Highlights of the 2008 International Conference on Malignant Lymphoma.

The recent International Conference on Malignant Lymphoma (ICML) brought together more than 3000 attendees with a clinical or laboratory interest in the various malignant lymphomas. A number of presentations reflected the international collaborations that are becoming so critical. Nancy Harris presented the deliberations of the working groups that have revised the World Health Organization Classification, which will be published in September.1 A number of new entities were proposed, while several controversial features were retained, such as the grading system for follicular lymphomas (FLs). The Lunenburg Consortium proposed an integration of molecular and genetic studies into the International Prognostic Index (IPI),2 while Federico and colleagues attempted to improve on the prognostic strength of the IPI, recognizing the importance of tumor bulk, which was not included in the initial recommendations.3 Workshops on lymphoma in underdeveloped countries and further attempts to standardize [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) in Hodgkin lymphoma (HL) were also featured. Several themes were prominent during the meeting, including recognition of the fiftieth anniversary of the discovery of Burkitt lymphoma, which featured a description of the history and biology by Ian Magrath and data on the Hoelzer regimen and dose-adjusted R-EPOCH (rituximab with etoposide/prednisone/vincristine/ cyclophosphamide/doxorubicin), both of which appear to advance the treatment of this now highly curable aggressive lymphoma. In recent years, important observations have been made in our understanding of the biology and molecular genetics of diffuse large B-cell lymphoma (DLBCL). Several laboratories have demonstrated different signatures that correlate with outcome, including the germinal B-cell and activated B-cell types originally described by Rosenwald and colleagues.4 Expression of a number of genes also appears to correlate with response and outcome: Mounier et al showed that rituximab improved the outcome of patients whose lymphoma was positive for Bcl-2 overexpression, but with less of an effect in Bcl-2–negative tumors, and in those with high numbers of tumor-associated macrophages.5,6 In a trial led by the Eastern Cooperative Oncology Group, Winter et al showed that, among Bcl-6–positive cases, the addition of rituximab to CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone) had no effect on outcome, which was very different than was observed with the Bcl6–negative cases.7 Indeed, Bcl-6 loses its prognostic significance when rituximab is added to the regimen. These data were updated and expanded at the ICML to include the investigation of p21, a cyclin-dependent kinase inhibitor that is a downstream effector of p53. Patients whose DLBCL was positive for p21 derived benefit from rituximab, in contrast with the negative tumors. The most favorable group included patients with Bcl-2–negative/p21-positive tumors, while the converse was associated with the poorest outcome. Other combinations were intermediate.8 Based on observations such as these, the Lunenburg Consortium was organized to create a clinico-biologic prognostic index for DLBCL. A controversial topic has been the role of radiation therapy in the management of patients with the DLBCL variant, primary mediastinal B-cell non-Hodgkin lymphoma (NHL). Dunleavy and colleagues presented important data with R-EPOCH and no radiation, with a 100% response rate, including 92% complete remissions, and at a median follow-up of 3.1 years, the overall survival (OS) was 100% with an 84% event-free survival.9 Despite the successes with DLBCL, mantle cell lymphoma (MCL) continues to provide challenges. This heterogeneous disorder (or disorders) remains incurable; nonetheless, the prognosis has likely been underestimated in most of the recent literature. Whereas the published data suggest a median survival of 3-4 years, more current results suggest values 2-3 times as long. An explanation for this discrepancy is not apparent as the therapeutic advances have been modest. CHOP or similar regimens remain a poor standard, and the initial excellent results with hyperCVAD (cyclophosphamide/vincristine/doxorubicin/dexamethasone) were not confirmed by a Southwest Oncology Group phase II clinical trial.10,11 Of note is the controversy regarding the role of rituximab in this disorder. Whereas this antibody when added to chemotherapy clearly improves survival of certain subsets of patients with follicular and low-grade, and diffuse large B-cell NHL, the benefits in MCL are not readily apparent. The initial data from Howard and colleagues showed impressive complete and overall response rates with rituximab with CHOP (R-CHOP), but with a disappointing time to progression of only about 18 months.12 The German Low-Grade Lymphoma Study Group randomized previously untreated patients to CHOP or R-CHOP, with a secondary randomization to one of several interferon or transplantation-based regimens, based on patient age. R-CHOP resulted in a higher complete and overall response rate, but with no effect on progression-free survival (PFS) or OS.13 The same cooperative group compared fludarabine/cyclophosphamide/mitoxantrone (FCM) with or without rituximab in patients with relapsed and refractory disease and showed a survival benefit from the antibody.14 When they evaluated the role of