Clinical Experience With Bendamustine: New Treatment for Patients With CLL

Abstract and Introduction

Abstract

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world, primarily affecting patients aged > 60 years. Because of the lack of curative therapies and the increasing prevalence of comorbid conditions in this older population, it is imperative that effective and tolerable agents be developed for patients with CLL. Although the exact mechanism of action has not been fully elucidated, bendamustine is an alkylator that appears to be structurally and mechanistically distinct from agents historically used in CLL treatment. Bendamustine induces extensive and durable double-stranded DNA breaks that result in initiation of the p53-dependent stress response and apoptosis. In addition, although most DNA alkylators target an alkyltransferase DNA-repair mechanism, bendamustine activates a base-excision DNA-repair pathway; this might partially explain bendamustine's activity in relapsed/refractory disease. Preclinical studies indicate that bendamustine and rituximab synergistically inhibit tumor growth and induce apoptosis in non-Hodgkin lymphoma and CLL disease models. Despite bendamustine's availability in Europe for 4 decades, the available clinical data shed little light on its role in the treatment of CLL. Adverse effects include myelosuppression and gastrointestinal complaints. In a recent phase III trial of previously untreated patients with CLL, bendamustine produced superior response rates and progression-free survival compared with chlorambucil, leading to its approval by the US Food and Drug Administration.

Introduction

Chronic lymphocytic leukemia (CLL) is the most common form of adult leukemia, estimated to comprise over one third of all new leukemia cases.^[1] The American Cancer Society estimates that in 2008, 15,110 new cases of CLL will be diagnosed and 4390 CLL-related deaths will be recorded. This disease occurs predominantly in older patients, with a median age at diagnosis of 72 years.^[2]

The current approach to CLL treatment focuses on reducing tumor bulk and associated symptoms while maintaining an acceptable quality of life.^[3] The strategy of disease management is determined by the stage and activity of disease, as well as the presence of symptoms. Historically, initial therapy has been alkylator based (eg, chlorambucil with or without prednisone).^[4] The introduction of purine analogues such as fludarabine and pentostatin has resulted in increased response rates but has not significantly improved overall survival (OS).^[5] Current recommendations for first-line treatment typically involve the combination of a purine analogue (fludarabine, pentostatin, or cladribine) and/or an alkylator (chlorambucil or cyclophosphamide) with rituximab.^[6,7] For previously untreated patients, the regimen with the best results reported to date combines fludarabine, cyclophosphamide, and rituximab (FCR), resulting in an overall remission rate of 95% and a complete remission rate of 70%. These high remission rates might translate into improved OS.^[8]

The efficacy of FCR has also been demonstrated as second-line therapy for fludarabine-refractory recurrent disease.^[9]

Regardless of the efficacy of initial treatment, however, most patients relapse, and prognosis is particularly poor for patients with rapidly relapsing disease. A retrospective review of patients with fludarabine-refractory CLL demonstrated a 22% response rate with the first salvage treatment, with a median survival of 10 months.^[10] A 33% response rate has been observed in a prospective evaluation of alkylator-pretreated, fludarabine-refractory population treated with alemtuzumab.^[11] Treatment options for patients with disease progression are similar to those available as initial therapy, although the determination of a second-line therapeutic strategy takes into account the duration of remission, as well as the initial therapeutic agents used.^[6] Because CLL predominantly affects older patients who are more likely to have comorbid conditions, well-tolerated agents are needed for newly diagnosed and relapsed/refractory disease.^[9]

Bendamustine HCl is an alkylating agent originally synthesized in 1963 in the German Democratic Republic with the intent to produce an agent with both alkylating and antimetabolite properties.^[12] It was formerly marketed in Germany under the trade name Cytostasan by Jenapharm (1971-1992) and is now marketed in that country as Ribomustin® by Mundipharma Deutschland, through a licensing agreement with Astellas Deutschland GmbH. Bendamustine is widely used in Germany to treat CLL,^{[13,14,15,16,17]} non-Hodgkin lymphoma (NHL),^{[18,19,20,21,22]} and multiple myeloma (MM).^[23,24] Unfortunately, most of the data supporting the use of bendamustine for these indications have been limited to case series and small studies, the methodology of which has been criticized.

In North America, bendamustine was approved by the US Food and Drug Administration (FDA) in March 2008 for the treatment of patients with CLL. There are no trials currently ongoing or recently completed in CLL in the United States. However, studies of bendamustine as a single agent and in combination with other agents such as rituximab are being developed. This review will describe the current understanding of bendamustine's mechanism of action and pharmacokinetic profile and discuss the efficacy and safety data available to date in both the United States and the European Union.

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