Previous studies have shown that FAMP in combination with CTX seems to have a significant advantage over single-agent FAMP in patients with relapsed CLL who had previously received alkylators or alkylators plus fludarabine, but are still fludarabine-sensitive. Despite the improved response rates, patients who achieve CR eventually relapse and require alternate therapies. The high rate of relapse in CLL affirms the need for improved treatments, which reduce or eliminate residual disease (MRD) to induce “better quality,” more durable responses. The monoclonal antibody alemtuzumab (Campath®), which is directed towards the CD52 antigen expressed on the surface of B-CLL cells, acts synergistically with fludarabine in vitro and appears to have synergistic activity in vivo. Alemtuzumab is one of a few single agents that has demonstrated the ability to eliminate minimal residual disease in CLL. Therefore, we designed a phase II study to determine the efficacy and safety of a 4-week combination regimen consisting of FAMP, CTX, and alemtuzumab (FCC) in relapsed patients with CLL. Objectives of this study also included the evaluation of the overall response rate (ORR), duration of response (DR), and the presence of MRD following treatment with FCC. Patients received FCC after a short period of alemtuzumab dose escalation, from 1 mg to 3 mg to 10 mg on consecutive days. The FCC regimen consisted of FAMP 40 mg/m2/day PO (Days 1–3), CTX 250 mg/m2/day PO (Days 1–3), followed by alemtuzumab 10 mg SC (Days 1–3). This combination was repeated on Day 29 for up to 6 cycles. MRD was measured by 4-color flow cytometry and consensus primer PCR. Nine patients (7 male and 2 female), have been enrolled in this trial. The median age of patients was 60.3 years (range, 43–78 years); 2 patients (22%) were in Binet stage C, 3 patients were in stage A and 4 patients were in stage B. Median number of prior treatment regimens was 2 (range, 1–3). Currently, 3 patients completed treatment, and 2 patients received 3 courses while the remaining 4 patients completed the first course. Among the 3 patients who completed treatment, 1 achieved a complete response (CR) and 2 patients a partial response (PR). MRD negativity was achieved in the peripheral blood in 1 patient. No CMV reactivation has been observed. No opportunistic infections have been recorded. Hematologic toxicity was manageable: 2 patients required G-CSF support. No nonhematologic toxicity was documented. This preliminary data on safety and efficacy of this regimen are encouraging and warrant further study.