Update of Experience with Fludarabine, Cyclophosphamide, Mitoxantrone Plus Rituximab (FCM-R) in Frontline Therapy for Chronic Lymphocytic Leukemia (CLL).

Combination therapy has developed into a gold standard of CLL therapy. Chemoimmunotherapy combinations currently achieve the highest rates of complete remission (CR) and molecular responses. Various combinations have been tried to maximize outcome. Based on our previous results with fludarabine, cyclophosphamide, rituximab (FCR) and more recent reports of favorable results with FC + mitoxantrone (M), we have designed an FCM-R (plus pegfilgrastim) combination for pts with previously untreated and symptomatic CLL. All patients were younger than 70 years with b2M levels < 4 mg/L. Pts received F 25 mg/m² i.v. d2–4, C 250 mg/m² i.v. d2–4, M 6 mg/m² i.v. d2, R 375 mg/m² i.v. d1, and pegfilgrastim 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 objective was assessment of clinical responses (NCI-WG criteria) and flow cytometry (CD5/CD19) response rate at 3 and 6 months as well as toxicity. Thirty-one pts were enrolled of whom 30 were treated. 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/L (1.4–4) and the median WBC 59.9 × 10⁹/L (5.6–355). Two pts had 11q23 and 17p- abnormalities by cytogenetics/FISH. Unmutated IgV_H occurred in 12/17 (71%) pts; ZAP-70 immunohistochemistry was positive in 11/19 (58%) pts. Twenty-nine pts were evaluable for response at 3 months and 30 at completion of therapy. 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 completion of therapy: 77% CR, 10% nPR, 10% PR for an OR rate of 97%. Seventeen pts (57%) had < 1% CD5/CD19+ cells in the marrow at the end of therapy. Grade >/= 3 neutropenia occurred in 19 (63)% of the pts, thrombocytopenia in 2 (7%). Infectious episodes were seen in 13 pts (45%). Seven (23%) did not complete 6 courses because of ongoing cytopenias. In conclusion, FCM-R has a high CR rate in symptomatic frontline patients with CLL. Time-to-event parameters and a comparison with FCR will be presented.