Rituximab, Fludarabine, Cyclophosphamide, and Mitoxantrone (R-FCM) Is a Highly Active Chemoimmunotherapy Regimen for Chronic Lymphocytic Leukemia.

The addition of monoclonal antibodies to chemotherapy has significantly improved treatment of patients with CLL. Based upon the excellent results obtained with our chemotherapy-only regimen fludarabine, cyclophosphamide and mitoxantrone (FCM) (Bosch et al. Clin Cancer Res, 2008) we have build up a new chemoimunotherapy combination, R-FCM (rituximab plus FCM). In November 2005 we initiated a multicentric phase II clinical trial that includes R-FCM as initial treatment followed by a maintenance therapy phase consisting of rituximab (375 mg/m2 every there months for 2 years). We report here the final results of the initial phase of this study, namely R-FCM treatment. From November 2005 to November 2007, 72 patients under the age of 70 with active CLL according the NCI and IWCLL criteria (Cheson et al. Blood, 1996; Hallek et al. Blood, 2008) were treated. Patients received rituximab 500 mg/m² on day 1 (375 mg/ m² in the first cycle), fludarabine 25 mg/ m² i.v. on days 1 to 3, cyclophosphamide 200 mg/ m² on days 1 to 3, and mitoxantrone 6 mg/ m² i.v. on day 1, given at 4-week intervals up to six cycles. Treatment outcome was correlated with clinical and biological parameters. Minimal residual disease (MRD) was evaluated by four-color flow cytometry (Rawstron et al. Leukemia, 2007). Median cycles of R-FCM administered were 5 (range, 3–6), with 91% of patients completing all planed treatment. Response was evaluated three months after finishing therapy. Altogether, the overall response, MRD-negative CR, MRD-positive CR, and PR rates were 93%, 46%, 36%, and 10%, respectively. Variables correlated with a lower CR rate were del(17p) (25% CR) and increased β2-M serum levels (72% CR). No differences in response were observed according to the age of the patients. Severe neutropenia developed in 13% of patients. Major and minor infections were reported in 8% and 5% of cycles, respectively. Treatment-related mortality was 1%. With a median follow up of 24 months no cases of secondary MDS/AML have been observed.. Although based in two different phase II studies that preclude a completely valid statistical comparison, the CR rate obtained with R-FCM (82%, of which 46% MRD-negative CRs) favorably compares with that achieved with FCM (CR 64%, MRD-negative CRs 38%). In summary the 82% CR rate obtained with R-FCM is among the highest ever reported for any form of therapy for CLL. Both high β2-M serum levels and del(17p) predicted lower CR rate. Treatment toxicity was acceptable and manageable. Based on these results, R-FCM warrants further investigation, particularly in randomized clinical trials.