Targeting CD20

Lymphocyte-predominant Hodgkin disease (LPHD) is a discrete subtype of Hodgkin disease with an indolent course and a characteristic pathologic appearance in which large cells known as lymphocytic and/or histiocytic cells are superimposed on a background of small B lymphocytes. Although LPHD is derived from follicular center B cells, the disease is distinct from B-cell NHL. Traditional approaches to the treatment of LPHD include irradiation, chemotherapy, or combined modality therapy. Deaths from secondary malignancies and other long-term complications of treatment are more common than deaths from recurrence, underscoring the need to identify new approaches with less toxicity.

Whereas the malignant cells in LPHD are CD20⁺, many have suggested a role for rituximab in its therapy. In this issue, Ekstrand and colleagues (page 4285) report the results of a phase 2 trial of rituximab in 20 previously untreated and relapsed patients with LPHD. Remarkably, all patients responded, with nearly one half achieving a complete response (CR) or an unconfirmed complete response (CRu). Remissions, however, have been relatively short-lived even among previously untreated patients. With very short follow-up of just over one year, the estimated freedom from progression is only 10.2 months for all patients. There is now the opportunity to build upon this exceptionally high response rate to increase the durability of remission. Investigators should now focus on studying new schedules, including the role of maintenance and the combination of rituximab with chemotherapy.

Results of treatment of the indolent NHL with a combination of rituximab and various chemotherapy regimens in phase 2 studies suggest that the 2 approaches may be additive or synergistic. Although diffuse, aggressive NHL is less susceptible to the anti-CD20 antibody than most low-grade lymphomas, the addition of rituximab to standard-dose CHOP improved response rates and overall survival in elderly patients with diffuse, large B-cell lymphoma, studied by the Groupe d'Etude des Lymphomes de l'Adulte (GELA) (Coiffier et al, N Engl J Med. 2002;346:235-242). In this issue, Mounier and colleagues (page 4279) report for the GELA that the impact of rituximab in the previously reported clinical trial was restricted to those with lymphomas that expressed the bcl-2 protein. In bcl-2–positive patients, response rates, overall survival, and event-free survival were better in patients receiving R-CHOP than in patients receiving CHOP. Among bcl-2–negative patients, there was no difference.

The GELA previously identified expression of bcl-2 protein, a negative regulator of apoptosis, as a predictor of poor outcome in patients with aggressive NHL (Hermine et al, Blood. 1996;87:265-272). Along with others, they have implicated bcl-2 protein expression in drug resistance in the lymphoid malignancies. Rituximab exerts its cytotoxicity, at least in part, through induction of apoptosis. In addition to the direct destruction of lymphoma cells through well-established mechanisms such as antibody-dependent cellular cytotoxicity and complement-mediated cell lysis, rituximab may also sensitize cells resistant to chemotherapy through its effects on pathways regulating programmed cell death. The GELA data are consistent with this hypothesis. Much remains to be known about the biologic basis for the association between bcl-2 protein expression and the enhanced effects seen with the addition of rituximab to CHOP chemotherapy.

Biologic correlates of clinical behavior, such as bcl-2, help to identify critical pathways and potential targets for which new therapies can be devised. The GELA trial shows how prognostic markers interact positively with novel treatments to yield improved clinical outcomes.