The Role of Rituximab in Lymphomas

O papel do Rituximab nos linfomas

Artigo Especial / Special Article

The Role of Rituximab in Lymphomas

Bertrand Coiffier

Over the last years the treatment of non-Hodgkin's lymphoma underwent a great advance in relation to the diagnosis, classification, high-dose chemotherapy, and hematopoietic stem cell transplantation. Simultaneously with this, there was the development of new drugs and support therapy which enabled an improvement in the evolution and survival of the patients. The use of monoclonal antibodies against cancer cells is an old idea and in this report the results of the role of the anti-CD20-Rituximab in lymphomas is discussed.

Keywords: Non-Hodgkin's Lymphoma, monoclonal antibodies, CD-antigen, Rituximab

Introduction

During the last 10 years, significant progress has been made in the treatment of non-Hodgkin's lymphoma (NHL) patients. The refinement of the classification of the lymphomas (1) and the incorporation of prognostic indices in decision making (2) have allowed to identify groups of patients who may be cured and others that need further research to find the correct therapeutic options. Therapeutic improvements came from the introduction of G-CSF allowing higher dose of curative drugs with less risk of severe infections, the development of high-dose therapy with autotransplant, and the addition of interferon to multidrug chemotherapy regimens. Through these options, around half of the patients with de novo NHL may expect to be alive 10 years later. However, the difficulty to overcome tumor cell resistance to standard drugs, the toxicity of the newly developed regimens, and the aging population of patients challenge us to develop less toxic but more effective treatments.

Monoclonal Antibodies against cancer cells

The idea of developing monoclonal antibodies (MAb) against cancer cells, particularly lymphoma cells, appeared more than 20 years ago with the description of the different antigens found on the cell membrane. Since the first attempt reported in 1980 by Nadler (3), the progress of molecular biology and protein engineering allowed an exponential work that recently culminated in the approval by drug agencies of rituximab (4) and, in a near future, of radiolabeled antibodies for treatment of lymphoma patients. Although monoclonal antibodies were used for a long time to ex-vivo purge hematopoietic stem cells before autotransplant or to T-cell deplete allogeneic cells and they are currently developed against non-lymphoma cancer cells, this review will only focus on the future roles for rituximab in the treatment of lymphoma patients.

Three main approaches have been used in the development of MAb therapy. Unconjugated antibodies mediate cell death through different mechanisms related to the antigen and the antibodies. Conjugated antibodies act mainly through the toxin or the radioisotope attached to the antibody. The selection of a suitable antigen was the first step for these treatments. It must not be shared by critical tissues such as hematopoietic stem cells, must not be associated with much toxicity if all target cells are eliminated, and be only present on lymphoma cells. Unfortunately, specific antigens for B or T lymphoma cells are unknown and all antigens we know of are shared by the normal B or T cells. The target antigen must be present either on all lymphoma cells or on the self-renewing clonogenic population of lymphoma cells. This target antigen must preferentially have a critical role in the homeostasis of these lymphoma cells and be necessary for the cell survival. Lymphoma cells should not be able to escape the antibody effect through the development of antigen variants, antigen-negative clones, or the modulation of the antigen on the cell surface. If MAb-toxin conjugates need to be internalized for the toxin to access the critical cellular processes, unconjugated MAbs must remain on the cell surface to allow the Fc portion of the antibody to activate immunologic mechanisms or to activate internal mechanisms leading to cell death. Humanized MAbs have a greater efficiency than mouse MAbs for activating these different mechanisms. Antigen density and MAb binding affinity may influence the cytotoxic efficacy for unconjugated antibodies but radioimmunoconjugates emit particles with enough energy to kill adjacent cells, cells with a low antigen density or non-antigen-bearing cells. However, they may kill vital normal cells and increase the toxicity of the treatment.

