Efficacy and Safety of Fludarabine/Cyclophosphamide (FC) as Front-Line Treatment of CLL. Final Results of a Phase II Clinical Trial in a Single Center.

BACKGROUND: Fludarabine (F), already demonstrated to be a highly active drug in the management of relapsing or refractory CLL, presents improved clinical and molecular responses when it is associated to alkylating agents such as Cyclophosphamide (C). This combination (FC) appears as a promising option as front-line treatment in CLL patients with good performance status and no previous treatments, in whom a much better outcome, and perhaps curation, is expectable.

Objectives: 1) Evaluation of the clinical and molecular response to FC as front-line treatment of CLL. 2) Assessment of toxicity and complications associated to this combination.

Patients and method: Since June 2001 to August 2004, 26 B-CLL untreated patients (pts) (19M/7F; M age: 60 years (43–74); ECOG:0 (0–1); Binet AII 4 pts, BI 4 pt, BII 14 pt, CIII 4 pt) were included in the trial to receive treatment with FC combination (F:25 mg iv/m²/d x3 d; C: 300 mg/m²/d x3d). Initially, 6 courses at 28-day intervals were programmed, but the scheme was reduced to 4 courses in accordance with the Local Ethics Committee due to the toxicity observed in the first patients. Anti-infectious prophylaxis: Trimetoprim-sulfametoxazol and fluconazol. Hemogram at inclusion: (Median (R) values) WBC: 70.7x10⁹/L (7.93–242), lymphocytes: 64,7x10⁹/L (6,2–179), Hb: 138 g/L (71–162), platelets: 151x10⁹/L (62–324). Renal and hepatic parameters within normal range limits. Cytogenetics by FISH: No alterations (9), +12 (8), p53 (4), 13q (17), ATM (6). Response to treatment was first assessed at course 3 and then at course 6 in pts receiving 6 courses, and after the 4^th course in those receiving 4 courses. The assessment was made according to the revised NCI criteria as well as by PCR amplification of the VDJ segment of IgH with FR3 and JH regions primers.

Results: 6/26 pts did not complete 4 courses yet, so they are not evaluable. Among the 20 evaluable: 6 pts completed 6 full courses, 5 courses: 1pt, 4 courses: 9 pts, 3 courses: 1 pt (due to renal toxicity), 2 courses: 2 pts (exitus before 3^rd course).

Responses: CR: 15 pts (75%); PR: 3 pts (15%); No response: 2 pts (10%). Only 1 pt, with initial PR, progressed after 21 months follow-up.

Median follow-up: 11,5 months (2–30). Up to 147 toxicity events were recorded (84 FC total), assessed according to WHO criteria, but only 50 were grade III-IV : 72% hematological (neutropenia most frequently), 18% liver toxicity, 10% renal. Toxicity occurred mainly after the first 3 courses, with increasing severity and extension, but regressing when the treatment was withdrawn, being hematological toxicity the most severe and prolongued. After reducing the number of courses from 6 to 4, hematological toxicity decreased, while other types of toxicity did not significantly improve.

Complications: 40 episodes of infection (associated neutropenia 12/40, requiring hospitalization 21/40), 2 cases of bleeding and 3 cases of thrombosis. Six patients died: 3 died of infectious complications due to prolongued hematologic toxicity: TRM: 3/20 (15%) and 3 pts due to disease progression.

Conclusions: 1) FC combination as front-line treatment is effective in B-CLL (90% overall response rate and 75% CR -clinical and molecular-). 2) Hematological toxicity is the most severe observed, causing treatment delays and leading to infections. 3) Reducing the number of FC courses from 6 to 4 caused a decrease in haematological toxicity, so 4 FC appears as an effective scheme in terms of efficacy and safety.