HOUSTONThe anti-CD20 monoclonal antibody rituximab
(Rituxan) is approved for treatment of relapsed or refractory
low-grade or follicular B-cell non-Hodgkins lymphoma but is
less effective in small lymphocytic lymphoma (SLL), the tissue
equivalent of chronic lymphocytic leukemia (CLL). In the pivotal
trial, the response rate for SLL patients was 13% vs 60% for those
with follicular lymphoma.
At the ASH meeting, Susan OBrien, MD, of M.D. Anderson Cancer
Center, reported that this low efficacy can be partly overcome with
higher doses. Her phase I/II dose-escalation study showed that
rituximab can be given safely up to at least a dose of 2,250
mg/m² IV to patients with CLL and that higher doses have
activity in CLL.
The lower response rates in CLL patients may be due to the low
expression of CD20 antigen by CLL cells or to higher numbers of
circulating B cells in these patients, Dr. OBrien said.
Rituximab binds specifically to the CD20 antigen expressed on the
surface of normal and malignant pre-B and mature B lymphocytes.
In the pivotal study, SLL patients had lower serum rituximab
levels, for unknown reasons. They also have lower levels of surface
CD20 expression, she said. We wanted to see whether
increasing the rituximab dose would overcome that limited activity
and produce better activity, so we know that it is an active drug.
This study included 23 patients with a median age of 68 years and a
median of two prior regimens. Fourteen of 23 patients were refractory
to fludarabine (Fludara).
All patients received a first rituximab dose of 375 mg/m² to
minimize infusion-related side effects. Doses were then escalated to
500, 650, 825, 1,000, 1,500, and 2,250 mg/m².
CLL patients have a high number of circulating cells, which may
serve as a sink for antibody. Increasing dose may
increase the response rate, Dr. OBrien said. Since
most side effects occur with the first dose, escalation started with
the second dose, she added.
To date, among 16 evaluable patients, there have been six responses
(38%), including one complete response (see
Almost all patients had a decline in circulating lymphocytes, Dr.
OBrien said. The median pretreatment absolute lymphocyte count
was 25.7 × 109/L, which fell to 2.2 × 109/L
Of 10 nonresponders to the antibody, four had a greater than 50% drop
in lymphocytosis but less than a partial remission.
Dr. OBrien said that five patients had severe toxicity (grade
3-4) after the first dose of rituximab at 375 mg/m². Two came
off study, one continued at the 375 mg/m² dose without
escalation, and two were able to tolerate further dose escalation
with no problems. No serious toxicity was observed after the first
dose at doses up to 2,250 mg/m² (see Table). Toxicity was not
significantly greater in patients over age 70.
It is probably possible to give much greater doses of rituximab
than we used in this study. We did not keep increasing it because the
point was to determine whether the drug is active, and we did see
activity in CLL. There was certainly no maximum tolerated dose
reached, Dr. OBrien said.
The study shows that rituximab is active in CLL, she said. This
is important, since a long-range goal is to use the antibody in
combination with chemotherapy, and this requires establishing that
the single agent has activity. She said that a phase II study
is ongoing at the 2,250 mg/m² dose.