ROCKVILLE, MdThe monoclonal antibody rituximab (Rituxan), which
is directed against the CD20 antigen expressed in most B-cell
malignancies, can be given repeatedly to patients with
non-Hodgkins lymphoma (NHL) and may produce longer responses
with retreatment. This unusual increase in response duration is in
contrast to the ever-diminishing efficacy seen with repeated rounds
of chemotherapy, researchers reported at the 41st annual meeting of
the American Society of Hematology (ASH).
The increase may indicate that some novel antitumor immune response
is acting in addition to classic antibody-dependent, cell-mediated
cytotoxicity in patients who respond to rituximab.
Thomas A. Davis, MD, and associates from the National Cancer
Institutes Investigational Drug Branch reported final data
showing the following results: Patients with NHL can be repeatedly
treated with rituximab. The overall response to retreatment (40%) is
about the same as the response to initial rituximab. The median
response duration following rituximab retreatment is longer than that
following initial treatment.
This study shows that patients can be treated safely and
effectively with multiple courses of rituximab without induction of
human antichimeric antibody (HACA) and without the myelosuppres-sion
common after multiple courses of chemotherapy, Dr. Davis said.
Ronald Levy, MD, commented that the data show that rituximab is a
rare example of a cancer treatment that produces second-course
results at least as good as, and sometimes better than, the initial
cycle. I dont know of any other cancer treatment for
which that is true, he said at a symposium sponsored by
Genentech BioOncology and IDEC Pharmaceuticals. Dr. Levy is chief of
the Division of Oncology, Stanford University.
Dr. Daviss study was an open-label, single-arm, phase II trial
conducted among 60 patients (33 males and 27 females). Patients
median age was 56 years (range, 31 to 81 years). Most (46/60) had
stage III or stage IV disease at the time of diagnosis. Median time
since diagnosis was 4.7 years (range, 0.2 to 17 years). All patients
were CD20-positive at baseline.
Inclusion criteria included response to previous rituximab therapy,
low-grade or follicular NHL, and measurable, relapsed disease
requiring further treatment. Nearly all patients (58/60) had prior
chemotherapy, with a median of two courses, and 30% had prior
radiotherapy. All patients had prior rituximab, with a median of 15.9
months between current and prior rituximab therapy. Patients were
treated with four weekly infusions of rituximab at 375 mg/m².
The overall response rate was 40%, comparable to that seen in
studies with patients naïve to rituximab therapy, Dr.
Davis reported (see Table 1).
Median time to progression and duration of response had not yet been
reached at the time of the ASH meeting report. Kaplan-Meier estimated
medians were 16.7+ months for time to progression and 15.0+ months
for duration of response. These times were longer than the medians
achieved during the patients prior courses of rituximab (see Table
The magnitude of responses was impressive. In the 6 patients with a
complete response, mean lesion reduction was 98%. In the 17 patients
with a partial response, mean lesion reduction was 86%. In the 31
patients with stable disease, mean lesion reduction was 32%. Even
more intriguing, Dr. Davis said, the median sum of the products
of the perpendicular diameters continued to decline through 16 months post-treatment.
Rituximab was well tolerated on retreatment. Dr. Davis said that 98%
of adverse events were transient and grade 1 or 2. Most (56%) were
associated with the first-infusion syndrome, and the incidence fell
after the first infusion. There was no significant myelosuppression.
The long duration of responses in retreated patients inspired
considerable discussion. Dr. Levy noted that the effect lasts long
after rituximab has disappeared from the circulation (140 days). With
other monoclonal antibodies, B cells tend to reappear soon after the
antibody has been eliminated from the circulation.
Dr. Levy proposed that this difference may be due to a novel
mechanism: a rituximab-mediated immunization against B cells,
resulting in induction of a wave of cytotoxic T cells against B
cell antigens, which may amplify antigen-mediated cellular
cytotoxicity against B cells. Nothing we have known about
monoclonal antibodies in the past would have predicted the result
[that B cells would not recur for more than 1 year], he said.