Monoclonal antibodies in the treatment of indolent lymphomas

Humanised monoclonal antibodies have transformed the treatment of patients with lymphomas. The first application of these new drugs appeared less than 10 years ago but currently a lymphoma patient will certainly receive at least one of them once or several times during the evolution of his/her disease. This review covers the use of these monoclonal antibodies alone or in combination with chemotherapy. Rituximab, an unconjugated anti-CD20 chimeric antibody, is certainly the most widely used but other unconjugated or radiolabelled monoclonal antibodies are catching up quickly. If there are randomised studies demonstrating the benefit of adding these drugs to the treatment of patients with lymphoma, very few studies have compared the activity of the different monoclonal antibodies. Many questions need to be answered before the best setting for these drugs will be known.     

Monoclonal antibodies combined to chemotherapy for the treatment of patients with lymphoma

Humanized monoclonal antibodies have transformed the treatment of patients with lymphomas. The first application of these new drugs appeared less than 10 years ago but currently one patient will certainly receive them once or several time during the evolution of his disease. This review will cover the use of these monoclonal antibodies alone or in combination with chemotherapy. Rituximab, an unconjugated anti-CD20 chimeric antibody, is certainly the most widely used but other unconjugated or radiolabeled monoclonal antibodies catch up quickly. If there are randomized studies demonstrating the benefit of adding these drugs to the treatment of patients with lymphoma, very few studies have compared the activity of the different monoclonal antibodies. A lot of questions needs to be answered before the best setting of these drugs will be known.     

Combination of chemotherapy and monoclonal antibodies for the treatment of lymphoma

Monoclonal antibodies (MoAbs) have transformed the treatment of lymphomas. The first reports of studies using MoAbs appeared 8 years ago, and current therapy for lymphoma patients usually includes treatment with MoAbs once or several times during the course of their disease. This review covers the use of MoAbs in combination with chemotherapy for the treatment of patients with lymphoma. Rituximab, an unconjugated anti-CD20 chimeric antibody, is certainly the most widely used MoAb, but the use of other unconjugated or radiolabeled MoAbs is increasing quickly. MoAbs are effective if used alone, but the duration of effectiveness is limited. Therefore, when MoAbs are used in curative treatment, they are combined with chemotherapy. There are randomized studies demonstrating the benefit of adding MoAbs to the treatment regimen of patients with diffuse large B-cell lymphoma, but results of ongoing studies regarding the benefit in other lymphomas have not been reported. Many questions must be answered before the best setting for MoAbs in the treatment of lymphoma patients can be determined.     

A 57-year-old man who developed arthritis during R-CHOP chemotherapy for non-Hodgkin lymphoma

Rituximab is a chimeric human-mouse anti-CD20 monoclonal antibody, which is used in the treatment of both B-cell lymphomas and rheumatic diseases. We describe a case of a previously healthy 57-year-old man developing arthritis while being treated with rituximab-CHOP chemotherapy (R-CHOP) for a non-Hodgkin lymphoma. The remittant arthritis developed at successively shorter time-intervals after R-CHOP administration and only improved after rituximab was removed from the chemotherapy schedule, suggesting a rituximab-related phenomenon, as extensive diagnostic testing ruled out any other diagnosis.     

Chemotherapy combinations with monoclonal antibodies in non-Hodgkin's lymphoma

Although the use of monoclonal antibodies as single agents has had a tremendous impact on the care of patients with non-Hodgkin's lymphoma (NHL), the greatest benefit has been generated by the addition of monoclonal antibodies to conventional cytotoxic chemotherapy. Rituximab is the monoclonal antibody responsible for all clinical improvement noted to date. The addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy (R-CHOP regimen) improves the response rate, progression-free survival (PFS), and overall survival (OS) in diffuse large B-cell lymphoma (DLBCL). Adding rituximab to CHOP chemotherapy improves response rates and PFS in mantle cell lymphoma (MCL). Finally, the addition of rituximab to a variety of chemotherapy regimens improves the response rates, PFS, and OS in follicular lymphoma (FL). Several other (epratuzumab, bevacizumab, alemtuzumab) monoclonal antibody-chemotherapy combinations are currently under study in NHL. This review will summarize the data supporting the addition of rituximab to chemotherapy in NHL and discuss preliminary data regarding the use of other monoclonal antibodies in combination with chemotherapy.     

