Phase III Trial of Fludarabine Plus Cyclophosphamide Compared With Fludarabine for Patients With Previously Untreated Chronic Lymphocytic Leukemia: US Intergroup Trial E2997

TLDR

Fludarabine plus cyclophosphamide is an effective regimen for chronic lymphocytic leukemia but is associated with higher toxicity than fludarabine alone. The E2997 phase III randomized Intergroup trial enrolled 278 previously untreated CLL patients, assigning them to fludarabine 25 mg/m² days 1‑5 (FC arm) or fludarabine 20 mg/m² days 1‑5 plus cyclophosphamide 600 mg/m² day 1 (F arm), with up to six 28‑day cycles. FC produced a higher complete response rate (23.4 % vs 4.6 %) and overall response rate (74.3 % vs 59.5 %), improved progression‑free survival (31.6 vs 19.2 months), and increased thrombocytopenia without raising severe infection rates compared with fludarabine alone.

Abstract

The combination of fludarabine and cyclophosphamide is an effective regimen for patients with chronic lymphocytic leukemia (CLL). However, it may be accompanied by increased toxicity compared with fludarabine alone. E2997 is a phase III randomized Intergroup trial comparing fludarabine and cyclophosphamide (FC arm) versus fludarabine (F arm) alone in patients receiving their first chemotherapy regimen for CLL.Symptomatic, previously untreated patients with CLL were randomly assigned to receive either fludarabine 25 mg/m2 intravenously (IV) days 1 through 5 or cyclophosphamide 600 mg/m2 IV day 1 and fludarabine 20 mg/m2 IV days 1 through 5. These cycles were repeated every 28 days for a maximum of six cycles.A total of 278 patients were randomly assigned in this Intergroup study. Treatment with fludarabine and cyclophosphamide was associated with a significantly higher complete response (CR) rate (23.4% v 4.6%; P < .001) and a higher overall response (OR) rate (74.3% v 59.5%, P = .013) than treatment with fludarabine as a single agent. Progression-free survival (PFS) was also superior in patients treated with fludarabine and cyclophosphamide than those treated with fludarabine (31.6 v 19.2 months, P < .0001). Fludarabine and cyclophosphamide caused additional hematologic toxicity, including more severe thrombocytopenia (P = .046), but it did not increase the number of severe infections (P = .812).Fludarabine and cyclophosphamide produced an increase in OR and CR, and it improved PFS in patients with previously untreated CLL compared with fludarabine alone and was not associated with an increase in infectious toxicity.