The presence of circulating antigens may be a problem leading to the formation of antigen-antibody complexes and a rapid clearance of the MAb. The MAb must not be eliminated through immunologic mechanisms because of its own difference with the host. When xenophobic (mouse) antibodies are used, a rapid appearance of human anti-mouse antibodies (HAMA) may alter the pharmacokinetics of the MAbs, particularly during the re-treatment phases. Genetic engineering has allowed the humanization of antibodies and to create chimeric proteins with a small antigen-binding mouse part and a large human constant Fc region. These chimeric MAbs have substantially decreased their immunogenicity and, then, prolonged their half-life. They also improve the ability to mediate complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC).

The MAb may kill the lymphoma cells through a variety of different mechanisms. Radioimmunoconjugates or immunotoxins kill the cells through the emission of particles or the internalization of the toxin. Unconjugated MAbs may trigger CDC or ADCC. They may have direct cytotoxic effects on tumor cells, either in blocking the binding of an endogenous ligand, which deprives the cell of a critical survival signal, or in mimicking it, which trigger growth arrest. These functions may potentiate the chemotherapy effects (5-7).

CD20 antigen - Rituximab

A large variety of antigens may potentially be chosen as the target. If the early trials focused on Ig idiotype, the CD20 antigen is probably the ideal target for B-cell lymphomas but other antigens are currently tested such as CD22 or CD52 (8, 9). The CD20 antigen is not expressed on stem cells or precursor B-cells but is found on normal mature B-cells and malignant B-cells, with the exception of plasma cells and myeloma cells. It is usually present on all cells of the tumor clone. It is expressed in high density in all B-cell lymphoma but usually faintly on chronic lymphocytic leukemia cells. This antigen is stable in the membrane of B-cell, does not have any known variant, and does not modulate or internalize in response to antibody binding.

Unconjugated MAbs constitute the simplest application of targeted MAb treatment. The first trials used MAb directed against the idiotype of the cell surface Ig, which certainly represents a unique tumor-specific antigen (10). In different trials, anti-idiotype antibodies produce responses in 50% to 70% of the patients. Although the median duration of these responses was only 6 months, some patients with complete response had long remissions. However, patients relapsed with idiotype-negative cells. The presence of circulating shed idiotype and the formation of HAMA further limited their efficacy. This associated with the constraint to make anti-idiotype specific for each patient precluded further development of this therapy.

Subsequently, investigators used pan-B antigens, such as CD20, and humanized antibodies. Rituximab (MabThera^®) is the most extensively studied unconjugated MAb, with over 100.000 patients treated. This chimeric antibody consists of the murine variable regions from the 2B8 MAb grafted onto a human IgG1 constant region. In the phase I trial, the dose limiting toxicity was not reached which attests to a low side-effect profile of the drug (11). Most of phase II trials used the dose of 375 mg/m² once a week for 4 weeks (12, 13). These trials accrued mostly patients with indolent or follicular lymphoma refractory to standard chemotherapy regimens. In more than 200 patients, the response rate was around 50%, with 6% complete responses, and responses were observed in different subgroups with adverse prognostic features, such as previous autotransplant or bulky tumor. Many patients had no detectable residual tumor cells in blood or bone marrow, even with the PCR analysis for the t(14;18) translocation (molecular remission). The median time to response was about 2 months, up to 6 or 9 months for some patients. This may be correlated with a long half-life of the antibody, some patients having residual levels detectable 6 months after the last infusion. Median time to progression in responding patients is longer than 12 months. Interestingly, patients who progressed after a first response may be re-treated and 50% of them responded and several successive responses were observed. Treatment of relapsing indolent lymphoma was the first approved indication.

Most adverse events are minor and associated with the first infusion. They consist primarily of fever, chills, mild nausea, mild fatigue, or malaise. Rarely, patients develop more serious reactions, including hypotension, bronchospasm, or sensation of throat swelling. These symptoms are usually managed by temporarily slowing or stopping the antibody infusion. The most serious reactions are observed in patients with peripheral blood involvement or large tumors. They may be prevented by stopping the infusion once mild adverse reactions occur. Myelosuppression is rare. As expected, the normal B-lymphocytes rapidly decline and recover over 6 to 9 months. However, there is no increase in infection rate and no occurrence of opportunistic infections, probably because Ig levels and T-cells remained normal. HAMA is observed in less than 1% of the patients and HACA (anti-chimeric antibody) is not observed.

