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Home , Bendamustine, Chlorambucil

Published OnlineFirst December 8, 2009; DOI: 10.1158/1078-0432.CCR-08-3041

CCR Drug Update

Bendamustine in B-Cell Malignancies: The New 46-Year-Old Kid on the Block Varsha Gandhi1,2 and Jan A. Burger2

Introduction former East German Democratic Republic (GDR) by Ozegowski and colleagues (2). In subsequent preclinical studies, benda- On March 20, 2008, HCl (Treanda, Cephalon, mustine (at that time called IMET3393) displayed encouraging Inc.) was approved by the U.S. Food and Drug Administration activities in hematopoietic , such as myeloma models. In (FDA) for treatment of chronic lymphocytic (CLL). 1971, bendamustine was introduced into the market as cytos- This approval was based on a randomized, multicenter trial tasan by the Volkseigener Betrieb/VEB (people-owned enter- n n comparing the test drug ( = 162) to ( = 157) prise) Jenapharm. Despite considerable activity in patients as a first line treatment (1). Overall response rates (ORR) were with CLL (3), Hodgkin's disease, mature B-cell , 68% and 31% for bendamustine and chlorambucil, respective- (4), and lung (5), cytostasan did ly, and were accompanied with an increased progression-free not become a broadly prescribed drug in the GDR (6). After survival (PFS) with bendamustine. the reunification of Germany in 1989, bendamustine was ac- About 6 months later, on October 31, 2008, bendamustine quired by Ribosepharm in 1993 and marketed as Ribomustin. was approved by the FDA for patients with indolent B-cell Three years later, in 1996, Ribosepharm became an operating non-Hodgkin's (NHL) that progressed during or unit of Klinge Pharma/Fujisawa Pharmaceutical Co., Ltd. In within 6 months of treatment with alone or in com- 2003, Salmedix Inc., a San Diego-based company, entered into n 3 bination ( = 100). This approval was based on a single arm a licensing agreement with Fujisawa Pharmaceutical to develop with an ORR of 74% with 9.2 months of duration this drug and gave a new name to bendamustine (SDX-105). In of response. 2005, Fujisawa Pharmaceutical merged with Yamanouchi Phar- maceutical Co., Ltd. to form Astellas Pharma, Inc. The German What Is Bendamustine? subsidiary (Astellas Deutschland GmbH, Munich) of the Tokyo-based Astellas Pharma Inc. was responsible for develop- Chemically, bendamustine is 4-{5-[bis(2-chloroethyl)amino]- ment of bendamustine in Europe. In October 2006, Mundiphar- 1-methyl-2-bezimidazolyl} butyric acid hydrochloride (Fig. 1). ma International Corp. Ltd. acquired exclusive development and Structurally, it contains three major moieties: first a 2-chloroethy- marketing rights for bendamustine from Astellas Deutschland lamine alkylating group, second a benzimidazole ring, and final- GmbH, Munich, Germany. Salmedix was responsible for intro- ly, a butyric acid side chain. Addition of the butyric acid side chain ducing bendamustine to the and was later (2005) results in water solubility. Functionally, the 2-chloroethyl group acquired by Cephalon, Inc., who now has the rights to develop N with a substituted amine group represents the -lost group of the bendamustine under the generic name of Treanda in the United family. The nitrogen mustard group, which is States and Canada. SymBio Pharmaceuticals Limited, a Japanese responsible for the alkylating action of the molecule, resembles company, acquired exclusive rights from Astellas Deutschland chlorambucil and (Fig. 1), the two most GmbH for the development and commercialization of benda- commonly used alkylating agents for treatment of CLL and mustine hydrochloride in Japan, China, Korea, Taiwan, and NHL. Bendamustine is chemically related to the alkylating agent Singapore. Cephalon, Mundipharma, and SymBio are actively chlorambucil with the benzene ring in the chlorambucil molecule pursuing clinical trials with bendamustine. replaced by a 1-methyl-benzimidazole nucleus. Metabolism and of Bendamustine: Revival of an Old Drug Bendamustine

Bendamustine originally was synthesized in 1963 at the Insti- Bendamustine undergoes extensive first-pass metabolism (7) tute for Microbiology and Experimental Therapy in Jena in the primarily in the by the action of the cytochrome p450 en- zyme complex. Yet, unmetabolized bendamustine accounts for

