Planned First Safety and Efficacy Analysis of Oral Fludarabine Combined with Subcutaneous Alemtuzumab in 2^nd Line Therapy of B-Chronic Lymphocytic Leukaemia (B-CLL): The FLUSALEM Study.

Background: In a previously published small-scale pilot study, the chemoimmunotherapy combination of alemtuzumab (Campath®)and fludarabine was effectively used in heavily pre-treated patients. The positive responses in 5 of 6 patients treated, and even among those that were unresponsive/refractory to either single-agent therapy, was attributed to the potentially synergistic activity between alemtuzumab and purine analogues (Kennedy, Blood, 2002). Although typically administered intravenously, following a dose escalation, alemtuzumab administered in a subcutaneous (SC) manner has been shown to significantly reduce the infusion-related toxicities. Here we present the first planned analysis of Fludarabine in combination with SC alemtuzumab in second line CLL therapy.

Methods: Patients with active CLL who had failed 1 regimen of therapy were treated with 4 cycles of oral fludarabine (30mg/m2 for 1–3d) and sc alemtuzumab 30 mg, 3 times per week for 16 weeks (FLUSALEM). The study follows a 2-step Gehan design, which features an early interim analysis after 7 patients have completed four cycles of concomitant therapy, to define minimally required efficacy and to facilitate protocol modifications. We evaluate feasibility, the safety profile and initial response rates.

Results: The results of the first 7 patients enrolled in the trial are presented. Clinical response was very fast and 5/7 Patients were in clinical CR, according NCI-WG 1996 criteria, also confirmed by CT-scan, after only 2 cycles of therapy. On an intent to treat basis, the overall response rate was 85% and the CR rate at the end of therapy was 85% (including evaluation of BM biopsy). MRD analysis was performed using a 4-colour flow cytometric assay. All evaluable patients who completed full course of therapy, (N=6) achieved MRD negativity usually within 2 cycles of therapy. One patient discontinued early due to a violation of inclusion criteria and pneumonia at the start of therapy. No tumor lysis syndrome was observed. Thirteen Grade III–IV adverse events were reported, and 3/7 patients (37%) developed clinically manageable CMV-reactivations, as was evidenced by a fever. The main other reason for hospitalization was pneumonia. Grade III–IV neutropenia was observed in 6/7 patients, however in most cases it was associated with initial BM infiltration and resolved quickly with treatment. A total of 4 febrile episodes were observed and only one patient required transfusions for anemia and no platelet transfusion was needed. For all patients the protocol was feasible on an out patient basis with weekly visits. An evaluation of quality of life questionnaires is planned after all 28 patients, which are planned to be recruited for this study, complete therapy.

Conclusions: We present a first planned interim analysis of the investigator initiated FLUSALEM pilot study. This protocol is being conducted on an out patient basis and shows very rapid responses with deep remissions. The therapy has manageable toxicity and may represent an attractive therapeutic approach in pretreated patients with CLL.