Consolidation Therapy with Subcutaneous Alemtuzumab Following Induction Treatment with Oral FC (Fludarabine and Cyclophosphamide) in Previously Untreated Patients Aged 65-70 Years with Advanced Stage Chronic Lymphocytic Leukemia (CLL): A Phase II Trial of the FCGCLL/MW.

New treatment approaches in CLL aim at lowering as much as possible the level of minimal residual disease (MRD) to prolong the duration of response and eventually overall survival. Such a goal should be achieved by combining chemotherapy and monoclonal antibodies. The present phase II study was designed to evaluate the efficacy and the safety of first line therapy with 3 courses of oral fludarabine and cyclophosphamide (FC : F 40 mg/m² and C 250 mg/m² D1 to D3 every 4 weeks) followed by consolidation treatment with alemtuzumab in previously untreated patients (pts) aged 65 to 70 years with Binet stages B and C CLL. Pts achieving complete response (CR) and partial response (PR) after FC were eligible for the second part of the study i.e. consolidation with alemtuzumab administered subcutaneously (SC) at the dose of 10 mg thrice a week for 8 weeks. CMV antigenemia was monitored every week and alemtuzumab was discontinued in pts with more than 3 positive nuclei. MRD was evaluated before and during alemtuzumab treatment using a highly sensitive 6 color flow cytometry technique. Since severe infectious toxicity has been reported by others with similar strategies, FC regimen was limited to 3 courses and the duration of alemtuzumab treatment to 8 weeks with stringent stopping rules for CMV in this trial targeting a population of elderly pts in first line treatment. From June 2004 to June 2006, 42 pts have been enrolled in the study of whom 37 are assessable so far for induction treatment with FC. CR was achieved in 11 pts (30%) and PR in 17 pts (46%) for an overall response rate of 76% (28 pts). FC regimen was discontinued in 5 pts (13.5%) and stable disease was observed in 3 pts (8%). All the responding pts but one (one woman with onset of breast cancer) proceeded to alemtuzumab consolidation after a 2 month rest period. Alemtuzumab therapy has been completed in 16 pts, discontinued in 5 pts because of CMV reactivation as defined above (none of them developed CMV disease) and is still on going in 6 pts. Blood MRD assessment by flow cytometry was centralized in one center (RL) and could be performed in 19 pts with a set of 14 pts having been tested sequentially before alemtuzumab, after 4 weeks and after 8 weeks of treatment. In most cases, there was an impressive decrease of MRD level following alemtuzumab therapy and residual tumor cells were no longer detected. Detailed results of MRD study will be presented at the meeting. In conclusion, 3 courses of FC yielded a high response rate in previously untreated elderly CLL patients and SC alemtuzumab consolidation could thereafter be administered safely in most of them, resulting in a striking reduction of blood MRD.