When therapy is indicated for patients with chronic lymphocytic leukemia who have symptomatic or advanced-stage disease, the standard therapies often provide improvement of blood counts and symptoms, but only a minority of patients achieve a complete response. Until recently, chlorambucil or other alkylator agents were the standard treatment. Fludarabine has replaced chlorambucil as the initial therapy of choice for patients with CLL due to a higher complete response rate, overall response rate, and longer progression-free survival. Despite the improved results seen with fludarabine, fewer than 20% of patients achieve CR.

Rituximab is a chimeric antibody that binds to the B-cell surface antigen CD20. This agent has activity in follicular non-Hodgkin lymphoma, where there are high levels of CD20 expression. Rituximab also appears to have a synergistic effect in B-cell non-Hodgkin lymphoma when used in combination with chemotherapy. In CLL, the level of CD20 expression is lower than other low-grade B-cell neoplasms, and as a consequence, response rates using rituximab at standard doses are inferior to those obtained in follicular lymphoma. Whereas this agent has activity in CLL, rituximab as a single agent has limited utility in initial management of this disease.

The report by Byrd and colleagues from CALGB (page 6) suggests that adding rituximab to fludarabine in the initial therapy for CLL may produce an increase in CR rate. In this randomized phase 2 study, patients either received rituximab concurrently with fludarabine followed by 4 additional doses of rituximab, or received fludarabine followed by rituximab therapy. Both regimens had high overall response rates; the complete response rate was 47% in patients who received concurrent therapy and 28% in the sequential therapy group. The only unanticipated toxicity was more granulocytopenia in patients who received concurrent fludarabine and rituximab; this was not associated with increased risk of infection when compared with historic use of fludarabine alone. Infusional toxicity was acceptable even in the concurrent arm, particularly when rituximab was given over several days with the initial administration.

This trial is an important step on the road to improving the complete response rate and, ultimately, the outcome in CLL. A phase 3 intergroup trial is now underway to determine whether the addition of cyclophosphamide to fludarabine is superior to fludarabine alone. Exploring the concept of combination therapy further, investigators at the M. D. Anderson Cancer Center have reported a CR rate of 66% with a fludarabine-rituximab-cyclophosphamide combination. Despite enthusiasm for combination therapy for CLL, carefully performed phase 3 clinical trials are needed in order to evaluate the efficacy and complications of these new therapies. As therapy becomes more intensive, unforeseen toxicity such as the granulocytopenia seen in Byrd et al's study or other complications such as opportunistic infections and myelodysplasia may be seen. These clinical trials are also needed for the appropriate correlative studies to understand this disease, as well as to improve therapy, so that achievement of a complete response in CLL is routine rather than a rarity.

Sign in via your Institution