Subcutaneous Alemtuzumab in Patients with Refractory/Relapsed B-Cell CLL after a Fludarabine-Based Regimen. An Interim Analysis.

Background: Alemtuzumab is the only single agent immunotherapy to demonstrate a survival benefit in patients with B-cell chronic lymphocytic leukemia (B-CLL), who have relapsed from or are refractory to Fludarabine therapy. The optimized schedule for alemtuzumab that achieves maximal efficacy with manageable toxicity is still being explored. Here, we report the second interim analysis of a new, less intensive schedule of alemtuzumab administered subcutaneously (SC) to patients with refractory/relapsed B-CLL.

Methods: Alemtuzumab was dose escalated from 10 to 20 mg during the first week, 30 mg twice week during the second and third weeks, and 30 mg once weekly during Weeks 4, 6, 8, 10, 12, 16, 20, 24, 28, 34, and 40. Antiviral prophylaxis included TMP/SMX bid 3 times a week and acyclovir 200 mg three-times daily.

Results: Of the 38 patients who were recruited to participate in the trial, 12 (31.6%)were refractory and 26 (68.4%) had relapsed from prior therapy. Patients had a median age of 66.5 years (range, 43–86 years), 30 were male (79%), 45%/53% had Binet stage B/C disease. The median number of prior therapies was 1 (range: 1–4). The median duration of therapy was 7 weeks (range, 2–24 weeks), with a median cumulative alemtuzumab dose of 457 mg (range, 120–1,080 mg). Among the 35 patients who were evaluable for response, the overall response rate was 88.6%: 45.8%complete response (CR), 2.9% unconfirmed CR, 42.8% partial response (PR). Four patients ( 11.5%) did not respond to therapy. Of the 9 patients with refractory disease, 1 achieved a CR, 6 a PR and 2 did not respond. Median follow up was 13 months and median overall survival was not achieved. Minimal residual disease (MRD) was measured by flow cytometry in 6 patients who achieved a CR: 4 patients had <0.5% of CD5/CD19+ cells, 1 patient had <5% of CLL cells, and 1 patient had <10% CLL cells. According to WHO toxicity criteria, over 38 evaluable patients, 4 (10,6%) experienced grade 3/4 infection; 2 patients had grade 2/3 granulocytopenia/thrombocytopenia; 1 patient had cytomegalovirus (CMV) reactivation without CMV disease; and 1 patient developed Epstein-Barr Virus with prolonged bone marrow hypoplasia.

Conclusion: Results of this second interim analysis suggest that a less intense regimen of alemtuzumab is feasible, effective, and safe for patients with refractory/relapse B-CLL after fludarabine therapy.