Subsequently, rituximab was used in patients with more aggressive B-cell lymphoma, mantle cell lymphoma (MCL) or diffuse large B-cell lymphoma (DLCL). In a phase II trial, patients with relapsing disease showed a 32% response rate (14). In another phase II trial, mantle cell lymphoma patients, either in first line or relapsing, showed a 40% and 30% response rate, respectively (15). In these studies, most of the responses were incomplete, with less than 10% complete responses, and median time-to-progression was less than 12 months. These results indicate that rituximab has an anti-tumor activity in nearly all B-cell lymphomas. Ongoing studies test its activity in nearly all B-cell lymphoproliferative diseases.

Rituximab has been used in conjunction with chemotherapy in FL and DLCL patients, mostly with the CHOP regimen (16, 17). In FL, a response rate of 95% was reached with 55% complete responses. With a median follow-up over 5 years, less than 50% of the patients progressed. In aggressive lymphoma, response rate seemed higher and time to progression longer than in identical patients treated with CHOP alone (17). The adverse events were not different from those expected from the CHOP regimen or rituximab treatment. No specific toxicity was observed with the combination of these drugs.

Because of these results, rituximab is currently widely tested in different B-cell lymphoproliferative diseases, either alone or in combination with chemotherapy. Large cooperative group randomized trials are addressing the use of rituximab in conjunction with multidrug chemotherapy as first line treatment or as maintenance after chemotherapy. Other trials test the in vivo purge before the harvest of peripheral stem cells for autotransplant. The first results being presented came from the GELA trial in elderly patients with untreated DLCL (18). Patients treated with the combination of rituximab plus CHOP (R-CHOP) had a significantly higher response rate, lower relapse rate, longer event-free survival, and longer overall survival (Figure 1). This study demonstrated the clear benefit of combining chemotherapy to rituximab and has opened the area of chemoimmunotherapy in lymphoma patients. Table 1 presents the different settings where rituximab is currently used or tested in lymphoma or other lymphproliferative diseases.

Conclusion

In conclusion, impressive responses have been documented with MAb therapy, even if their definitive role in the treatment of lymphoma remains to be determined. Although the unconjugated MAb, and particularly rituximab, have showed activity as single agents, they may have a greater role in combination with chemotherapy or as maintenance in responding patients. Their ability to purge blood and bone marrow to an undetectable level of lymphoma cells may allow to re-infusion of minimally contaminated hematopoietic stem cell harvests after high dose therapy.

O papel do Rituximab nos linfomas

Resumo

Nos últimos anos o tratamento do linfomas não Hodgkin apresentou um grande avanço no diagnóstico, classificação, quimioterapia com altas doses e o transplante de células percursoras hematopoiéticas. Simultaneamente houve o desenvolvimento de novas drogas e no tratamento de suporte o que possibilita um avanço na evolução e sobrevida dos pacientes. A idéia do emprego de anticorpos monoclonais no tratamento do câncer é antiga e neste relato são apresentados os resultados e o papel do anti-CD20-Rituximab nos linfomas.

Palavras-chave: Linfomas não Hodgkin, anticorpos monoclonais, antígeno CD20, Rituximab

Recebido: 10/07/2002

Aceito: 22/07/2002

Hospices Civils de Lyon, France

Correspondence to: Bertrand Coiffier

CH Lyon-Sud, 69495 Pierre-Benite. France

Tel: [phone]. Fax: [phone]

E-mail: [e-mail]

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Publication Dates

• Publication in this collection
  14 Jan 2003
• Date of issue
  2002