CURRENT STATUS AND FUTURE PERSPECTIVES IN THE TREATMENT OF LOW-GRADE NON-HODGKINS-LYMPHOMAS

Low-grade non-Hodgkin lymphomas (NHL) comprise a heterogeneous group of disorders both in terms of their cellular and histological composition as well as in terms of their clinical course. The most usually applied classification systems, the Working Formulation and the Kiel classification as well as the recently proposed Revised European American Lymphoma classification, discriminate between low-, intermediate- and high-grade subtypes. In general, low-grade NHL are characterized by a low to moderate proliferative activity and a long clinical course with median survival times ranging from approximately 3 years for centrocytic (CC) or mantle-cell lymphomas (MCL) to 5-8 years for centroblastic-centrocytic (CB-CC) or follicular lymphomas (FL). Recent cytogenetic and molecular biologic analyses indicate that these differences may result from distinct genetic abnormalities such as the translocation t(14;18), which is frequently observed in FL-NHL and is associated with a bcl-2 overexpression and inhibition of apoptosis, or the deregulation of PRAD1 in MCL-NHL induced by the translocation t(11;14). Therapy of low-grade lymphomas depends mainly on the extent of the disease. In the early stages I and II, at which approximately 15 to 20% of low-grade NHL are diagnosed, radiotherapy may be applied with curative intention. The treatment of patients with more advanced stages III and IV is controversial. The currently available information justifies a conservative approach of observing the natural course of the disease until therapeutic intervention is required due to the occurence of B-symptoms, hematopoietic insufficiency or lymphoma progression. Intensive chemotherapy seems not to translate into an improved disease-free or overall survival and can therefore not be recommended for first-line treatment. After successful initial cytoreductive therapy, however, prolonged disease-free and possibly even overall survival may be achieved by long term application of interferon-alpha. New perspectives have arisen from the introduction of novel cytostatic agents such as the purine-analogs and the development of immunotoxins and antibody conjugated radioisotopes. Most promising at the present time appears the application of myeloablative radio-chemotherapy followed by autologous bone marrow or peripheral blood stem cell transplantation which may provide a curative approach even for advanced stages of the disease.