Current treatment strategy of diffuse large B-cell lymphomas

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin’s lymphoma, accounting for approximately 25–30% of all new patients. Rituximab, a genetically engineered chimeric monoclonal antibody that specifically binds to CD20, is the first monoclonal antibody approved for the treatment of B-cell lymphoma. Rituximab significantly improves treatment outcome in DLBCL. A large-phase III study demonstrated improved overall survival (OS) in patients with DLBCL treated with R-CHOP therapy. The Groupe d’Etude des Lymphomes de l’Adulte (GELA), Eastern Cooperative Oncology Group (ECOG) and German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL) studies designed for patients older than 60 years have clearly shown prolonged event-free survival (EFS) and OS among patients who received rituximab and chemotherapy. For patients under 60 years, the MabThera International Trial Group (MInT) study demonstrated improved EFS and OS after the addition of rituximab to CHOP therapy. However, the R-CHOP therapy does not provide a satisfactory treatment outcome in the high-risk group according to the international prognostic index. Therefore, R-CHOP therapy is the new standard therapy in elderly and young, low-risk DLBCL patients. For young, high-risk DLBCL patients, treatment that incorporates rituximab and hematopoietic stem cell transplantation has been administered in clinical studies.     

Recent advances in antigen-targeted therapy in non-Hodgkin's lymphoma

 Substantial advances in antigen-targeted lymphoma therapy have been achieved in recent years that make the use of monoclonal antibodies a highly attractive concept and promise further improvements in the clinical management of malignant lymphoma. The development of the chimeric anti-CD20 antibody IDEC-C2B8 (Rituximab) proved the concept of an effective therapy with a single unconjugated monoclonal antibody in lymphoma patients. Radioimmunoconjugates with myeloablative activity induced response rates of 80–100% in heavily pretreated patients. Progress in the genetic engineering of immunotoxins has improved the efficacy of these constructs. Ongoing prospective clinical trials will define the optimal use of these innovative therapeutic agents in patients with malignant lymphoma, and may establish therapeutic strategies with a high anti-lymphoma specificity and a low unspecific toxicity. Received: June 2, 1999 / Accepted: August 16, 1999     

Cholestatic hepatitis C after chemotherapy containing rituximab in diffuse large B cell lymphoma

Rituximab is a chimeric anti-CD20 monoclonal antibody that is a widely used for the treatment of B cells non-Hodgkin lymphoma. The use of chemotherapy regimens containing rituximab in HCV-positive patients with non-Hodgkin lymphoma has been associated with liver dysfunction, but no cases of cholestatic hepatitis C were described. To our knowledge, this is the first case of cholestatic hepatitis C in an HCV-positive patient with diffuse large B-cell lymphoma describes in the literature. We discuss the pathogenetic mechanisms underlying this severe form of hepatitis and describe its evolution after antiviral treatment.     

Treatment of patients with malignant lymphomas with monoclonal antibodies

Malignant lymphomas represent a heterogenous group of B and T cell-derived malignancies. Most lymphomas are sensitive to chemo- and radiotherapy, however many patients will eventually relapse. Immunotherapeutic approaches including monoclonal antibodies, cytokines or vaccination approaches may offer an alternative treatment of chemotherapy-resistant residual cells especially in cases with low tumor burden or residual disease following chemo- or radiotherapy. Monoclonal antibodies have been successfully applied in their native form, or coupled with radioisotopes or toxins to selectively destroy lymphoma cells and promising results in early clinical trials have been obtained. Alternatively, bispecific antibodies and idiotypic vaccination strategies are used to target autologous T cells to eliminate lymphoma cells. A humanized anti-CD20 antibody showed excellent results in chemotherapy refractory lymphomas and has recently been approved for clinical application in CD20 positive B cell lymphomas.     

