Outcome of First Salvage Therapy in Patients With Chronic Lymphocytic Leukemia Relapsing After First-line Fludarabine, Cyclophosphamide, and Rituximab

Abstract

Patients receiving salvage therapy for relapsed CLL following first-line FCR have overall response rates of 60% and median survival of 38 months. We describe pre-treatment characteristics predicting for outcome after salvage therapies. Patients receiving chemoimmunotherapy had better response rates and duration compared to antibody therapy alone.

Brief Abstract

Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) is an effective initial therapy with an estimated 40% relapse rate at 6 years. There is no consensus salvage therapy for relapsed patients. All patients with chronic lymphocytic leukemia (CLL) who relapsed or were refractory following first-line FCR administered between July 1999 and December 2003 were included for analysis. Patients with Richter's transformation were excluded. We analyzed the impact of pre-treatment characteristics (Table 1) and response duration following FCR on responses and survival after salvage therapy. Response outcomes were analyzed using 1996 National Cancer Institute response criteria. Overall survival (OS) and time to treatment failure (TTF) were calculated using the method of Kaplan and Meier. Of 300 patients treated with first-line FCR, 111 patients (37%) have required salvage therapy. Median age at relapse was 61 years, and 36% of patients had Rai stage III or IV disease (Table 1). The salvage regimen included antibody alone, chemoimmunotherapy, or novel therapeutic approaches including lenalidomide. Responses included 17% CR, 12% nodular PR, and 32% PR with an overall response (OR) of 60%. Median OS was 38 months, and median TTF was 9 months. Rai stage III/IV disease, β2M > 4 mg/L, deletion of 17p by fluorescence in situ hybridization and TTF < 12 months following FCR were associated with significantly shorter TTF and OS following first salvage. Patients treated with single-antibody therapy had low response rates (CR/nPR, 9%; OR, 44%) and short TTF (6 months). Combination of alemtuzumab and rituximab improved responses (CR/nPR, 50%; OR, 75%) but did not improve TTF (8 months). Patients treated with FCR or CFAR (cyclophosphamide/fludarabine/alemtuzumab/rituximab) demonstrated good responses (CR/nPR, 50%; OR, 83%) with improved TTF (20 months) but no significant improvement in OS (44 months) compared to patients receiving antibody only (OS, 41 months). Patients who relapse after FCR can be successfully retreated with a similar chemoimmunotherapy regimen (FCR, CFAR) with reasonable response rates and remission duration; however, chemoimmunotherapy does not appear to improve OS over antibody therapy alone in first salvage.