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Higher Rituximab Doses Show Activity in Small Lymphocytic Lymphoma Patients

Higher Rituximab Doses Show Activity in Small Lymphocytic Lymphoma Patients

HOUSTON—The anti-CD20 monoclonal antibody rituximab (Rituxan) is approved for treatment of relapsed or refractory low-grade or follicular B-cell non-Hodgkin’s 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 O’Brien, 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.

Possible Causes

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. O’Brien 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. O’Brien said. “Since most side effects occur with the first dose, escalation started with the second dose,” she added.

Response Rates

To date, among 16 evaluable patients, there have been six responses (38%), including one complete response (see Table).

Almost all patients had a decline in circulating lymphocytes, Dr. O’Brien said. The median pretreatment absolute lymphocyte count was 25.7 × 109/L, which fell to 2.2 × 109/L post-treatment.

Of 10 nonresponders to the antibody, four had a greater than 50% drop in lymphocytosis but less than a partial remission.

Dr. O’Brien 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. O’Brien 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.

 
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