Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL

Abstract

Optimal management of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) is dictated by patient characteristics, prior therapy, and response to prior therapy. We report the final analysis of combined fludarabine, cyclophosphamide, and rituximab (FCR) for previously treated patients with CLL and identify patients who benefit most from this therapy. We explore efficacy of FCR in patients beyond first relapse, patients with prior exposure to fludarabine and alkylating agent combinations, and patients with prior exposure to rituximab. The FCR regimen was administered to 284 previously treated patients with CLL. Patients were assessed for response and progression by 1996 National Cancer Institute-Working Group (NCI-WG) criteria for CLL and followed for survival. The overall response rate was 74%, with 30% complete remission. The estimated median overall survival was 47 months and median progression-free survival for all patients was 21 months. Subgroup analyses indicated that the following patients were most suitable for FCR treatment: patients with up to 3 prior treatments, fludarabine-sensitive patients irrespective of prior rituximab exposure, and patients without chromosome 17 abnormalities. FCR is an active and well-tolerated therapy for patients with relapsed CLL. The addition of rituximab to FC improved quality and durability of response in this patient population.

Figure 1

FCR overall and progression-free survival. Overall survival (OS) and progression-free survival (PFS) for all relapsed/refractory patients treated with fludarabine, cyclophosphamide, and rituximab.

Figure 2

Overall and progression-free survival by subgroups. (A) Progression free survival (PFS) by NCI-WG response for relapsed/refractory patients treated with FCR (n = 267). Early deaths (n = 13) shown in panel B. (B) Overall survival (OS) by NCI-WG response for relapsed and refractory patients treated with FCR (n = 280). Four patients were not evaluable for response. (C) PFS by karyotype for relapsed/refractory patients treated with FCR (n = 182). (D) OS by karyotype for relapsed/refractory patients treated with FCR (n = 182). CR indicates complete remission; nPR, nodular PR; PR, partial remission; NR, no objective response; ED, early death; Chr 17, chromosome 17 abnormalities; 11q−, 11q deletion; +12, trisomy 12; and Dip/13q−, diploid or 13q deletion.

Figure 3

Time to progression by MRD. (A) Time-to-progression by flow cytometry (Flow) minimal residual disease (MRD) status for patients achieving a complete response (n = 82 evaluable). (B) Time-to-progression by polymerase chain reaction (PCR) MRD status for patients achieving a complete response (n = 66 evaluable).

Figure 4

Percentage of patients completing courses of FCR. Patients have been divided into subgroups of age 70 years or younger and age over 70 years. Significant differences in proportion of patients per age group completing corresponding courses of therapy denoted by asterisks (*P < .05, **P < .001).

Figure 5

Progression-free and overall survival for patients receiving fludarabine and cyclophosphamide (FC), and FCR as salvage therapy at MD Anderson Cancer Center. (A) Progression-free survival (PFS) for relapsed/refractory patients treated with FCR versus a historic group treated with fludarabine and cyclophosphamide (FC). (B) Overall survival (OS) for relapsed/refractory patients treated with FCR versus a historic group treated with FC.