Fludarabine, Cyclophosphamide, Mitoxantrone Plus Rituximab (FCM-R) as Frontline Therapy for CLL: Results of a Phase 2 Study.

Abstract

Combinations of monoclonal antibodies (moabs) with chemotherapy have produced higher rates of complete remission (CR) and better quality of responses (minimal residual disease [MRD]-negative) than have been achieved with chemotherapy or moabs alone. We have previously shown an overall response (OR) rate of 95% with a CR rate of 73% when combining fludarabine, cyclophosphamide, and rituximab (FCR) as first-line treatment for symptomatic patients with CLL (Keating et al. J Clin Oncol 23:4079; 2005). Recent reports of FC plus mitoxantrone (FCM) have demonstrated response rates of 60% and up to 88% in pts with relapsed and untreated CLL, respectively. Here we report preliminary results of a pilot study exploring FCM plus rituximab and pegfilgrastim as frontline therapy for pts with untreated and symptomatic CLL and b2M < 4 mg/L. Treatment consisted of F 25 mg/m2 i.v. d2–4, C 250 mg/m2 i.v. d2–4, M 6 mg/m2 i.v. d2, and R 375 mg/m2 i.v. d1. Pegfilgrastim was 6 mg s.c. d4. For courses 2–6, FCM started day 1 together with R 500 mg/m2, and pegfilgrastim on d3. Courses were repeated q4–6 wks. The primary objectives included efficacy [clinical response by NCI-WG criteria and based on 2-color flow (CD5/CD19) response rate at 3 and 6 mos] and toxicity (especially myelosuppression). Thirty-one pts were enrolled of whom 29 pts are evaluable for response at 3 mos, and 21 pts at 6 mos (1 pt was taken off for insurance reasons after one course, and 1 did not receive any therapy). The median age was 57 yrs (range 38–69). Fourteen pts (48%) were male. Four pts (14%) had Rai stage ≥ 3. Median b2M was 2.6 mg/dL (1.4–4) and the median WBC 59.9 x 109/L (5.6–355). Two pts had 11q23 and 17p− abnormalities by cytogenetics/FISH. Unmutated IgVH occurred in 12/17 (71%) pts; ZAP-70 immunohistochemistry was positive in 11/19 (58%) pts. Twenty-eight pts (97%) responded at 3 mos (41% CR, 17% nPR, 39% PR); 10 pts (34%) had <1% CD5/CD19+ cells in the marrow. Response rates at 6 mos: 33% CR, 10% nPR, 57% PR for an OR rate of 100%. Nine pts had PR because of persistent cytopenias without marrow involvement or residual lymphadenopathy. Eleven pts (55%) had < 1% CD5/CD19+ cells in the marrow at 6 mos. Grade >/= 3 neutropenia occurred in 77% of the pts, thrombocytopenia in 7%, and anemia in 13%. Infectious episodes were seen in 13 pts (45%). Of 21 pts who completed therapy, 3 have received less than 6 courses because of ongoing cytopenias. In conclusion, FCM-R is an active induction regimen for symptomatic patients with CLL. However, clinical response rates and frequency of pts with flow cytometry response < 1% CD5/CD19+ cells does not appear to be different from the FCR experience. Neutropenia occurs in most patients and continued use of hematopoietic growth factors throughout therapy is recommended.