Phase II Study of Rituximab in Combination With Fludarabine in Patients With Chronic Lymphocytic Leukemia

This phase II trial investigated the safety and efficacy of a combined-modality treatment with rituximab (Rituxan) and fludarabine (Fludara) in patients with fludarabine- and anthracycline-naive chronic lymphocytic lymphoma (CLL). The rationale for combining rituximab and fludarabine includes the single-agent efficacy of both drugs, the possible synergism of rituximab and chemotherapy, and no apparent overlapping toxicities.

A total of 32 patients were treated with fludarabine administered at a standard dose of 25 mg/m²/d (days 1-5, 29-33, 57-61, 85-89). The first two infusions of rituximab were given together with fludarabine on days 57 and 85, while the following doses (375 mg/m²) were given on days 113 and 151. Baseline characteristics of 30 eligible patients (19 previously untreated, 11 relapsed) were as follows: median age, 59 years (range: 30-70 years); males, 21 patients (70%); Binet stage B, 21 patients (70%), Binet stage C, 9 (30%); median number of prior regimens in previously treated patients, 1 (range: 1-3).

Side effects consisting of fever, chills, and exanthema of the skin were mild. Fever and chills were mainly related to the first rituximab infusion. Toxicity was World Health Organization grade 1/2 in 47% of patients and grade 3/4 in 3%. Hematologic toxicity included neutropenia (grade 1/2 in 30%, grade 3/4 in 37%) and thrombocytopenia (grade 1/2 in 20%, grade 3/4 in 10%). One patient died after the second cycle of fludarabine, during prolonged thrombocytopenia due to cerebral bleeding. No hemolytic anemia has been noted. There was a total of 29 infections in 15 patients (sinusitis/rhinitis/tonsillitis in 5 patients, herpes labialis/zoster infection in 5 patients, and fever of unknown origin in 4 patients). None of these infections was fatal.

The overall response rate (complete plus partial response) was 90% (26/29 evaluable patients). In previously untreated patients, 16 of 18 responded (89%). Out of 29 patients, 10 achieved a complete response: 5/18 were untreated, 5/11 pretreated; 9/21 Binet stage B, 1/8 Binet stage C. There were 1/29 patients with no change and 2/29 patients with progressive disease. The median time to progression has not been reached after a median follow-up of 10 months.

CONCLUSION: The combination regimen of rituximab and fludarabine is very effective and feasible in this group of patients.

Click here to read Dr. Bruce Cheson's commentary on this abstract.