Malignant Lymphomas • Decision Making and Problem Solving

Follicular lymphoma (FL) is one the most frequent subtypes of lymphoma worldwide and its incidence is rapidly increasing in western countries. The vast majority of patients with follicular lymphoma present with advanced stage disease (Ann Arbor stage III or IV) at initial diagnosis, which is considered incurable by conventional therapeutic approaches. Until recently, decades of intense clinical research and exploration of different therapeutic strategies seemed not to have had a major impact on overall survival of these patients. However, a recent analysis using a large population-based registry challenged this belief and reported better survival over the last 25 years, attributed most likely to improved supportive care and sequential application of effective therapies. In this rapidly evolving field of established and innovative therapeutic options, physicians will have to face the challenge of deciding on appropriate treatment algorithms in patients with FL. It is generally accepted that patients with advanced stage FL do not have an overall survival benefit from immediate treatment at diagnosis rather than to a watch and wait strategy until the disease becomes symptomatic. When FL becomes symptomatic chemotherapy induces remissions in the majority of patients but does not prevent recurrent relapses resulting finally in refractory disease or transformation to aggressive lymphoma. In recent years various novel treatment options have been developed for this group of patients, including the promising concept of myeloablative chemoor radiochemotherapy supported by autologous bone marrow transplantation (BMT) or peripheral blood stem cell transplantation (PBSCT). Dose intensification has the potential to eradicate disease more completely, but is limited by its treatment-related short-term and long-term toxicity including a considerably increased risk of secondary leukemias and myelodysplastic syndromes. Allogeneic stem cell transplantation, representing mainly a cellular immuno-therapeutic approach, is currently considered the only curative treatment option in appropriate patients with advanced stage FL. However, even with dose-reduced conditioning this therapeutic approach is hampered by considerable treatment-related morbidity and mortality mainly caused by serious graft-versus-host disease (GvHD) and infectious complications and is therefore generally not recommended for the majority of patients or as front-line treatment. There is, therefore, an urgent need for innovative therapeutic strategies with increased lymphoma specificity and reduced treatment-related toxicity. Several epitopes virtually restricted to lymphoproliferative malignancies and normal lymphoid tissues represent valid targets for immunotherapeutic approaches. Immunotherapy with monoclonal antibodies promises increased lymphoma specificity, reduced toxicity and synergistic efficacy with conventional chemotherapy, based on their different modes of action. Monoclonal antibodies may be used as direct anti-lymphoma agents or can serve as carriers for either cytotoxins (immunotoxins) in the setting of targeted cytotoxic therapy or radioisotopes in the setting of a targeted radiation therapy (radioimmunotherapy). The introduction of the monoclonal chimeric anti-CD20 antibody rituximab and the emerging concepts of radioimmunotherapy have already substantially added to the therapeutic repertoire and clearly changed the standard clinical approach for patients with indolent lymphoma. Additional antibodies with promising activity and different target molecules as well as multimodal approaches are now being widely tested in preclinical and clinical trials. This review will focus on the current status in FL emphasizing the importance of All authors from the Department of Internal Medicine III, Grosshadern Hospital, Ludwig-Maximilians University, Munich, Germany