Initial treatment of chronic lymphocytic leukemia (CLL) with fludarabine (Fludara) or fludarabine/cyclophosphamide (Cytoxan, Neosar) resulted in complete remission (CR) rates of 28% and 35%, respectively. Recently, rituximab (Rituxan) has been shown to have significant dose-related efficacy in CLL and to sensitize lymphoid cells to chemotherapy. Based on these data, 68 patients with previously untreated CLL who have progressive or advanced-stage disease (National Cancer Institute Working Group Criteria) have been entered on a fludarabine/cyclophosphamide/rituximab protocol (fludarabine at 25 mg/m², cyclophosphamide at 250 mg/m²) daily for 3 days for six courses every 4 weeks. Rituximab is given at 375 mg/m² on day 1 of course 1 and 500 mg/m² on day 1 of courses 2 through 6.

Thirty-five patients are evaluable after six courses and 21 patients are evaluable after three courses. The patients were younger than usual (median age: 58 years; range: 36 to 83 years) and 40% were Rai stage III/IV with a median white blood cell count of 111 × 10³/mL. The results by course number are as follows:

 Toxicities associated with the first infusion of rituximab were mainly fever and chills or changes in blood pressure. Toxicity grade was I/II in 61% and grade III/IV in 14%. Reactions to rituximab in courses 2 through 6 were uncommon. Toxicities associated with fludarabine/cyclophosphamide were nausea in 21% of courses associated with vomiting in 7%. Alopecia was noted in one patient. Major (pneumonia 1.1%, septicemia 1.9%) and minor infections (fever of unknown cause 4.2%, herpes infection 1.5%, soft tissue infection 4.2%) occurred in 13% of courses. Opportunistic infections were not noted. Neutropenia was the most common hematologic toxicity leading to dose reduction of fludarabine/cyclophosphamide in 21% of patients. No hemolytic anemia has been noted. Chemical (3 patients) and clinical (2 patients) tumor lysis was noted before allopurinol prophylaxis was initiated. One patient died of pneumonia after the second course.

As shown above, a high response rate is noted after three courses. After six courses, all responders except two PRs had < 5% CD5- and CD19-coexpressing lymphocytes (median: 0.8%) in the marrow. Four of 10 CR patients studied became polymerase chain reaction (PCR)-negative for immunoglobulin heavy-chain rearrangement.

CONCLUSION: Fludarabine/cyclophosphamide/rituximab is the most active regimen explored by our group in previously untreated CLL. The toxicity profile is similar to that seen with fludarabine/cyclophosphamide alone.

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