1 about 45% of the total drug recovered in the urine (7). Hydrox- Authors' Affiliations: Departments of Experimental Therapeutics and ylation of the alkylating group leads to formation of monohy- 2Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, Texas droxy- and dihydroxy-bendamustine, which are virtually Received 9/10/09; revised 10/2/09; accepted 10/6/09; published OnlineFirst inactive. Beta-oxidation of the butyric acid side chain produces 12/8/09. γ-hydroxy bendamustine (previously thought to be β-hydroxy), Grant support: Grant CA81534 and Lymphoma SPORE CA136411 from the which is an active metabolite (8). Further hydroxylation of this National Cancer Institute and US/European Alliance of CLL Global Research β Foundation (J.A. Burger, V. Gandhi). metabolite leads to hydroxy- -hydroxybendamustine (9). In Requests for reprints: Varsha Gandhi, Department of Experimental Thera- addition to hydroxylation, the benzimidazole ring can be peutics, Unit 71, The University of Texas M.D. Anderson Cancer Center, demethylated to form N-demethylbendamustine (8, 10). Houston, TX 77030. Phone: 713-792-2989; Fax: 713-794-4316; E-mail: vgandhi@ mdanderson.org. F 2009 American Association for Cancer Research. 3 FDA approval for bendamustine hydrochloride, 2009, http://www.cancer. doi:10.1158/1078-0432.CCR-08-3041 gov/cancertopics/druginfo/fda-bendamustine-hydrochloride.

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Bendamustine in B-cell Malignancies

Fig. 1. Structures of chlorambucil, cyclophosphamide, and bendamustine. Alkylating agent portion of the structure is shown in red.

Following intravenous (IV) administration, a high percentage and properties (13). The majority of the pub- (>95%) of the drug is bound to protein, primarily albumin lished literature suggests that bendamustine acts primarily as and only unbound bendamustine is active (11). The extent an alkylating agent and causes the formation of intrastrand of binding and formation of metabolites are different among and interstrand cross-links between DNA bases (14–16). This mice, rats, dogs, and humans, and hence extensive pharmaco- property directly inhibits DNA replication, repair, and transcrip- kinetic investigations are required to understand metabolism tion. Treatment with bendamustine also leads to disruption of of the drug in patients. the matrix function of DNA in DNA synthesis. There is some Peak plasma concentrations of bendamustine are dependent evidence that cross-linkage may also occur between DNA and on the dose. For example, concentrations of 0.1 to 30 μg/mL proteins and among proteins; however, these phenomena are are obtained at 30 to 200 mg/m2 dose range of the adminis- not clearly understood (17). tered drug. Elimination of bendamustine is rapid, with peak metabolite concentrations found in the urine 1 hour after ad- Is Bendamustine Different from Other Alkylating ministration. Elimination is biphasic with a half-life (t1/2α)of Agents? 6 to 10 minutes, and a terminal elimination half-life (t1/2β)of approximately 30 minutes. The central volume of distribution For leukemia and lymphomas, the most commonly used al- is 8.6 to 11.2 L following IV administration; under steady-state kylating agents are chlorambucil and cyclophosphamide, conditions, the volume of distribution is 15.8 to 20.5 L (12). whereas for myeloma, is the choice. When these es- Bendamustine is eliminated primarily by the renal route and tablished alkylating agents were compared with bendamustine therefore should not be given to patients in whom renal func- in the NCI 60-panel cell lines using COMPARE analyses, mel- tion is compromised (glomerular filtration rates <1.8 L/h). phalan, cyclophosphamide, and chlorambucil showed Pearson Similarly, as primary metabolism occurs in the liver, benda- correlation coefficient of >0.8 (>65% agreement) with several mustine is contraindicated in patients with severe hepatic alkylating agents, whereas bendamustine did not reach that val- damage. ue (16). There was also incomplete cross-resistance between bendamustine and other alkylating agents (15). These are lim- Mechanisms of Action of Bendamustine ited data but suggest additional and/or unique mechanisms of action of bendamustine. Bendamustine was originally synthesized with the intention When used in equitoxic concentrations, bendamustine in- of producing an anticancer agent that contained both alkylating duces more DNA double-strand breaks than other commonly

