Consolidation with Alemtuzumab Improves Progression-Free Survival in Patients with Chronic Lymphocytic Leukemia (CLL) in First Remission - Long-Term Follow-Up of a Randomized Phase III Trial of the German CLL Study Group (GCLLSG).

Purpose: Alemtuzumab (MabCampath) is a humanized monoclonal antibody that targets the CD52 antigen, which is highly expressed on most human B and T lymphocytes. Alemtuzumab has shown considerable activity in both relapsed/refractory CLL and in the frontline treatment setting. In a recent study, treatment with single-agent alemtuzumab induced MRD-negative remissions in 20% of patients with relapsed/refractory CLL (Moreton et al JCO 2005;23:2971–2979). Other studies suggest that MRD negativity can also be attained when alemtuzumab is administered as consolidation for patients with CLL who achieve incomplete initial responses to chemotherapy. Here, we report our long-term experience within a randomized phase III trial that investigates the role of alemtuzumab for consolidation therapy in patients with previously untreated CLL.

Methods: Pts in complete or partial remission after induction chemotherapy, with either fludarabine (F) or fludarabine plus cyclophosphamide (FC), were randomized to receive either alemtuzumab 30 mg, 3 times a week for ≤12 wks or no further treatment. Of 21 eligible pts, who had responded to induction with F or FC (1 CR, 1 nPR, 9 PRs), 11 pts (median age: 60 years) randomized to receive alemtuzumab consolidation and 10 to the observation arm. Pts in the alemtuzumab arm received standard premedication and infection prophylaxis with famciclovir and trimethoprim/sulfamethoxazole.

Results: After a median follow-up of 48 months, calculated from time of randomization within this consolidation trial, progression-free survival (PFS) was significantly improved for pts who received alemtuzumab consolidation compared to those who received no further treatment (median PFS not reached versus 20.6 months, P = 0.004). PFS from the beginning of induction therapy with F or FC is also significantly greater for patients in the alemtuzumab consolidation arm versus the observation arm. So far, 3 of 11 pts presented with disease progression after alemtuzumab consolidation compared with 8/10 progressing pts in the observation arm. Differences in PFS between both arms were not associated with disease stage before first line treatment, type of first line chemotherapy (F vs. FC) or response status before initiation of consolidation therapy (CR vs. nPR vs. PR). Correlations between achievement of MRD negative responses and PFS is still under investigation and is planned for presentation. With the exception of 2 patients (1 pt in each arm) all patients remain alive. The study was stopped prematurely due to severe infections (7 CTC III infections, which included 4 CMV reactivations, 1 CTC IV infection) in 7/11 patients being treated with alemtuzumab. However, these infections were successfully treated, not associated with the cumulative dose of alemtuzumab, and no late complications of consolidation therapy have been observed.

Conclusions: Although based on few pts due to incomplete accrual, long-term PFS was significantly prolonged in patients with CLL receiving alemtuzumab consolidation after first line chemotherapy with F or FC. An ongoing phase I/II trial of the GCLLSG (CLL2i) is currently evaluating the optimal dose and schedule of alemtuzumab in CLL pts after fludarabine-based chemotherapy.