The role of the anti-CD20 antibody rituximab in hematopoietic stem cell transplantation for non-Hodgkin's lymphoma

Autologous hematopoietic stem cell transplantation is widely accepted as effective therapy for patients with relapsed aggressive B-cell non-Hodgkin's lymphoma, and to a lesser extent, for indolent and mantle cell lymphoma, resulting in prolonged disease-free survival. Despite these advances, disease recurrence remains a problem and a major clinical challenge. Allogeneic transplantation has also been increasingly utilized in patients with relapsed aggressive and indolent lymphoma but is associated with high toxicity and graft-versus-host disease. Recently, nonmyeloablative preparatory regimens have shown encouraging results, attributed to graft-versus-lymphoma effects. Rituximab, a monoclonal antibody targeted against the CD20 antigen, is a potent therapeutic tool with documented efficacy in B-cell lymphomas. It is effective when used alone or in combination with chemotherapy, resulting in a significantly improved response rate compared with chemotherapy alone, in both aggressive and indolent lymphomas. Increasing evidence suggests that rituximab is also effective at in vivo purging prior to transplantation and may prevent relapse by eradication of residual disease when administered after transplantation. This review summarizes the available data on the use of rituximab and discusses the current evidence for its role in conjunction with auto- and allotransplantation.     

Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with clonal lymphoproliferative disorders after orthotopic liver transplantation: a report of three cases

BACKGROUND/AIMS: Post-transplant lymphoproliferative disorders (PT-LPD) are a well-known complication of organ transplantation. Their incidence after liver transplantation in adults ranges from 1.8 to 4%. Reduction of immunosuppression led to remission in a few cases. Other treatments include chemotherapy, interferon alpha therapy and/or intravenous-immunoglobulins, or antiviral drugs. However, monoclonal antibodies directed against B-cell specific antigens have rarely been used in those patients. Our aim was to study the feasibility and efficacy of Rituximab, a new, promising human chimeric antibody that recognizes the CD20 antigen, for the treatment of patients with clonal lymphoproliferative disorders after orthotopic liver transplantation. METHODS: Rituximab (IDEC-C2HB8; Roche Laboratories, Neuilly-sur-Seine, France) was administered at a 375 mg/m2 dose on days 1, 8, 15, and 22, in an outpatient setting, in three patients with PT-LPD. The tumor was classified as polymorphic PT-LPD in two cases and PT-LPD with features of large cell lymphoma in one case. All the tumors expressed the CD20 antigen and were EBV-related, and the clonality was confirmed in all three cases. The 4 injections of the anti-CD20 monoclonal antibody were associated with reduced immunosuppression in the three patient. RESULTS: The treatment with Rituximab was well tolerated without any side effects. The two patients with polymorphic PT-LPDs underwent rapid complete remission, whereas the treatment modalities were ineffective in the patient with the large-cell non-Hodgkin-lymphoma. CONCLUSION: These results must be confirmed in a larger cohort of liver transplant recipients suffering from lymphoproliferation. However, they indicate rapid efficiency of Rituximab in association with reduced immunosuppression in these disorders.     

Current status and perspective of antibody therapy in follicular lymphoma

The development of antibody--based therapeutic strategies has clearly changed the standard clinical approach to patients with advanced stage follicular lymphoma. The chimeric monoclonal anti-CD20 antibody rituximab has shown high efficacy in previously untreated and relapsed or refractory patients. Rituximab combined with conventional chemotherapy is a highly attractive approach with proven synergism in vitro and in vivo and is widely accepted as standard treatment for advanced stage follicular lymphoma. Furthermore, rituximab maintenance has been shown to improve disease control after successful cytoreduction with rituximab as a single agent therapy or polychemotherapy. Additional antibodies, different target molecules and modified schedules are currently being evaluated in preclinical and clinical trials. Strategies to enhance the efficacy of antibody--based therapies include stimulation of innate immunity and the generation of immunotoxins and radioimmunoconjugates (radioimmunotherapy). Ongoing studies are evaluating the role of monoclonal antibodies in multimodal therapeutic approaches to further improve response rates and duration with the final aim of prolonging overall survival of patients with advanced stage follicular lymphoma.     

