ROCKVILLE, MarylandThe 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 ASH meeting. The
increase may indicate that some novel anti-tumor immune response is
acting in addition to classic antibody-dependent, cell-mediated
cytotoxicity (ADCC) in patients who respond to rituximab.
Final data for the multicenter study was presented by Thomas A.
Davis, MD, who at the time of the study was staff physician at
Stanford University Medical Center (one of the study sites) but is
now senior investigator with the National Cancer Institute Cancer
Therapy Evaluation Program. Dr. Davis reported the following results.
Patients with NHL can be repeatedly treated with rituximab.
The overall response to retreatment (40%) is about the same as to
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 anti-chimeric antibody (HACA) and without the myelosuppression
common after multiple courses of chemotherapy, Dr. Davis said.
In commenting on the data, Ronald Levy, MD, of Stanford University
School of Medicine, pointed out that the data showed 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 Corp.
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 non-Hodgkins lymphoma, and measurable,
relapsed disease requiring further treatment. Nearly all patients
(58/60) had prior chemotherapy, with a median of 2 courses. Thirty
percent of patients 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 4 weekly infusions of
rituximab at 375 mg/m².
Overall response rate (CR and PR) was 40%, comparable to that
seen in studies with patients naive 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
complete responses (CR), mean lesion reduction was 98%. In the 17
patients with partial responses (PR), the mean lesion reduction was
86%. In the 31 patients with stable disease, the mean lesion
reduction was 32%.
Even more intriguing, Dr. Davis reported, 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 well-known
first-infusion syndrome, and the incidence declined following the
first infusion. There was no significant myelosuppression.
The long duration of rituximab 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 (ADCC) 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 observed.