Frontline Chemoimmunotherapy with Fludarabine/Cyclophosphamide/Rituximab versus Bendamustine/Rituximab in Advanced CLL: Final Analysis of the CLL10 Study
For physically fit patients with chronic lymphocytic leukemia (CLL) with low comorbidity burden, the combination of fludarabine, cyclophosphamide, and rituximab (FCR) is the standard frontline regimen. CLL10 was a randomized, multicenter, international, phase 3 study designed to evaluate the efficacy and tolerability of bendamustine/rituximab (BR) compared with FCR as frontline therapy for fit patients with advanced CLL without a deletion in chromosome 17p (del17p; Eichhorst B, et al. Blood. 2014;124. Abstract 19).
A total of 564 patients with CLL with a Cumulative Illness Rating Scale (CIRS) of ?6, creatinine clearance >70 mL/min, and without del17p were randomly assigned to receive 6 courses of FCR (N = 284) or BR (N = 280) according to a schedule that has been established for each regimen. Approximately 40% of the patients were Binet stage C.
After a median observation time of 35.9 months, the overall response rate in both arms was approximately 95%, but the complete response (CR) rate in the FCR arm was 40% compared with 31% in the BR arm (P = .034). Moreover, at final restaging, 27% of the patients in the FCR arm were minimal residual disease (MRD)-negative in their bone marrow and 49% were MRD-negative in their peripheral blood compared with 11% and 38%, respectively, in the BR arm. The median progression-free survival (PFS) was 55.2 months and 41.7 months in the FCR and BR arms, respectively (P <.001). No significant difference in overall survival (OS) was observed between the FCR and BR arms at 36 months (91% for FCR vs 92% for BR).
The subgroups that appeared to benefit most from FCR were those who were especially physically fit (CIRS ?3, with only 1 CIRS item and aged ?65 years). Grade 3/4 neutropenia (84% vs 59%, respectively; P <.001) and thrombocytopenia (22% vs 14%, respectively; P = .03) were significantly more pronounced in the FCR arm than in the BR arm, but there were no significant differences among the treatment arms in the incidence of anemia. However, severe infections occurred more frequently in the FCR arm, especially in older patients (39% in the FCR arm vs 27% in the BR arm; P <.001). The occurrence of secondary neoplasms (including acute myeloid leukemia or myelodysplastic syndrome) was not significantly different among the patients in the 2 arms.
This final analysis of the CLL10 study showed that FCR remains the standard therapy in fit patients with CLL as a result of the higher CR rates, more MRD negativity, and longer PFS compared with BR. However, fit but elderly patients with CLL or those with previous infections may benefit from BR as an alternative regimen because of the lower serious infection rate associated with this regimen, and because of the dose reductions that are often required as a result of toxicity in patients receiving FCR may yield similar efficacy rates as those seen with BR.