From the bench to the bedside: ways to improve rituximab efficacy

Rituximab (MabThera, Rituxan) is a chimeric IgG1 monoclonal antibody that specifically targets the CD20 surface antigen expressed on normal and neoplastic B-lymphoid cells. Rituximab is currently used in the treatment of both follicular and aggressive B-cell non-Hodgkin lymphomas. Despite its demonstrated clinical effectiveness, its in vivo mechanisms of action remain unknown and could differ by subtype of lymphoma. Rituximab has been shown to induce apoptosis, complement-mediated lysis, and antibody-dependent cellular cytotoxicity in vitro, and some evidence points toward an involvement of these mechanisms in vivo. Rituximab also has a delayed therapeutic effect as well as a potential "vaccinal" effect. Here, we review the current understanding of the mechanism of action of rituximab and discuss approaches that could increase its clinical activity. A better understanding of how rituximab acts in vivo should make it possible to develop new and more effective therapeutic strategies.     

Antikörpertherapie maligner Lymphome

In the last years monoclonal antibodies directed against B-cell associated epitopes have enriched our armentarium of therapeutic strategies against malignant B-cell lymphoma. Monoclonal antibodies are characterized by a different mode of action compared to chemotherapy, thereby opening new avenues in lymphoma treatment. These monoclonal antibodies can exert their anti-lymphoma activity directly by an intrinsic cytotoxic effect or indirectly as a carrier of cytotoxic drugs or radioisotopes. Rituximab, an anti-CD20 monoclonal antibody, was proven to be highly active in indolent as well as aggressive lymphoma, in particular when combined with chemotherapy. The anti-CD52 antibody alemtuzumab was shown to induce remissions in high risk CLL. Furthermore, clinical trials have demonstrated promising activity of monoclonal antibodies conjugated to radioisotopes such as the (131)iodine anti-CD20 antibody tositumomab or the (90)yttrium anti-CD20 antibody ibritumomab tiuxetan.     

Treatment of hematological malignancies with monoclonal antibodies

The success of rituximab, the first monoclonal antibody ever licensed for the treatment of a human malignancy, has not only increased survival and cure rates in many non-Hodgkin lymphomas of the B-cell type, but has prompted an explosion in the development of novel antibodies and biologically active substances with specific cellular targets ("targeted therapy") both in the field of hematological malignancies and solid tumors. The chimeric anti-CD20 monoclonal antibody rituximab is the first drug that was shown to increase overall survival in follicular lymphomas and to cut lymphoma-associated deaths in patients with CD20+ aggressive lymphomas into half. In this review the current role of monoclonal antibodies in the treatment of different hematological neoplasms will be discussed and perspectives for their future use in leukemia and lymphomas will be shown.     

Treatment of B-cell non-Hodgkin's lymphoma with anti CD 20 monoclonal antibody Rituximab

Rituximab is a chimeric anti CD-20 monoclonal antibody containing human IgG1 kappa constant regions, with murine variable regions. The anti-lymphoma effects of Rituximab are probably due to complement and antibody-dependent cell-mediated cytotoxicity, and induction of apoptosis. Phase II trials have demonstrated a strong activity of rituximab alone in indolent B non-Hodgkin lymphoma, especially in patients with follicular lymphoma. The most utilized dose-schedule is 375 mg/m(2) weekly x 4. The association with chemotherapy or with interferon-alpha increases Rituximab efficacy. More recently, Rituximab have showed activity also in diffuse large cell lymphoma, mantle cell lymphoma and in other B-malignancies. Good results have also been obtained utilizing Rituximab for in vivo purging. However, we are still far from having found a definite position for Rituximab in the treatment of lymphoproliferative disorders. The aim of future studies should be to develop new strategies that will hopefully produce the most effective Rituximab-based regimens in order to find the Rituximab key position in the treatment of B-malignancies     

