Chemoimmunotherapy with Fludarabine, Cyclophosphamide, and Rituximab versus Bendamustine and Rituximab in Previously Untreated and Physically Fit Patients with Advanced Chronic Lymphocytic Leukemia

Eichhorst and colleagues conducted an international phase 3 study to evaluate the efficacy and tolerability of bendamustine and rituximab (BR) compared with fludarabine, cyclophosphamide, and rituximab (FCR) in first-line therapy of physically fit patients with chronic lymphocytic leukemia (CLL), who did not have a chromosome deletion 17p.

In this study, 688 patients with CLL were screened centrally for immunophenotype, genomic aberrations, immunoglobulin heavy chain variable (IgHV) sequencing, comorbidity burden, and renal function. A total of 564 patients with Cumulative Illness Rating Scale score ≤ 6, creatinine clearance > 70 mL/min, and without deletion 17p were enrolled between October 2008 and June 2011.

Patients were randomly assigned to receive 6 courses of either FCR (n= 284) or BR (n= 280). The intent-to-treat population consisted of 561 patients; 3 patients were excluded because of deferred treatment. Significantly more patients in the BR arm (68%) than in the FCR arm (55%; P= 0.003) had unmutated IgVH, a high-risk feature. All other characteristics, including median age, were well balanced.

The median observation time was 27.9 months. Overall, 547 patients were evaluable for response, and a total of 561 patients were evaluable for progression-free survival (PFS), event-free survival (EFS), and overall survival (OS). Although the overall response rate was identical in both arms (98%; P=1.0), the complete response (CR) rate was higher with FCR (47%) than with BR (38%; P=.031). The minimal residual disease (MRD) data at the final analysis showed that 72% of patients in the FCR arm and 67% of patients in the BR arm achieved MRD-negative status (P=.448).

The PFS at 2 years was 85% in the FCR arm and 78% in the BR arm (P=.041). In addition, the EFS at 2 years was 83% in the FCR arm and 76% in the BR arm (P=.037).  There was no significant difference in the OS rate at 2 years between the study arms (94% for FCR vs 96% for BR; P=0.593). A multivariate analysis identified treatment arm, β₂ microglobulin, deletion 11q, and IgHV status as independent prognostic factors for PFS and EFS.

Severe hematologic AEs, including neutropenia and infections, were more frequent in the FCR arm than in the BR arm. Furthermore, teatment-related mortality occurred in 4% of patients in the FCR arm and in 2% of patients in the BR arm.

Eichhorst and colleagues concluded that FCR appears to be more effective than BR in the first-line treatment of physically fit patients with CLL, with a higher CR rate, longer PFS, and longer EFS. These advantages are tempered by the higher rate of severe AEs, particularly neutropenia and infections, associated with FCR. In light of these results, no firm preference can be determined regarding first-line treatment of physically fit patients with CLL.

References

Eichhorst B, Fink A, Busch R, et al. chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) versus bendamustine and rituximab (BR) in previously untreated and physically fit patients with advanced chronic lymphocytic leukemia (CLL): results of a planned interim analysis of the CLL10 trial, an international, randomized study of the German CLL Study Group (GCLLSG). Blood. 2013;122(21). Abstract 526.