Rituximab (Rituxan), a chimeric monoclonal antibody (MoAb), binds
with high affinity to the CD20 antigen found on malignant and normal
B-cells, but not on other normal tissues. CD20 is an attractive
target because of the accessibility and sensitivity of malignant
B-cells to lysis via immune effector mechanisms. This MoAb mediates
complement-dependent cell lysis and antibody-dependent cellular
cytotoxicity. Also, it has been shown to sensitize chemoresistant
human lymphoma cell lines and to induce apoptosis in vitro.
In a single-agent, pivotal trial in 166 patients with refractory,
low-grade or follicular non-Hodgkins lymphoma (NHL)
(International Working Formulation [IWF] types A, B, C, D) treated
with rituximab at 375 mg/m² weekly for four infusions, the
overall response rate (ORR) was 48% (6% complete and 42% partial
responses). Responses (computed tomographic [CT] scans) were
confirmed in a blinded audit by independent lymphoma experts (LEXCOR
panel) using rigorous response criteria. Median time to progression
for responders was 13.2 months, and median duration of response was
Of 80 responders, 20 remain in ongoing remission at 19.3+ to 36.7+
months. The ORR did not vary significantly with the number of prior
courses of chemotherapy: one, two, or three courses (P = .19) but
decreased, as expected, with the number of relapses: one, two, or
three (P = .04), ranging from 57% to 38%. Refractory patients with
zero relapses (never responded, never relapsed) had an ORR of 29% (6/21).
This pivotal study had internal (patient as own control) and external
(literature) controls. An intent-to-treat analysis (N = 166) showed a
median duration of response to last chemotherapy of 12 months
compared to 11.6 months following treatment with rituximab. The
Kaplan-Meier graphs overlap and there is no significant difference in
duration of response (P = .072; log rank test).
The overall response rate of 48% was compared to matched literature
reports for fludarabine (Fludara) and cladribine (2-CdA [Leustatin]).
The overall response rate to fludarabine across four studies (N =
138) was 41% (P = .23) and to 2-CdA in two studies (N = 61) 43% (P = .46).
CONCLUSION: A short (four infusions, 22 days) outpatient course of
rituximab produces responses in patients with refractory low-grade or
follicular NHL of equivalent duration to prior chemotherapy. The
overall response rate obtained with rituximab compares favorably to
that of other single agents. Furthermore, successful retreatment with
rituximab has been reported and maintenance regimens are being
studied. The MoAb has shown clinical activity in first and subsequent
relapses, and in refractory and bulky disease. Front-line,
combination, maintenance, and other studies are in progress. Initial
studies in combination with chemotherapeutic and biological agents
have shown promising results. Rituximab is now being evaluated in
large randomized studies in patients with intermediate/high-grade NHL.