper overviews our understanding of the mechanisms of action of rituximab and identifies how this knowledge could be applied in a clinical setting to maximize response in both sensitive and resistant patients.     

Aggressive lymphoma: improving treatment outcome with rituximab

The standard therapy for patients with aggressive lymphoma is cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy, which achieves a complete response in more than 60% of patients but is curative in only about 40-50%. More aggressive and/or dose-intensified chemotherapy regimens have failed to provide significant survival advantages compared with CHOP, and may have higher toxicity. Rituximab, a chimeric monoclonal antibody to the CD20 antigen, is effective as monotherapy in aggressive lymphoma and in combination with chemotherapy has demonstrated high response rates in phase II trials. A scheduled interim analysis of a randomized, prospective trial comparing rituximab plus CHOP with CHOP alone in elderly patients with untreated diffuse large B-cell lymphoma has shown significantly better response rates and survival with rituximab plus CHOP compared with CHOP alone. These results represent the first significant improvement in overall survival over CHOP in aggressive lymphoma for over 20 years. The addition of rituximab was not associated with significant additional toxicity over that seen with CHOP alone. Ongoing studies are underway to establish whether the survival benefit of rituximab plus CHOP is seen in younger patient populations. Rituximab in combination with chemotherapy is also being evaluated as salvage treatment for patients who relapse after initial chemotherapy. In a preliminary analysis of a study in 50 patients with refractory or relapsed aggressive lymphoma, rituximab plus etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (EPOCH) chemotherapy has demonstrated promising results when used as sole salvage therapy and as an induction therapy prior to autologous stem-cell transplantation, again without significant additional toxicity.     

Combination chemotherapy and rituximab

Rituximab is a human-mouse chimeric monoclonal antibody that has demonstrated efficacy against non-Hodgkin's lymphoma (NHL). There is a powerful rationale for combining rituximab treatment with chemotherapeutic agents that have also shown efficacy in NHL, since the mechanisms of action are distinct and there is also evidence that rituximab may sensitize chemoresistant tumor cells to the actions of cytotoxic drugs. A study of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemoimmunotherapy has been carried out in 40 patients with low-grade NHL. In the 35 patients who completed the study, the overall response rate was 100%, with 63% achieving a complete response. Median time to progression has not yet been reached at 47.2+ months. Molecular analysis (polymerase chain reaction) showed that CHOP plus rituximab (unlike CHOP alone) could completely clear blood and bone marrow of cells containing the bcl-2 gene translocation, a molecular marker of NHL cells. Rituximab can therefore add to the efficacy of CHOP without significantly increasing toxicity. A further study is underway to determine whether similar efficacy with less overall toxicity can be achieved using rituximab in combination with fludarabine.     

Rituximab and other emerging monoclonal antibody therapies for lymphoma

The recent approval of rituximab, gemtuzumab ozogamicin, alemtuzumab and ibritumomab tiuxetan by the FDA in the US revealed clear evidence that monoclonal antibodies (mAbs) have significant roles in the current treatment of haematologic malignancies. Among the mAbs under clinical development, anti-CD20 mAbs have been most extensively investigated and have shown definitive clinical efficacy. Rituximab is a genetically engineered chimeric anti-CD20 mAb, with mouse variable and human constant regions. Consecutive clinical trials conducted in the US, Europe and Japan have revealed that rituximab is a highly effective agent with acceptable toxicities against indolent and aggressive B cell non-Hodgkin's lymphomas (B-NHLs) as a single agent and in combination with cytotoxic drugs. A recent French Phase III study in elderly patients with untreated aggressive B-NHL suggested that the addition of rituximab to standard CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy increases the complete response rate and prolongs event-free and overall survival. Lymphoma cells are inherently sensitive to radiation. The aim of radioimmunotherapy is to use the mAb to target radiation to lymphoma tissue while minimising toxicity to normal cells. The clinical trials of 90Y ibritumomab tiuxetan and (131)I tositumomab showed they have definitive efficacy in relapsed indolent B-NHL with acceptable toxicities. A recent comparative study in relapsed indolent B-NHL showed that 90Y ibritumomab tiuxetan produces higher response rates than rituximab. In addition, BL22, a recombinant anti-CD22 immunotoxin, showed significant efficacy in patients with chemotherapy-resistant hairy cell leukaemia. MAbs will have significant roles in the treatment of lymphoid malignancies in the future.     

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.     

美罗华治疗侵袭性B细胞淋巴瘤疗效观察

目的：探讨美罗华治疗侵袭性B细胞淋巴瘤的临床疗效及优越性。方法：回顾性分析我院78例侵袭性B细胞NHL患者治疗情况,其中39例为观察组采用美罗华联合CHOP化疗方案,39例为对照组采用CHOP化疗方案,观察两组近期疗效及不良反应情况,并进行对比分析。结果：观察组CR率和有效率（CR＋PR）率分别为79.49%和92.31%,明显高于对照组的53.85%和64.10%,组间比较差异有统计学意义（P〈0.05）;两组不良反应发生率比较差异无统计学意义（P〉0.05）。结论：含美罗华的联合化疗方案可提高侵袭性B细胞淋巴瘤治疗的临床疗效,且不会增加其不良反应,是目前侵袭性B细胞淋巴瘤治疗的一种较佳方案,值得临床推广应用。     

