SAN DIEGOPatients with relapsed or refractory low-grade or follicular non-Hodgkins lymphoma (NHL) may respond to rituximab(Drug information on rituximab) (Rituxan) up to 4 months after completion of therapy. Salvage therapy should therefore be delayed at least until that time for patients with stable disease after rituximab treatment, Antonio J. Grillo-Lopez, MD, of IDEC Pharmaceutical Corp., advised in a poster presentation at the ASH meeting.
In low-grade or follicular NHL patients, tumor regression observed with rituximab therapy appears to continue for months after completion of therapy. Nonresponders may become responders, and patients with an initial partial response may achieve complete response, Dr. Grillo-Lopez said.
Two Mechanisms of Action
Dr. Grillo-Lopez described rituximabs two mechanisms of action. The direct one is via induction of apoptosis and sensitization of chemoresistant cells. The indirect one is via induction of complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). Rituximab causes an immediate effect on the lymphoma cells as evidenced by the profound and selective B-cell depletion occurring immediately after the first infusion and tumor regression seen within the first 7 days of treatment. There may also be a more prolonged and sustained effect depending at least partially on the quality and availability of effector cells and complement, and on the levels of circulating antibody achieved and sustained over time, reflecting saturation of antigenic sites, Dr. Grillo-Lopez said. Pharmacokinetic studies in rituximab monotherapy trials have revealed the presence of circulating antibody as far out as 6 months from first infusion.
Phase II and III Trials
This report was based on data from a Phase III trial of rituximab monotherapy (N = 166) and from a Phase II trial of rituximab plus CHOP chemotherapy (N = 40). In both trials patients with relapsed or refractory, low-grade or follicular NHL were treated with rituximab at 375 mg/m² by weekly IV infusion for 4 doses.
In the rituximab monotherapy trial, 150 of the 166 patients were evaluable. Dr. Grillo-Lopez reported that there were 75 responses in 150 patients. Overall response rate was 50%, complete response (CR) rate was 6%, and partial response (PR) rate was 44%. Median progression-free survival was 13.2 months. As might be expected, estimated progression-free survival was better for patients with complete responses than for those with partial responses.
In the rituximab/CHOP trial, all 38 evaluable patients had responses (overall response rate 100%), and median progression-free survival had not been reached after 47.8+ months. Kaplan-Meier progression-free survival curves for CR vs PR patients showed that patients who had CR had significantly better progression-free survival.
In both trials there was a rapid decline in the mean sum of the products of the perpendicular diameters of all measurable lesions (SPD), with a slower decline continuing for over 10 months, Dr. Grillo-Lopez said. In the rituximab monotherapy trial, median time to response was 50 days, but some patients who initially had stable disease later achieved a PR, and some patients with an initial PR later achieved complete response (see Figure 1).
Patients with stable disease should be observed with no further therapy if they are showing continued regression, as they may become responders, Dr. Grillo-Lopez advised.