SAN DIEGOPatients with relapsed or refractory low-grade or
follicular non-Hodgkins lymphoma (NHL) may respond to 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
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.