Early clinical and pharmacokinetic results of lower dose fludarabine and cyclophosphamide, and high dose rituximab (FCR-Lite) for patients with untreated chronic lymphocytic leukemia (CLL).

Introduction Standard FCR therapy in untreated CLL patients (F-25 mg/m2 d1–3 q 4wk; C-250 mg/m2 d 1–3 q 4wk; R-500 mg/m2 d1 q 4wk for 6 cycles) was recently reported to have complete remission (CR) of 70% and overall responses (OR) of 95% (J Clin Oncol 2005;23:4079). The major toxicity was grade 3/4 neutropenia during 52% of courses. One approach to decrease neutropenia without compromising efficacy could be by reducing the doses of F and C and increasing the dose of R. Methods We conducted a phase II study for previously untreated advanced CLL patients treated with FCR-Lite (F-20mg/m2 d1–3 q 4 wk; C-150 mg/m2 d1–3 q 4 wk; R-500mg/m2 d1 and d14 q 4wks; maintenance R-500 mg/m2 q 3 months until progression). A Simon two-stage design was used where 15 patients were accrued in the first stage and because of acceptable toxicity and response rate in stage I an additional 35 patients will be treated. The primary endpoint was response rate. Results Twenty eight patients (19 male, 9 female), age 36–85 years (median 58) were treated with a total of 154 FCR-Lite courses. All 28 patients were evaluable for toxicity. Grade 3/4 neutropenia occurred during 12 (8%) courses. There was one episode of neutropenic fever. Grade 3/4 thrombocytopenia occurred during 4 (3%) courses. Grade III anemia occurred during 2 (1%) courses. One patient had pneumonia. Among the 21 evaluable patients for response, the CR rate was 86%, PR rate was 14% with an OR rate of 100%. Seventeen of the CR patients were tested by flow cytometry and had no evidence of CD5+/CD19+ cells in their bone marrow after therapy. Preliminary data from pharmacokinetics performed on 16 patients showed time dependent increase in trough and peak antibody concentrations throughout treatment (Table 1). Conclusions Our results in the first 28 patients suggest FCR-Lite is highly effective with considerably less grade 3/4 neutropenia than standard FCR. Complete responders had no detectable CD5+/CD19+ cells in their bone marrow following FCR-Lite. | Infusion No. | Concentration (μg/ml) (Mean) | |:-------------- | ---------------------------- | | C1,d1, before | | | C1,d1, after | 116.1 | | C1,d14, before | 10.0 | | C1,d14, after | 207.8 | | C2,d1, before | 33.2 | | C2,d1, after | 231.4 | | C3,d14, before | 125.3 | | C3,d14, after | 345.5 | | C4,d1, before | 173.2 | | C4,d1, after | 390.8 | Table 1. Serum Rituximab Concentrations Before and After Infusion (N=16 patients)