Clinical Status and Optimal Use of Rituximab for B-Cell Lymphomas

The standard management of low-grade lymphoma remains controversial. Long-term follow-up studies of patients treated with conventional regimens have shown that currently available treatments are not curative. New Treatment Approaches for Low-Grade Lymphoma Nucleoside Analogs—Newer chemotherapeutic agents, such as fludarabine (Fludara) and cladribine (2-chlorodeoxyadenosine [Leustatin]), have significant single-agent antitumor activity in low-grade lymphoma and are currently being tested in combination regimens.[1,2] Because these nucleoside analogs cause significant myelosuppression and immunosuppression and are associated with an increased risk of opportunistic infections, their role in the treatment of low-grade lymphoma remains undefined. Interferon-Alfa—Recently, a meta-analysis of randomized trials evaluating the role of interferon-alfa (Intron A, Roferon-A) in the treatment of follicular lymphoma concluded that interferon-alfa prolonged overall survival in patients receiving more intensive initial therapy with regimens containing doxorubicin or mitoxantrone (Novantrone), as compared with patients receiving less-intensive therapy with single-agent alkylator therapy or CVP (cyclophosphamide, vincristine, and prednisone).[3] In contrast, the Southwest Oncology Group (SWOG) reported that the use of interferon-alfa after inten-sive induction chemotherapy with ProMACE-MOPP (prednisone, methotrexate, Adriamycin, cyclophosphamide, etoposide, mechlorethamine, Oncovin, and procarbazine) did not extend relapse-free or overall survival in patients with advanced low-grade lymphoma.[4] These conflicting results make it difficult to specify recommendations regarding the role of interferon-alfa in the management of low-grade lymphoma. Stem-Cell Transplantation—Autologous stem-cell transplantation is an effective therapy for relapsed diffuse aggressive lymphoma and histologically tranformed lymphoma,[5] but its role in low-grade lymphoma is still under investigation. A number of phase II trials have demonstrated the feasibility of this intensified approach in patients with low-grade lymphoma.[6] In the absence of randomized trials, however, it has been impossible to demonstrate that autologous stem-cell grafting has curative potential or prolongs survival in patients with low-grade lymphoma. Although the acute toxicities of autologous stem-cell transplantation have been significantly reduced during the 1990s, there is still a significant risk of long-term complications, such as treatment-related myelodysplasia and acute leukemia. Monoclonal Antibody Therapy of Lymphoma The development of monoclonal antibodies (MoAbs) with defined specificities to lymphoma-associated antigens represents a revolution in the treatment of patients with lymphoma. Phase I/II clinical studies have been conducted using native or modified MoAbs directed against lineage-specific surface markers, such as CD19, CD20, and CD22. To enhance cytotoxicity, modified MoAbs, such as toxin-conjugated or radiolabeled antibodies, have also been designed. Rituximab (Rituxan) is a genetically engineered, chimeric, murine/human MoAb that targets the CD20 antigen found on the surface of most B-cell lymphomas. This product was recently approved by the FDA for use as a single agent in the treatment of relapsed low-grade lymphoma. It also is under investigation for use in combination regimens for follicular, mantle cell, and diffuse aggressive lymphomas. McLaughlin and colleagues provide an excellent review of the mechanisms of action and