Fludarabine Versus Fludarabine Plus Epirubicin in the Treatment of Chronic Lymphocytic Leukemia - Final Results of a German Randomized Phase-III Study.

Based on promising results from our previous phase-II study demonstrating an overall response rate (ORR) of 92% and a high rate of complete remissions (CR) of 40% we initiated a multicenter randomized phase-III study to compare efficacy and toxicity of the combination fludarabine plus epirubicin (FluEpi) versus monotherapy with fludarabine (Flu) as first-line therapy or therapy of first relapse. In addition, cytogenetic aberrations were investigated in all patients to evaluate, if special chromosomal abnormalities are associated with prognosis and response to fludarabine. Treatment schedule: Fludarabine 25 mg/qm day 1–5, epirubicin 25 mg/qm day 4+5 for a maximum of 6 cycles every four weeks. Results: 150 patients (pts) are evaluable for response (77 pts with Flu, 73 pts with FluEpi). Median age of the patients is 62 years. All pts were in need of treatment with 86 pts being in stage Binet B and 64 pts in Binet C. Cytogenetic aberrations were well balanced between both groups. The ORR for the total group of 150 pts was 79% with a CR-rate of 19%. The ORR for patients treated with FluEpi was 88% compared to patients treated with Flu monotherapy reaching an ORR of 73%. This difference is statistical different with a p-value of 0.0255. CR are different in favor for combined treatment modality (29% CR for FluEpi vs 9% for Flu) with a significance level of 0.0029. Patients treated with FluEpi have a longer median duration of progression free survival with 26 months in comparison to 20 months for patients treated with fludarabine alone (p=0.085). There is a trend for a longer median overall survival time, which is 76 months for patients with FluEpi compared to the median survival time of 63 months for the Flu monotherapy group, however this difference is not statistical different (p=0.10). The event free survival (EFS), which was defined as not achieving any remission, progression/relpase of disease or death for any cause, was superior for pts treated with FluEpi (30 months) in comparison to the pts treated with Flu monotherapy (19 months) with a significance level of 0.048. Conclusions: The combination therapy of fludarabine plus epirubicin achieves statistically higher response rates and a longer duration of event free survival, however this does not translate in an statistical significant overall survival benefit.