Rituximab Shows Activity Against CLL

HOUSTON—The treatment of relapsed or refractory non-Hodgkin’s 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 lymphoma—the lymphoma equivalent of CLL—exhibiting 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 O’Brien, 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. O’Brien 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 to treatment.

Dose-Response Striking

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. O’Brien 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. O’Brien 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.

Toxicities Vary

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. O’Brien noted.

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. O’Brien 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.