Originally published as JCO Early Release 10.1200/JCO.2008.21.1128 on July 13 2009

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Subcutaneous Alemtuzumab in Fludarabine-Refractory Chronic Lymphocytic Leukemia: Clinical Results and Prognostic Marker Analyses From the CLL2H Study of the German Chronic Lymphocytic Leukemia Study Group

From the Department of Internal Medicine III, University of Ulm, Ulm; Institute of Medical Statistics and Epidemiology, Technical University Munich, Munich; Department of Internal Medicine V, University of Heidelberg, Heidelberg; Department of Hematology, University Hospital Essen, Essen; Department of Internal Medicine I, University Medical Center Freiburg, Freiburg; Department of Medicine, Mannnheim University Hospital, Mannnheim; Department of Hematology and Oncology, University of Göttingen, Göttingen; Gemeinschaftspraxis, Kassel; Praxis Dr Schlag, Würzburg; Medical Clinic II, University Hospital Schleswig-Holstein, Kiel; and Clinic I of Internal Medicine, University of Cologne, Cologne, Germany; and Department of Internal Medicine I, Medical University of Vienna, Austria.

Corresponding author: Stephan Stilgenbauer, MD, Klinik für Innere Medizin III, Universitätsklinikum Ulm, Albert Einstein Allee 23, D-89081 Ulm, Germany; e-mail: stephan.stilgenbauer{at}uniklinik-ulm.de.

Purpose The phase II CLL2H trial evaluated safety and efficacy of subcutaneous alemtuzumab in patients with fludarabine-refractory chronic lymphocytic leukemia (CLL). Clinical and biologic markers were evaluated for their impacts on outcome.

Patients and Methods One hundred nine patients were enrolled, and 103 received at least one dose of alemtuzumab. After dose escalation, alemtuzumab was administered subcutaneously at 30 mg three times weekly for up to 12 weeks. Response was assessed every 4 weeks during treatment and quarterly thereafter.

Results The overall response rate was 34% (complete response, 4%; partial response, 30%). The median progression-free survival was 7.7 months, and the median overall survival (OS) was 19.1 months. Grades 3 to 4 neutropenia, thrombocytopenia, and anemia occurred in 56%, 57%, and 49% of patients, respectively. Grades 3 to 4 noncytomegalovirus and cytomegalovirus infections occurred in 29% and 8% of patients, respectively. Injection-site skin reactions were generally mild. Efficacy did not vary significantly in subgroups defined by genetic parameters (in particular, in 17p deletion, 11q deletion, mutated TP53, and unmutated VH), but efficacy was inferior in patients with increased β2-microglobulin (β2-MG) and thymidine kinase (TK). In multivariate analysis of clinical and biologic variables, age, performance status, β2-MG, and TK were independent prognostic factors for OS.

Conclusion Subcutaneous alemtuzumab appears as effective and safe as intravenous alemtuzumab in fludarabine-refractory CLL. Subcutaneous administration should be the preferred delivery route because of its efficacy, convenience, improved adverse effect profile, and cost savings. In contrast to chemotherapy-based therapy, alemtuzumab treatment overcomes the adverse prognostic impact of VH mutation status, TP53 mutation, and genomic aberrations.

Written on behalf of the German Chronic Lymphocytic Leukemia Study Group.

Supported by research grants from the Chronic Lymphocytic Leukemia Global Research Foundation; by Grant No. P20/07//A11/07 from Else Kröner-Fresenius Stiftung; by Grants No. R08/26f and R06/28v from Deutsche José Carreras Leukämie-Stiftung e.V.; by Bayer Schering Pharma AG, Berlin, Germany; and by Amgen, Munich, Germany.

Presented in part at the 49th Annual Meeting of the American Society of Hematology, Atlanta, GA, 2007; and at the 50th Annual Meeting of the American Society of Hematology, San Francisco, CA, 2008.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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