Therapie bösartiger Hämoblastosen mit monoklonalen Antikörpern

The success of rituximab, the first monoclonal antibody ever licensed for the treatment of a human malignancy, has not only increased survival and cure rates in many non-Hodgkin lymphomas of the B-cell type, but has prompted an explosion in the development of novel antibodies and biologically active substances with specific cellular targets (“targeted therapy”) both in the field of hematological malignancies and solid tumors. The chimeric anti-CD20 monoclonal antibody rituximab is the first drug that was shown to increase overall survival in follicular lymphomas and to cut lymphoma-associated deaths in patients with CD20⁺ aggressive lymphomas into half. In this review the current role of monoclonal antibodies in the treatment of different hematological neoplasms will be discussed and perspectives for their future use in leukemia and lymphomas will be shown.     

Pneumocystis jiroveci pneumonia in patients with non-Hodgkin’s lymphoma after Rituximab-containing regimen: two cases of report and literature review

Rituximab, a monoclonal antibody against CD20+ antigen specific B cell, has been increasingly used in the treatment of non-Hodgkin’s lymphoma and some other autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. It is noted that Rituximab could enhanced the efficacy of CHOP-based chemotherapy. Meanwhile it could increase the opportunity of lung infection. Pneumocystis jiroveci pneumonia (PCP), a rare opportunistic infection that was not reported in the large-scale clinical trials of Rituximab, was found recently in patients with non-Hodgkin’s lymphoma treated with remedy containing Rituximab. We herein report two cases of PCP in lymphoma patients after Rituximab-containing chemotherapy. Both patients were successfully treated, with trimethoprim-sulfamethoxazole (TMP-SMX) in one case and Caspofungin alone in the other. We also reviewed the literature and concluded that PCP is an infrequent but potentially life-threatening infection in patients with non-Hodgkin’s lymphoma subjected to Rituximab-containing regimen. Therefore, adequate prophylaxis, timely diagnosis and treatment are necessary.KEY WORDS : Rituximab, non-Hodgkin’s lymphoma, pneumocystis jiroveci pneumonia (PCP), Caspofungin     

Current management of follicular lymphomas

After decades of stagnation, the prognosis of patients with follicular lymphomas (FL) has changed substantially within the last few years due to new and effective therapeutic modalities. These include myeloablative therapy followed by autologous stem cell transplantation (ASCT) in younger patients in first remission, which showed a significant prolongation of remission duration in three prospective randomised trials while the impact on overall survival still needs to be determined. Adding the anti-CD 20 antibody Rituximab to conventional chemotherapy resulted in a significant increase in remission rate, remission duration and, in two of four currently available prospective randomised studies, even in a longer overall survival. A prolongation of remission duration was also seen when Rituximab was given as maintenance after cytoreductive therapy including Rituximab. Radio-immunotherapy (RIT) with radioisotopes coupled to monoclonal antibodies produced encouraging data in several phase II studies. New therapeutic perspectives have also emerged from increasing insights into the biology of the disease that unravel molecular targets for novel agents, some of which have entered clinical evaluation already.     

Rituximab in the treatment of adult acquired hemophilia A: a systematic review

Rituximab is a monoclonal chimeric antibody to the CD20 antigen, which has proven to be effective in the treatment of non-Hodgkin lymphomas. Recently, rituximab has also been employed in many non-malignant autoimmune disorders (i.e., idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, connective tissue disorders and autoimmune hemolytic anemia) in which it has been used with the aim of interfering with the production of pathologic antibodies. Moreover, this agent has also shown to be effective in the treatment of acquired antibodies against factor VIII. Through a careful literature search, the current knowledge on rituximab therapy in adult acquired hemophilia A is presented in this review. Although mostly based on uncontrolled studies, the literature data suggest that this drug can be useful in the treatment of disorders of acquired inhibitors to factor VIII. However, large, prospective, randomized trials are needed to confirm these positive preliminary results.