Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. The French Cooperative Group on CLL.

Background: Fludarabine seems to be a promising treatment for patients with advanced chronic lymphocytic leukaemia (CLL). We compared fludarabine therapy with the combination of cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of CLL in a randomised, multicentre prospective trial.
Methods: Patients older than 18 years of age were entered into the study if they presented with previously untreated B-cell lineage CLL (B-CLL) of Binet stages B or C or relapsed B-CLL pretreated with chorambucil or similar non-anthracycline-containing regimens. Patients were randomly assigned to either fludarabine (25 mg/m2 per day on days 1-5) or CAP (cyclophosphamide 750 mg/m2 per day and doxorubicin 50 mg/m2 per day on day 1, and prednisone 40 mg/m2 per day on days 1-5), both given for six courses.
Findings: Of 196 evaluable patients, 100 were previously untreated whereas 96 patients had received prior therapy. Remission rates were significantly higher after fludarabine than CAP, with overall response rates of 60% and 44%, respectively (p = 0.023). A higher response rate to fludarabine was observed in both untreated (71% vs 60%, p = 0.26) and pretreated (48% vs 27%, p = 0.036) cases, although the difference was statistically significant only in pretreated cases. In the latter group, remission duration and survival did not differ between treatment groups with a median remission duration of 324 days after fludarabine and 179 days after CAP (p = 0.22) and median survival times of 728 days and 731 days, respectively. In untreated cases, on the other hand, fludarabine induced significantly longer remissions than CAP with the median not yet reached after fludarabine and a median of 208 days after CAP (p < 0.001). This effect also translated into a tendency towards longer overall survival after fludarabine (p = 0.087). Treatment-associated side-effects consisted in both regimens of predominantly myelosuppression and in particular granulocytopenia. CAP-treated patients had a higher frequency and severity of nausea and vomiting (25% vs 5%, p < 0.001) and alopecia (65% vs 2%, p < 0.001).
Interpretation: Fludarabine provided an effective and well-tolerated therapy for patients with advanced CLL, which compared favourably with CAP as one of the most effective standard regimens. In second-line therapy, fludarabine induced a significantly higher rate of complete and partial remissions, while in first-line therapy a significant prolongation of remission was obtained, which may translate into an improvement of overall survival.