Activity and Safety of Combined Fludarabine and Alemtuzumab Followed by Low-Dose Alemtuzumab Maintenance Therapy in Patients with B-CLL.

Patients (pts) with purine analog-refractory CLL have extremely poor prognosis, with a median survival of 10 months. Alemtuzumab (MabCampath) has demonstrated significant responses in relapsed/refractory CLL. Studies have shown that combining alemtuzumab with purine analogues, such as fludarabine, results in improved efficacy, even in pts who are refractory to either agent alone. This study assessed the efficacy and safety of combined therapy with fludarabine and reduced-dose alemtuzumab (FluCam), followed by maintenance with reduced-dose alemtuzumab monotherapy in pts with progressive B-CLL. Pts with relapsed/refractory B-CLL received induction therapy comprising fludarabine 25 mg/m² IV and alemtuzumab10 mg IV for 3 days (or 30mg SC for the first day) of a 4-week cycle for ≤6 cycles. Antihistamines and antipyretic agents were administered with therapy, and acyclovir and cotrimoxazole were administered as anti-infective prophylaxis. After successful completion of FluCam induction, alemtuzumab 30 mg maintenance was administered monthly for 4–5 doses. Response and toxicity were evaluated according to NCI-WG and WHO criteria, respectively. Minimal residual disease (MRD) was assessed by 4-color flow cytometry. Ten pts (mean 57 yrs; range, 49–69 yrs) have been treated to date. The study included patients with Rai stage low risk (n=1), intermediate risk (n=3) and high risk (n=6) disease. Six pts had elevated serum beta-2 microglobulin, 9 had <6 months lymphocyte doubling time, and 3 had increased ZAP-70 and/or CD38 expression. Pts received a median 3 prior therapies (range, 2–6); 1 received prior alemtuzumab, and all 10 received prior fludarabine alone or in combination with cyclophosphamide. Pts received a mean of 4 FluCam cycles. Following induction, 6 pts completed a mean of 3 months (range, 1–5) with alemtuzumab maintenance. Mean duration of follow-up was 14 months (range, 4–23 months). Among the 10 pts, 2 achieved a CR following 3 cycles of FluCam, of whom 1 achieved MRD negativity, and 9 achieved a PR. Mean time to progression was 11 months (range, 2–21 months)[b1]. Short-term improvements were seen in 2 pts; however, treatment was discontinued after 2 cycles because of disease progression. Two pts progressed after 12 and 14 months, respectively, and were effectively treated a second time with alemtuzumab. Moderate adverse effects including chills, fever, and skin redness were observed in all pts during alemtuzumab dose escalation. Despite low counts of T cell subsets, alemtuzumab was well tolerated. Grade 2 or 3 inflammatory complications occurred in 3 pts after the first 2 courses of therapy. Although 1 pt with severe immune deficiency died after 23 months of follow-up due to bacterial pneumonia, cytomegalovirus reactivation did not occur in any pt. Preliminary results from this study suggest that an altered schedule of alemtuzumab has favorable clinical activity and safety profile when combined with fludarabine. This altered FluCam regimen is a viable alternative for pts with advanced B-CLL who have relapse or are refractory to either agent alone. Maintenance with low-dose alemtuzumab may also prolong time to progression and overall survival without increased toxicity or complications in pts with advanced disease. Further study is warranted in a larger pt population to develop a convenient dosing schedule with alemtuzumab maintenance therapy for long-term control of persistent disease.