Dose De-Escalation in Fit, Older Patients with CLL: Balancing Efficacy, Safety, and Tolerability
The combination of fludarabine, cyclophosphamide, and rituximab (FCR) is the standard first-line therapy for CLL based on the results of the CLL8 study, which showed improved PFS and OS with FCR versus fludarabine plus cyclophosphamide (FC); this study established FCR as the new standard of treatment for physically fit patients with CLL (Molica S. Expert Rev Anticancer Ther. 2011;11:1333-1340). However, the median age in the CLL8 study was 61 years compared with 72 years overall for patients with CLL. Therefore, Mulligan and colleagues undertook a study to assess the safety, tolerability, and efficacy of FCR in elderly patients with CLL and to see whether dose de-escalation was possible in cases where toxicity occurs with full-dose FCR (Blood. 2014;124. Abstract 3325).
Patients aged ?65 years with previously untreated progressive CLL were randomized to 1 of 3 treatment arms: FR5 (fludarabine on days 1-5 plus rituximab), FCR3 (FC on days 1-3 plus rituximab on day 1 of each cycle), or FCR5 (FC on days 1-5 plus rituximab on day 1 of each cycle) for 6 cycles.
The response data are shown in Table 1. Although the ORR was high in all the groups, complete remission (CR) was the highest in the FCR5 group versus the FCR3 and FR5 groups. Differences in PFS and OS between the arms were not significant. Toxicity was significantly lower with FR5 than with FCR3 and FCR5, and the early cessation of therapy was most frequent in the FCR5 group (Table 2). Overall, FCR5 resulted in the highest CR rate, but also in higher rates of incomplete marrow recovery, hematologic toxicity, and earlier cessation of therapy.
The study results suggest that oral FCR5 is the most effective regimen and is generally safe and well-tolerated as first-line therapy in patients with CLL aged ?65 years, allowing for early cessation in the case of prolonged toxicity. Dose-reduced FCR3 provides a balance of efficacy, safety, and tolerability in this patient population, but the exclusion of cyclophosphamide from the FR5 regimen results in a significantly lower CR rate; thus, the FR5 regimen cannot be recommended for routine patient care.