Chemoimmuno-Therapy with Fludarabine, Cyclophosphamide and Alemtuzumab (FC-Cam) in Patients with Relapsed or Genetic High-Risk CLL: Final Analysis of the CLL2L Trial of the German CLL Study Group.

Purine nucleoside combination therapy has become the standard treatment approach in B-CLL. In order to enhance efficacy, various combinations with monoclonal antibodies are under investigation. Alemtuzumab has been proven to be the most effective antibody in CLL treatment. Since the combination of Fludarabin and Campath (FluCam) resulted in impressive responses, we developed a multicenter phase II trial combining fludarabine, cyclophosphamide and alemtuzumab in a 4-weekly schedule

Fludarabine 25mg/m² iv, cyclophosphamide 200mg/m² iv and alemtuzumab 30 mg sc were given on days 1 – 3 and repeated on day 29 for up to six cycles. A 2-day escalation of alemtuzumab was administered prior to the first cycle. Minimal residual disease (MRD) was measured by 4-color flow cytometry. Antiinfective prophylaxis consisted of TMP-SMZ DS twice daily 3d/wk and valacyclovir during and at least two months after completion of treatment. CMV antigen in blood was tested in 14-days intervals.

Target recruitment of 61 patients has been reached, 5 patients were excluded due to protocol violation (withdrawn consent, secondary malignancies, death prior to therapy). Data for all 56 patients are available for response and adverse event analysis. Median age is 63 years (range 36–78) with a medium number of 1 prior regimen (range 0–4); 38/56 patients completed at least four cycles with a median number of 5 given cycles. Pretreatment included fludarabine (15/56), fludarabine and cyclophosphamide (24/56) or rituximab combinations (16/56). CTC grade III/IV thrombocytopenia and neutropenia were the most common serious side effects. 12/56 patients died during or within 6 months after last chemoimmunotherapy, of which 5 were related to therapy, 3 were related to concomitant disease and 4 patients died due to progressive disease. Serious adverse events (SAE) included CMV-reactivation (5 patients), herpes-zoster-reactivation (1 patient), pneumonia (5 patients, 2 of which had Aspergillosis-pneumonias), AIHA (1 patient) and fever of unknown origin (12 patients). Four of 56 treated patients were excluded from response analysis: 1 patient stopped therapy because of secondary malignancy, 3 patients died within therapy. The overall response rate for the remaining 52 patients was 68% with 11 CR (22%), 6 CRu (11%), 18 PR (35%), 8 SD (15%) and 9 PD (17%), response was independent of FISH status. A correlation of response with prior treatment was observed, with 81% ORR for fludarabine pre-treatment versus only 63% for those patients pretreated with fludarabine and cyclophosphamide. Finalized data of all patients will be presented.

The concomitant application of fludarabine, cyclophosphamide and alemtuzumab is as an effective approach for patients with relapsed CLL. There is some increased toxicity due to the addition of cyclophosphamide compared to the original FluCam regimen.

Elter:BayerSchering AG: Honoraria, Research Funding. Off Label Use: The anti-CD52 antibody Alemtuzumab (Campath, MabCampath) is normally administered three-weekly as monotherapy. We are using a four-weekly schedule in combination with fludarabin for the same indication.. Stilgenbauer:BayerScheringAG: Honoraria, Research Funding. Hallek:BayerScheringAG: Honoraria, Research Funding. Engert:BayerScheringAG: Honoraria, Research Funding.