Originally published as JCO Early Release 10.1200/JCO.2008.20.8389 on August 3 2009

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Phase III Randomized Study of Bendamustine Compared With Chlorambucil in Previously Untreated Patients With Chronic Lymphocytic Leukemia

From the Department of Hematology/Oncology, Onkologische Praxis, Frankfurt; Onkologische Gemeinschaftspraxis, Leipzig; Onkologische Schwerpunktpraxis, Minden; Department of Hematology, University Hospital, Jena; DSH Statistical Services, Rohrbach; Oncology Consulting, Miesbach, Germany; Hematology & Transfusion Medicine, National Hematological Center, Sofia; Department of Hematology, University Hospital, Varna; Department of Hematology, University Hospital, Plovdiv, Bulgaria; Department of Oncology, Universita degli Studi, Perugia; Ematologia, Ospedale Niguarda Ca'Granda, Milano; Dip. Ematologia, Universita "La Sapienza," Roma, Italy; Department of Hematology, Hopital de la Princesa, Madrid, Spain; Hematology & Oncology, Hopital Universitaire Hautepierre, Strasbourg; Department of Hematology, Hopital Purpan, Toulouse, France; Department of Hematology, University Hospital, Lund, Sweden; Ludwig Boltzmann Institute–Applied Cancer Research and Applied Cancer Research–Institute for Translational Research VIEnna Kaiser Franz Josef-Spital, Vienna, Austria; and the Cephalon Research Data Management & Programming, Frazer, PA.

Corresponding author: Wolfgang Knauf, MD, PhD, Onkologische Gemeinschaftspraxis, Frankfurter Diakonie Kliniken, Im Pruefling 17-19, 60389 Frankfurt, Germany; e-mail: wolfgang.knauf{at}telemed.de.

Purpose This randomized, open-label, parallel-group, multicenter study was designed to compare the efficacy and safety of bendamustine and chlorambucil in previously untreated patients with advanced (Binet stage B or C) chronic lymphocytic leukemia (CLL).

Patients and Methods Patients ( 75 years of age) were randomly assigned to receive bendamustine 100 mg/m²/d intravenously on days 1 to 2, or chlorambucil 0.8 mg/kg (Broca's normal weight) orally on days 1 and 15; treatment cycles were repeated every 4 weeks for a maximum of six cycles. The response to treatment was assessed according to National Cancer Institute Working Group criteria, and the final determination of response was made by a blinded independent review committee.

Results A total of 319 patients were randomly assigned (162 bendamustine, 157 chlorambucil). Complete or partial responses were achieved in 110 (68%) of 162 bendamustine-treated and 48 (31%) of 157 chlorambucil-treated patients (P < .0001). More patients showed complete responses with bendamustine than with chlorambucil (31% v 2%). Median progression-free survival was 21.6 months with bendamustine and 8.3 months with chlorambucil (P < .0001). Bendamustine was also associated with an improvement in duration of remission, compared with chlorambucil (median, 21.8 v 8.0 months). Hematologic National Cancer Institute Common Toxicity Criteria grade 3 to 4 adverse events were more common with bendamustine than with chlorambucil (occurring in 40% v 19% of patients). Severe infections (grade 3 to 4) occurred in 8% of bendamustine-treated patients and 3% of chlorambucil-treated patients.

Conclusion Bendamustine offers significantly greater efficacy than chlorambucil, and a manageable toxicity profile, when used as first-line therapy in patients with advanced CLL.

Supported by grants from Ribosepharm GmbH, Germany. and Mundipharma International, United Kingdom.

Presented in part at the Annual Meeting of the American Society of Hematology, Atlanta, GA, December 6-9, 2008, and San Francisco, CA, December 8-11, 2007.

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

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