Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma.
BACKGROUND
Monoclonal antibodies are being utilized for treatment of patients with low-grade non-Hodgkin's lymphoma as well as other cancers. Results from phase I and II clinical studies has shown that the chimeric monoclonal antibody Rituximab has minimal toxicity and significant therapeutic activity in low grade non-Hodgkin's lymphoma.


METHODS
We have recently reported on a multicentre pivotal phase III clinical trial involving 166 patients with recurrent low-grade lymphoma who were treated with four infusions of Rituximab. Eighty patients (48%) achieved objective responses including 10 patients (6%) with complete responses. Overall, 126 patients (76%) had a > or = 20% reduction in overall tumor size. The median response duration and time to progression are 11.6 and 13.2 months, respectively. The infusional and long term toxicities were limited.


RESULTS
In this report we describe the pharmacokinetic data obtained on these patients. Measurable concentrations of Rituximab were detected in all patients after the first infusion and increased throughout the treatment course. The half-life of the monoclonal antibody increased from 76.3 hours after the first infusion to 205.8 hours after the fourth infusion and was concomitant with a four-fold decrease in the antibody clearance. At three months and six months post-treatment, the median Rituximab serum levels were 20.3 micrograms/ml (range 0.0 to 96.8 micrograms/ml in 104 patients) and 1.3 micrograms/ml (range 0.0-28.7 micrograms/ml in 13 patients), respectively. A statistically significant correlation was found between the median antibody concentration and response for multiple time points during the treatment and followup. The mean serum antibody concentration was also inversely correlated with measurements of tumor bulk and with the number of circulating B cells at baseline.


CONCLUSIONS
We conclude that Rituximab is therapeutically effective against B-cell lymphoma. Pharmacokinetic data suggests that certain subsets of patients may possibly benefit from increased dosing and studies to address this are currently underway.
Berinstein
N L
NL
Department of Medicine, Toronto-Sunnybrook Regional Cancer Centre, Ontario, Canada. neil.berinstein@utoronto.ca
Grillo-López
A J
AJ
White
C A
CA
Bence-Bruckler
I
I
Maloney
D
D
Czuczman
M
M
Green
D
D
Rosenberg
J
J
McLaughlin
P
P
Shen
D
D
D000911:Antibodies, Monoclonal / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006207:Half-Life; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000627:therapeutic use; D008224:Lymphoma, Follicular / Q000188:drug therapy / Q000378:metabolism*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000378:metabolism*; D009364:Neoplasm Recurrence, Local; D000069283:Rituximab; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D016756:Immunoglobulins, Intravenous; D000069283:Rituximab