HOUSTONThe treatment of relapsed or refractory
non-Hodgkins lymphoma has clearly been improved by the
monoclonal antibody, rituximab (Rituxan). Because of encouraging
results in this setting, rituximab is being studied in previously
treated patients with chronic lymphocytic leukemia (CLL), where it is
showing significant activity as well, according to a presentation at
ASH by M. D. Anderson investigators.
Rituximab binds to CD20, present on lymphocytes from most patients
with mature B-cell leukemias and lymphomas. In previous trials
leading to approval by the Food and Drug Administration, 166 patients
with low-grade lymphomas had an overall response rate of 48% to 375
mg/m² of rituximab weekly x 4. There was a striking difference
in response rate according to histology, with well-differentiated
lymphocytic lymphomathe lymphoma equivalent of
CLLexhibiting the poorest response, 12%.
These [types of] patients have lower CD20 surface expression
and on pharmacokinetics demonstrated significantly lower levels of
rituximab antibody, noted Susan OBrien, MD, Professor of
Medicine, University of Texas, Houston. We took both of these
factors into consideration in the design of our trial for CLL. We
wanted to conduct a dose-escalation trial until significant toxicity
was seen. The study also aimed to evaluate for dose response
and first-dose reactions.
Current Study Results
In the current study of 50 patients, 40 had refractory CLL and 10 had
other B-cell leukemias. Median number of prior therapies was two.
Median age was 66, and 80% had advanced stage disease. Patients
received a first dose of 375 mg/m², then three subsequent
escalated doses. The three subsequent doses were the same in each
patient. The highest dose was 2,250 mg/m². All patients were premedicated.
Overall response rate was 40%, climbing to 80% at the highest dose
levels. Patients who were previously sensitive to the standard agent
fludarabine (Fludara) had the best responses, and severe toxicity was
seen in only 2% of CLL patients with the first dose, Dr. OBrien reported.
All the patients with CLL who responded to rituximab achieved a
partial remission. Only one complete remission was seen, which was in
a patient with prolymphocytic leukemia. Of the 10 patients with
B-cell leukemias other than CLL, 6 of 7 evaluable patients responded
Dose-response was striking: response rate was 23% at the lowest dose
level (375 mg/m²), 44% at the intermediate dose level
(1,000-1,500 mg/m²), and 80% at the highest dose level (2,250
mg/m²). Median time to progression in responders was 8 months,
and the longest ongoing response was 15 months.
Multiple prognostic factors for response were analyzed. The only
significant association was seen for refractoriness to prior
chemotherapy. Patients who were sensitive to prior fludarabine had a
56% response rate, compared to 20% for patients who were refractory
(P = .02). The distribution of fludarabine-refractory patients was
similar among the dose levels. Therefore, higher dose did not explain
this association, Dr. OBrien noted.
Role for Antibody
We are happy with the results of this trial. We wanted to see
if there is any role for this antibody and I think clearly the answer
is yes, Dr. OBrien stated. This now allows us to go
ahead and combine the antibody with chemotherapy, hoping to see some
synergy. We have just begun a trial using fludarabine,
cyclophosphamide, and Rituxan and have seen some very dramatic,
precipitous drops in white blood cell counts within the first days of therapy.
At the 375 mg/m² dose, toxicities were noted in 94% of patients,
the vast majority being grades 1 and 2 toxicities, mostly fever and
chills. Severe toxicity was seen in 12% of the patients, with all six
(12%) suffering grade 3 and 4 toxicities consisting of fever, chills,
dyspnea, and hypoxia, hypotension in five, and hypertension in one patient.
Severity of toxicity appeared to be related to leukemia type. Severe
toxicity developed in only one of the 40 patients with CLL, compared
to five of the 10 patients with the other B-cell leukemias. The
toxicity in the CLL patients was surprisingly minimal. We were
expecting to see more. Where we saw toxicity was in the other
leukemias, who have more CD20 surface expression, Dr.
Toxicities as related to dose escalation were as follows: among
patients treated with 500-1,500 mg/m², only 3 of 35 had any
toxicity, all grade 1; at 2,250 mg/m² most patients began to
show moderate toxicity (fever, chills, nausea, and malaise) but no
grade 3 or 4 toxicity was seen. Although others have seen more
toxicity with the first dose, we did not see a significant
amount, she remarked.
Dr. OBrien concluded that this study demonstrates significant
activity for rituximab in CLL, however, it does not clarify the
optimal dose and schedule. The results also suggest the drug may be
active in patients with other mature B-cell leukemias, many of whom
have a poor response to standard chemotherapy, although toxicity may
be higher in this group.