Advancing therapy for chronic lymphocytic leukemia--the role of rituximab

Chronic lymphocytic leukemia (CLL) remains incurable despite decades of clinical trials. Some patients survive for long periods without requiring definitive therapy, while others die rapidly despite intensive treatment. Because most patients with CLL express CD20 on their malignant cells, the chimeric anti-CD20 monoclonal antibody rituximab has been incorporated into treatment regimens in efforts to improve outcome. Rituximab monotherapy has limited activity in previously untreated and refractory/relapsed CLL patients with response rates that are generally lower than those seen in non-Hodgkin's lymphoma. Although increased dosing intensity and frequency leads to higher response rates than seen in patients treated with standard dose rituximab, responses are almost always partial remissions and the doses used are not feasible in routine clinical practice. On the other hand, combining rituximab with chemotherapy has proved to be feasible and appears to be synergistic with fludarabine-based chemotherapy in the treatment of CLL on the basis of recent phase II trials. In these studies, response rates (including complete remissions) to rituximab in combination with fludarabine-containing regimens are higher than those reported in similar phase II studies with any other treatment regime. The highest response rates reported are for the combination of rituximab, fludarabine, and cyclophosphamide. A randomized phase III trial has been initiated to evaluate the addition of rituximab to fludarabine and cyclophosphamide in patients with relapsed CLL. The combination of rituximab with other agents is also being investigated, and these ongoing trials will help define the role of rituximab in CLL.