Rituximab Added to Fludarabine in Untreated CLL Patients

SAN FRANCISCO—Preliminary results from the Cancer and Leukemia Group B (CALGB)-9712 trial indicate that rituximab (Rituxan) given concurrently with fludarabine (Fludara) improves response in previously untreated chronic lymphocytic leukemia (CLL) patients, compared with a sequential approach. The results were presented at the 37th Annual Meeting of the American Society of Clinical Oncology (ASCO abstract 1116).

Rituximab is a chimeric monoclonal antibody directed against CD20 that is very effective in the treatment of non-Hodgkin’s lymphoma. "Rituximab is clearly synergistic with chemotherapy and has a favorable toxicity profile, including minimal myelosuppression and a low rate of infection," said John C. Byrd, MD, director, Hematologic Malignancy Program, Ohio State University Medical Center.

In 1998, CALGB initiated this phase II clinical trial on the hypothesis that, as in non-Hodgkin’s lymphoma, rituximab will improve response in CLL patients receiving fludarabine-based therapy.

The study randomized previously untreated, symptomatic CLL patients to receive either concurrent fludarabine and rituximab for six monthly cycles, followed after 2 months by consolidation rituximab (weekly for 4 weeks) or a sequential approach of fludarabine alone for six cycles followed 2 months later with 4 weeks of rituximab consolidation.

A total of 104 patients were enrolled; 51 were randomized to the concurrent arm and 55 to the sequential arm. The median patient age was 64 years (range, 36 to 86 years). Dr. Byrd noted that 41% of the patients were high risk.

Response Rates

Response rates in each arm were assessed 2 months after induction therapy. In the concurrent arm, there was a complete response rate of 33% and a partial response rate of 57%, for an overall response rate of 90%. The sequential arm had a 15% complete response, a partial response of 62%, and an overall response rate of 77%, "similar to what has been seen in other phase II and III trials of fludarabine alone," Dr. Byrd reported.

The response rate (after induction and consolidation therapy) for the concurrent arm was 47% complete response, 43% partial response for an overall response rate of 90%. The sequential arm had a 28% complete response rate and a 49% partial response rate for an overall response of 77%.

At a median follow-up of 20 months, median progression-free survival had not been reached in either arm. In terms of overall survival, "what’s interesting is that, although follow-up is short, there have been only five events in both arms combined," Dr. Byrd said.

The most significant difference in adverse events was grade 3-4 infusion toxicity in the first rituximab cycle, which developed in 9 of the first 44 patients on the concurrent arm. After this, Dr. Byrd said, the schedule was altered to administer rituximab using a stepped-up dosing approach in the first cycles (with more gradual escalation), and no further infusional toxicity was seen.

Although myelosuppression was higher in the concurrent arm, the incidence of grade 3-4 infection was similar, he pointed out. Overall, consolidation therapy was well tolerated in both arms.

The results show that rituximab and fludarabine can be given concurrently or sequentially "very safely and this approach appears to improve the complete response rate in CLL," he said. "In our opinion, based on the results of this trial, phase III testing of concurrent fludarabine and rituximab is warranted."