Preliminary Results of the Combination Rituximab, Fludarabine, Cyclophosphamide and Mitoxantrone (R-FCM) Followed by Rituximab Maintenance in Previously Untreated Chronic Lymphocytic Leukemia (CLL).

Immuno-chemotherapy (rituximab + combination chemotherapy) is emerging as the new gold standard for CLL treatment. However, the best combination chemotherapy to be given along with rituximab has not yet been determined. In addition, there is some indication that rituximab maintenance could be of benefit in CLL, as it has already been demonstrated in follicular lymphoma. In patients with previously untreated CLL, FCM results in a response rate of 90%, including a high proportion of MRD-negative CRs. These results suggested that FCM could be an ideal companion for rituximab in CLL therapy. Against this background, we have recently conducted a prospective clinical trial in which patients with untreated CLL receive R-FCM followed by maintenance with rituximab. Patients are eligible for therapy if they are younger than 70 yrs, have active disease (NCI-WG criteria), and adequate performance status. R-FCM consists of rituximab 500 mg/m² on day 1 (375 mg/m² 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 a 4-week intervals up to six courses. All patients receive G-CSF and cotrimoxazole. Patients achieving response (CR or PR) are subsequently treated with rituximab 375 mg/m² every three months up to two years. Response is assessed three months after R-FCM treatment and includes MRD evaluation by four-color flow cytometry. Out of 69 patients included in the study, 38 (74% male, median age. 59 years) are evaluable for response to the first part of the treatment (R-FCM induction therapy). At study entry, 83% of the patients were in advanced (B and C) Binet’s clinical stage and 64% had increased (>20%) ZAP-70 expression. Ninety per cent of the patients have received the entire planed treatment. Overall response rate is 92%. MRD-negative CR is 36%, MRD-positive CR 41% (CR rate, 77%), nPR 7%, and PR 8%. Two out of 4 PR cases are MRD-negative. Toxicity has been manageable, with grade III–IV neutropenia being observed in 8% of the cases. Six serious adverse events have been documented (4 infections, 1 coronary disease, 1 CMV reactivation), two of them unrelated to the treatment. In conclusion, R-FCM is a well tolerated regimen that induces a high CR rate, including an important proportion of MRD-negative CRs. Whether these already extremely promising results are improved by maintenance therapy with rituximab remains to be seen.