A ae August 2011 www.clinicaladvances.com Volume 9, Issue 8, Supplement 19 Moderator Bruce D. Cheson, MD Deputy Chief Division of Hematology-Oncology Head of Hematology Lombardi Comprehensive Bendamustine: Mechanism Cancer Center Georgetown University Hospital of Action and Clinical Data Washington, DC Discussant Lorenzo Leoni, PhD Actus Advisory Abstract Lugano, Switzerland Bendamustine is a chemotherapeutic agent that displays a unique pattern of cytotoxicity compared with conventional alkylating agents. Bendamustine was originally synthesized in the former East German Democratic Republic in the 1960s. It was designed to have both alkylating and antimetabolite properties. The alkylating agent properties are similar to those seen with cyclophosphamide, chlorambucil, and melphalan, and the benzimidazole ring is similar to cladribine. Molecular analyses have revealed that bendamustine differs from other alkylating agents in its mechanism of action. Differences have been observed in regard to its effects on DNA repair and cell cycle progression. Moreover, bendamustine can induce cell death through both apoptotic and nonapoptotic pathways, thereby retaining activity even in cells without a functional apoptotic pathway. Bendamustine has demonstrated significant efficacy in patients with indolent lymphomas and chronic lymphocytic leukemia (CLL), including in patients with disease refractory to conventional alkylating agents and rituximab. The toxicity profile of bendamustine is also superior to that of conventional alkylating agents. Combination therapy with bendamustine and rituximab has demonstrated superior efficacy to a standard rituximab-containing chemotherapy regimen in patients with previously untreated indolent B-cell non-Hodgkin lymphoma, and it is currently being compared against the standard first-line regimen in CLL: fludarabine, cyclophosphamide, and rituximab. Ongoing and planned studies are evaluating new strategies in which bendamustine is being combined with existing agents and with novel therapies to optimize use in different clinical settings. Supported through funding from Cephalon, Inc. C l I n ica l r O u n D t ab l e mo n O g r A p H Introduction to Bendamustine Bruce D. Cheson, MD endamustine could be considered either the reductions, hair loss, infertility, and secondary malignan- newest “old” drug or the oldest “new” drug that cies. Thus, the interest in developing another alkylating we have for the treatment of hematologic malig- agent was tepid, at best. However, molecular studies have Bnancies. It was initially synthesized in the 1960s at the revealed that bendamustine has a pattern of activity that Institute for Microbiology and Experimental Therapy in differs from other DNA alkylating agents. Bendamustine Jena in the former East German Democratic Republic. It activates the DNA-damage stress response, induces apop- was intended to be a less expensive form of other effective tosis, inhibits mitotic checkpoints, and induces mitotic drugs available at the time, such as cyclophosphamide. catastrophe. Moreover, bendamustine differs from other Bendamustine was designed to have both alkylating alkylators in the type of DNA repair pathways activated. and antimetabolite properties and to have an acceptable Together, these differences may explain the efficacy of toxicity profile. It has demonstrated efficacy in multiple bendamustine observed in a variety of clinical settings. types of non-Hodgkin lymphoma (NHL) and in chronic In the United States, the development program for lymphocytic leukemia (CLL), including in patients whose bendamustine began in the early 2000s, when Salmedix, disease is refractory to conventional alkylator chemo- Inc., acquired the rights to the agent in North America therapeutic agents. from the German company Ribosepharm. After a series The alkylating properties of bendamustine are similar of clinical trials demonstrated the safety and efficacy of to those in the nitrogen mustard family alkylators, such bendamustine, the agent was rapidly approved by the as cyclophosphamide, chlorambucil, and melphalan, US Food and Drug Administration (FDA). In 2008, and the butyric acid side chain is like that found in chlo- bendamustine was approved for use in patients with rambucil.1 Alkylating agents have been in existence for CLL and in patients with indolent B-cell NHL that has decades, beginning with the use of nitrogen mustard in progressed during or within 6 months of treatment with chemical warfare in World Wars I and II. People exposed rituximab or a rituximab-containing regimen.2 to the agent developed skin alterations, blindness, lung In this clinical roundtable monograph, Dr. Lorenzo damage, nausea, and vomiting. Nitrogen mustard was Leoni will examine the molecular characteristics