Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia

Purpose: To assess the efficacy of combination therapy with fludarabine and cyclophosphamide in patients with chronic lymphocytic leukemia (CLL) based on data suggesting in vitro synergistic activity of the two agents. Patients and Methods: A total of 128 patients with CLL were treated with fl udarabine 30 mg/m(2) intravenously daily for 3 days and cyclophosphamide at either 500 mg/m(2) daily for 3 days (n = 11), 350 mg/m(2)/d for 3 days (n = 26), or 300 mg/m(2) daily for 3 days (n = 91). The cyclophosphamide dose wets decreased because of myelosuppression in the early part of the study. Patients were divided into four groups based on the expectation for respons e to single-agent fludarabine, including previously untreated patients, pat ients previously treated with alkylating agents, patients successfully trea ted with alkylating agents and fludarabine but relapsing, and patients refr actory to fludarabine with or without alkylating agents. Results: Fludarabine and cyclophosphamide produced greater than or equal to 80% response rates in all patients not refractory to fludarabine at the st art of therapy as well as a 38% response rate in patients who were refracto ry to fludarabine. The complete remission (CR) rate was 35% in previously u ntreated patients, which was not significantly different from the CR rate i n historical control patients treated with single-agent fludarabine. Howeve r, residual disease assessed by flow cytometry occurred in only 8% of previ ously untreated patients achieving CR, and median time to progression has n ot been reached after a median follow-up of 41 months. The main complicatio n of therapy was related to myelosuppression and infection, Neutropenia to less than 500 x 10(9)/L was noted in 48% of patients who received cyclophos phamide 300 mg/m(2). Pneumonia or sepsis occurred in 25% of patients, and f ever of unknown origin occurred in another 25%. Pneumonia or sepsis were si gnificantly more frequent ire patients who were refractory to fludarabine a t the start of combination chemotherapy. Conclusion: Fludarabine and cyclophosphamide seem to have a significant adv antage over single-agent fludarabine in the salvage setting. Although the C R rate was not increased in previously untreated patients, residual disease detected by flow cytometry was rare and remission durations seemed to be p rolonged in this subset. Myelosuppression and infection remain the most sig nificant complications of therapy in CLL. J Clin Oncol 19:1414-1420. (C) 20 01 by American Society of Clinical Oncology.