Diffuse Aggressive Lymphoma
Authors: Fisher Richard I. , Miller Thomas P. , O'Connor Owen A. 
Published: November 2004

Abstract
The aggressive non-Hodgkin’s lymphomas can be cured in more than half of the cases. However, there has been great variation in the results reported from individual clinical Phase II trials. This variation in result can be attributed to unrecognized heterogeneity in this group of diseases. Recent clinical and molecular studies have enabled us to define more homogenous population in which new therapies can be studied. For patients with advanced stages of diffuse large B cell lymphoma, a new standard of therapy exists. For patients with localized aggressive non-Hodgkin’s lymphomas, heterogeneity in patient selection prevents us from defining a new standard of care. Finally, in mantle cell lymphoma, new opportunities in drug discovery may permit advances in the treatment of this uniformly fatal malignancy.
In Section I, Dr. Richard Fisher reviews the development of combination chemotherapy for patients with advanced stage diffuse large B cell lymphoma. Because of great heterogeneity in patients enrolled in Phase II studies, large randomized Phase III studies were required in the 1980s to define CHOP has the standard of care. This heterogeneity has now been defined carefully in the international prognostic factor index and more recently by gene array studies. It will now need to be incorporated prospectively into studies or retrospectively analyzed to understand clinical trial results. The addition of rituximab to CHOP has now been demonstrated to improve survival in two large Phase III studies in elderly patients. A recently presented study in younger patients suggests a similar benefit. Thus CHOP/rituximab has become the established standard of care for all patients with advanced stage diffuse large B cell lymphoma. Other concepts being evaluated to further improve on these results include: dose intensification; initial treatment with chemotherapy plus allogeneic stem cell transplantation; and infusional chemotherapy. Finally, the status of the treatment for relapsed patients will be defined.
In Section II, Dr. Thomas Miller defines the treatment for limited stage aggressive non-Hodgkin’s lymphoma. Randomized trials have demonstrated the critical importance of initial chemotherapy for treatment of these patients. The amount of chemotherapy given needs to be increased for patients with bulky tumors. In most circumstances radiotherapy after the completion of chemotherapy has been shown to be advantageous. A modification of the international prognostic factor index for patients with early stage disease is presented to permit comparisons among different populations. Recently reported early-stage studies need to be analyzed in terms of the heterogeneity of the patients involved to understand the reported results. The addition of monoclonal antibodies, as well as radioimmunotherapy, are being tested in an effort to improve on the results for the poor prognosis patients.
In Section III, Dr. Owen O’Connor describes the pathology immunophenotype and natural history of mantle cell lymphoma. Conventional treatment strategies with combination chemotherapy achieved objective responses in approximately half of the patients but no significant impact on survival. The addition to rituximab to CHOP chemotherapy or other treatment strategies appears to improve the remission rate; however, no major changes in survival have also been reported. Excellent single institution results have been reported with HyperCVAD plus rituximab regimen, which is currently being tested in a national cooperative group trial. The most excitement in this field currently relates to the variety of new agents which appear to have significant activity in relapsed patients with mantle cell lymphoma. This includes the proteosome inhibitor, bortezomib, which is shown to have approximately a 50% response rate with some CRs and reasonable durability in early single institution Phase II studies. Larger national multi-center trials are ongoing. In addition, agents such as thalidomide, flavopiridol, and piroxantrone will be reviewed.