Antibody therapy of lymphoma

The availability of rituximab and the possible imminent availability of two new radiolabelled monoclonal anti-CD20 antibodies (Yttrium-90 (90Y)-ibritumomab and Iodine-131(131I)-tositumomab) have captured much attention in the treatment of lymphoma. The chimeric monoclonal anti-CD20 antibody, rituximab has truly heralded a new era for the treatment of lymphoma and human malignancies. The full potential of antibody-based therapy to improve the outcome in patients with B-cell non-Hodgkin's lymphoma has yet to be defined, but recent data suggests that the combination of chemotherapy plus rituximab may significantly improve outcome for patients with aggressive lymphoma over chemotherapy alone. Highly promising data are also emerging for the use of rituximab in combination with chemotherapy in other types of lymphoma. New advances in antibody therapy, driven by new technologies and defining novel antigen targets, offer the promise of more effective tumour specific therapies. Combinations of antibodies, either conjugated with radioisotopes or unlabelled, used with chemotherapy are likely to provide definitive advances in the treatment of lymphoma in the immediate future.     

Pharmacokinetics,efficacy and safety of the rituximab biosimilar CT-P10

Introduction: Rituximab, an anti-CD20 monoclonal antibody, is a key therapeutic in the treatment of B cell lymphomas and rheumatoid arthritis (RA). Global rates of non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia (CLL) and RA are increasing, with a concomitant rise in individual and overall treatment costs. As such, biosimilar development may help facilitate greater access to treatment. The rituximab biosimilar CT-P10 (Truxima®) has recently received approval in Europe and South Korea for all indications held by reference rituximab (RTX).

Areas covered: Here, the unmet needs and current market in the treatment of NHL, CLL and RA are outlined, followed by a comprehensive examination of the analytical, pre-clinical and clinical data demonstrating the equivalence and similarity of CT-P10 to RTX including with respect to pharmacokinetics, efficacy, safety and immunogenicity.

Expert commentary: The rising treatment costs of NHL, CLL and RA pose a challenge to constrained healthcare budgets worldwide. Biosimilars may provide an effective solution to this conundrum. CT-P10 is equivalent to RTX in terms of efficacy and pharmacokinetics, and has a similar safety and immunogenicity profile. Approved in all indications held by RTX, CT-P10 has the potential to reduce treatment costs and thereby increase patient access to rituximab therapy.     

Rituximab: the first monoclonal antibody approved for the treatment of lymphoma

Rituximab, a genetically engineered monoclonal chimeric antibody, targets the CD20 antigen expressed on B cells. It was approved by the US Food and Drug Administration on November 26, 1997, for the indication of relapsed or refractory, CD20-positive, B-cell, low-grade or follicular non-Hodgkin's lymphoma (LG/F NHL), and by the European Agency for the Evaluation of Medicinal Products on June 2, 1998, for therapy of patients with Stage III/IV, follicular, chemoresistant or relapsed NHL. Eight Phase II or II clinical trials in LG/F NHL patients have been completed: five single-agent studies and three combination studies. Rituximab has a favorable safety profile: most adverse events (AEs) are Grade 1 or 2, and the frequency of AEs decrease with subsequent infusions. AEs in the combination studies are consistent with those seen with individual agents. For evaluable patients in the single-agent studies, overall response rates (ORR) ranged from 40% to 60%, median duration of response (DR) ranged from 5.9 to 15.0+ months, and median time to progression (TTP) ranged from 8.1 to 19.4+ months. For evaluable patients in the combination studies, the ORR ranged from 45% to 100%, median DR ranged from 11.7+ to 39.1+ months, and median TTP ranged from 12.9+ to 40.5+ months. Studies in intermediate- and high-grade NHL are ongoing. Long-term development plans include evaluating the safety and efficacy of rituximab in various types of lymphoma and in combination with other lymphoma regimens. Future studies may explore ways to increase rituximab efficacy by upregulating CD20 or increasing effector function with different cytokines.     

Current treatment of follicular and low-grade non-Hodgkin's lymphoma

Patients with low-grade non-Hodgkin's lymphoma (NHL) have a median survival of 4-8 years from diagnosis and a cause-specific survival of about 10 years. Radiotherapy can be curative in a small proportion of patients with very localized disease, but the majority of patients have advanced disease at diagnosis and it is not clear that any current therapy is curative in this situation. While in many instances patients with high-grade NHL are cured by chemotherapy, those with low-grade NHL, despite impressive response rates, almost invariably relapse. A 'watch-and-wait' strategy can therefore delay the onset of chemotherapy by 2-3 years, without affecting survival. Results with autologous stem cell transplantation have been similarly disappointing to date. Rituximab is a human-mouse chimeric monoclonal antibody that represents a novel approach to treatment of low-grade NHL, targeting malignant cells without the side effects associated with chemotherapy. A pivotal study has demonstrated a response rate of 56% in relapsed or refractory low-grade NHL. The relatively benign side-effect profile means rituximab can be used early in the disease process, and in combination with chemotherapeutic regimens and autologous transplantation. Ongoing and future studies will define the optimal role of rituximab in treatment of low-grade NHL.