of found to be mutagenic and carcinogenic, and accidental bendamustine, with a focus on the ways it does and exposure led to lowering of white blood cell counts. This does not act as a typical alkylating agent. I will examine observation suggested that the agent might have a similar the clinical trial data of bendamustine in indolent lym- effect on cancer cells. The first intravenous treatment of phoma and CLL. lymphoma with nitrogen mustard, administered in the 1940s, yielded impressive, albeit brief, results.1 These observations led to the subsequent development of other References alkylating agents, which remain a prominent component 1. Leoni LM, Bailey B, Reifert J, et al. Bendamustine (Treanda) displays a distinct of chemotherapeutic regimens for lymphoprolifera- pattern of cytotoxicity and unique mechanistic features compared with other alkyl- tive disorders. The alkylating agents are associated with ating agents. Clin Cancer Res. 2008;154:309-217. 2. Treanda (bendamustine HCl) prescribing information. Frazer, PA: Cephalon, toxicities including nausea and vomiting, blood count Inc. Revised July 2010. Disclaimer Funding for this clinical roundtable monograph has been provided through a grant from Cephalon, Inc. Support of this monograph does not imply the supporter’s agreement with the views expressed herein. Every effort has been made to ensure that drug usage and other information are presented accurately; however, the ultimate responsibility rests with the prescribing physician. Millennium Medical Publishing, Inc., the supporter, and the participants shall not be held responsible for errors or for any consequences arising from the use of information contained herein. Readers are strongly urged to consult any relevant primary literature. No claims or endorsements are made for any drug or compound at present under clinical investigation. ©2010 Millennium Medical Publishing, Inc., 611 Broadway, Suite 310, New York, NY 10012. Printed in the USA. All rights reserved, includ- ing the right of reproduction, in whole or in part, in any form. 2 Clinical Advances in Hematology & Oncology Volume 9, Issue 8, Supplement 19 August 2011 C l I n ica l r O u n D t ab l e mo n O g r A p H The Alkylating Properties of Bendamustine Lorenzo Leoni, PhD lkylating agents, including the nitrogen mustards mustard family alkylators, and the butyric acid side chain cyclophosphamide, chlorambucil, and melpha- is shared by chlorambucil. However, it has been proposed lan, as well as bendamustine, exert cytotoxic that the benzimidazole ring system, which is unique to Aeffects primarily through their effects on DNA. The first bendamustine, may provide enhanced antitumor activ- mechanism by which nitrogen mustards induce DNA ity.1 The heterocyclic ring structure could allow benda- damage is alkylation, a process in which an alkyl group mustine to better penetrate and localize within DNA is added to a DNA residue. Some agents may show some and remain there for a longer period of time. This could degree of sequence selectivity for the alkylation, although explain the unique activity of bendamustine compared this has not yet been determined for bendamustine. This with cyclophosphamide, chlorambucil, and melphalan. linkage between the highly reactive nitrogen mustard This hypothesis may soon be verified by ongoing studies residue and the DNA is damaging to the DNA, and quantifying the effects of bendamustine on DNA. induces a number of signaling pathways involved in DNA In vitro studies have revealed differences in the damage repair. nature of DNA strand breaks caused by bendamustine DNA damage is a normal process that occurs on a versus conventional alkylators. Studies in human ovarian regular basis in every cell in the body, and it is usually and breast cancer cell lines have shown that bendamus- resolved through effective mechanisms of DNA repair. tine induces more DNA double-strand breaks than other However, DNA repair mechanisms cannot overcome alkylating agents, including melphalan, cyclophospha- the superpharmacologic damage induced by antitumor mide, and carmustine.2 Moreover, the DNA double- agents. Because cells cannot recover from this damage, strand breaks induced by bendamustine persist longer they initiate programmed cell death through apoptosis. than those induced by other alkylating agents.2 Another mechanism by which alkylating agents induce The more extensive and more durable DNA breaks DNA damage is by cross-linking strands of DNA, creat- induced by bendamustine may reflect a difference in the ing links both between strands (interstrand cross-linking) way bendamustine acts on the DNA, or they may suggest and within strands (intrastrand cross-linking). Both that bendamustine exerts effects on DNA repair mecha- alkylation