Rituximab, Fludarabine, Cyclophosphamide, and Mitoxantrone: A New, Highly Active Chemoimmunotherapy Regimen for Chronic Lymphocytic Leukemia

Abstract

PurposeThe addition of monoclonal antibodies to chemotherapy has significantly improved treatment of chronic lymphocytic leukemia (CLL). Based on excellent results with the chemotherapy-only regimen fludarabine, cyclophosphamide, and mitoxantrone (FCM), we built a new chemoimmunotherapy combination—rituximab plus FCM (R-FCM). We report a phase II clinical trial consisting of an initial treatment with R-FCM followed by rituximab maintenance.Patients and MethodsSeventy-two untreated CLL patients age 70 years or younger received rituximab 500 mg/m2on day 1 (375 mg/m2the first cycle), fludarabine 25 mg/m2IV on days 1 to 3, cyclophosphamide 200 mg/m2on days 1 to 3, and mitoxantrone 6 mg/m2IV on day 1, given at 4-week intervals with up to six cycles supported with colony-stimulating factor. Patients achieving response received maintenance with rituximab 375 mg/m2every 3 months for 2 years.ResultsThe overall response, minimal residual disease (MRD) –negative complete response (CR), MRD-positive CR, and partial response rates were 93%, 46%, 36%, and 11%, respectively. Severe neutropenia developed in 13% of patients. Major and minor infections were reported in 8% and 5% of cycles, respectively. Advanced clinical stage, del(17p), or increased serum β2-microglobulin levels correlated with a lower CR rate.ConclusionR-FCM is highly effective in previously untreated CLL, with an 82% CR rate and a high proportion of MRD-negative CRs (46%). Treatment toxicity is acceptable. Parameters correlating with a lower response rate were advanced clinical stage, high serum β2-microglobulin levels, and del(17p). Based on these results, R-FCM warrants further investigation in randomized clinical trials.