Rituximab Given Three Times Weekly Has Significant Activity in CLL

WASHINGTON, DC—Rituximab (Rituxan) given three times per week has significant activity in chronic lymphocytic lymphoma (CLL) and in small lymphocytic lymphoma (SLL), but platelets must be monitored closely in patients with preexisting thrombocytopenia. These results from a phase-I/II rituximab study were described by John C. Byrd, MD, of Walter Reed Medical Center in Washington, DC.

The 33 patients in the trial, 26 with CLL and 7 with SLL, received dose 1 of rituximab (100 mg) over 4 hours. In cohort 1 (n = 3; 250 mg/m²) and cohort 2 (n = 7; 375 mg/m²), rituximab was administered on day 3 and thereafter 3 times weekly for 4 weeks according to a standard administration schedule. In cohort 3 (n = 23; 375 mg/m²), rituximab was administered similar to cohort 2 for the first two treatments, and then over 1 hour thereafter.

Patients had a median age of 66 (range 50-80) years. Dr. Byrd said that 24 (73%) were high risk according to modified Rai criteria. Patients had a median of two prior treatments (range 0-6), and 17 were refractory to fludarabine (Fludara).

Response Varied by Treatment

Thirty-three patients were evaluable for response. One patient discontinued treatment due to infusion-related toxicity.

After an intent-to-treat analysis, the overall response rate was 45%, with 3% achieving complete response and 42% partial response (95% CI, 28%-64%). Response varied by treatment status. The response was 83% in previously untreated patients, 41% in fludarabine-refractory patients, and 30% in patients previously treated with alkylators or with fludarabine. Response was not predicted by age, stage, presence of bulky nodal disease, or CD20 density.

"Median progression-free survival was 11 months for responders," Dr. Byrd said. Response duration was only 6 months (range 3-11) in patients who were refractory to fludarabine.

Monitoring Platelets

Thirteen patients developed transient hypoxemia, hypotension, or dyspnea requiring temporary cessation of therapy. These symptoms were associated with significant increases in baseline TNF-alpha (2-hour peak), IL-6 (2-hour peak), IL-8 (4-hour peak), and IFN-gamma (4-hour peak) as compared to those patients not experiencing such reactions. Infusion-related toxicity was rare after the second treatment. Older age (median age 73 vs 62 years; P = 0.02) but no other pretreatment clinical or laboratory features (including CD20 expression) predicted for infusion-related events.

Dr. Byrd said that three of six patients with preexisting thrombocytopenia had transient worsening after rituximab, "emphasizing the importance of monitoring platelets in such patients."

"Administration of three-times-weekly rituximab is feasible in CLL and SLL patients," Dr. Byrd summarized. "Infusion reactions can be minimized by using a stepped up dosing approach. After treatment is given two times at a slower rate, it can safely be given as a 1-hour infusion. This schedule produces both high response and sustained response duration similar to that seen in follicular lymphoma patients receiving this therapy. Responses include both hematologic improvement and a decrease in lymphadenopathy and organopathy. Future combination studies of rituximab with other therapies in CLL appear warranted," Dr. Byrd said.