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CCR Drug Update used agents including melphalan, cyclophosphamide, and car- cycle for up to eight cycles. The ORR was 74% and median du- mustine (15). Following treatment with bendamustine, repair ration of remission was 9.2 months. Complete remissions were of damaged DNA is slow, compared with other alkylating reported in 13%, unconfirmed complete remissions in 4%, and agents (15). Bendamustine shows only partial cross-resistance partial remissions in 57% (Table 1). The most frequently re- with other alkylating agents, which is thought to be related to ported nonhematologic adverse reactions were (75%), the relatively slow repair rate associated with this agent. fatigue (57%), (40%), (37%), and pyrexia There have been postulates that the benzimidazole ring in (34%). Grade 3 or 4 adverse reactions were reported in 71%, bendamustine may act as an antimetabolite. Previous studies, the most frequently reported nonhematologic grade 3 or 4 ad- starting with the synthesis (2) and comparison with other nu- verse reactions were fatigue (11%), febrile (6%), cleoside analogs (18) have suggested that this ring may act as and pneumonia, hypokalemia, and dehydration (each reported purine analog. The chances, that a chemical addition of sugar to in 5% of patients). Grade 3 or 4 hematologic laboratory abnor- the benzimidazole ring followed by its phosphorylation to pro- malities were lymphocytopenia (94%), neutropenia (60%), duce a purine nucleotide analog would occur in vivo,areex- leukopenia (56%), (25%), and tremely slim. It is however, feasible that this ring may bind to (11%). Three patients died of myelosuppression-related adverse enzymes. Collectively, these observations underscore the need reactions; one each from neutropenic sepsis, diffuse alveolar for additional investigations to establish the mechanism of ac- hemorrhage with grade 3 thrombocytopenia, and pneumonia tion of bendamustine. from a cytomegalovirus infection. These data supported the FDA approval for patients with indolent NHL who are rituxi- Clinical Activity of Bendamustine mab-refractory and the recommended dose of bendamustine in NHL of 120 mg/m2 on days 1 and 2 of a 21-day cycle for Dose-finding studies. In early studies, the dosing of benda- up to eight cycles.3 mustine has been largely empiric; but with the more common Bendamustine combinations in indolent NHL. Over the last use of bendamustine in CLL and NHL patients over the last de- decade, combinations of with rituximab (R) R cade, it became obvious that bendamustine displays a rather such as -CHOP (cyclophosphamide, adriamycin, , R narrow therapeutic window, and that dosing depends upon ), -CVP (cyclophosphamide, vincristine, and pred- R the disease to be treated, and the intensity of prior treatments. nisone), and - have become the most commonly 2 used treatment approaches in newly diagnosed and relapsed Single dose administration defined 260 mg/m as the maxi- patients with indolent NHL (28, 29). At relapse, there is no mum tolerated dose, with cardiovascular dose-limiting toxici- standardized treatment approach, and the therapeutic options ties (19). Early studies in CLL and NHL patients used 2 2 range from low-intensity treatments, such as single agent ritux- bendamustine doses of 100 mg/m up to 120 mg/m on two imab, over radio-immunotherapy, chemotherapy with or with- consecutive days every 3 to 4 weeks (20, 21). Because fraction- out monoclonal antibodies, to more intensive approaches, such ated bendamustine administration generally was better tolerat- as high-dose chemotherapy with autologous or allogeneic stem ed, bendamustine given on two consecutive days every 3 to 4 cell transplantation. Because of the major impact of rituximab weeks has become the most widely used regimen (22). (30), bendamustine combinations with rituximab and/or che- Indolent NHL. Because of the early experience from the motherapy have been explored or are being investigated. 1970s, in which high remission rates with single-agent benda- In patients with relapsed indolent B-cell NHL or mantle cell mustine in front-line treatment of CLL and multiple myeloma lymphoma (MCL) without documented resistance to prior ri- were reported (5) and its particular toxicity toward B lympho- tuximab, rituximab 375 mg/m2 on day 1 and bendamustine cytes (23), mature B-cell malignancies became a major focus in 90 mg/m2 on days 2 and 3 of each 28-day cycle for four to the clinical development of bendamustine. A more recent Ger- six cycles was given. The authors reported an ORR of 92% with man study in relapsed or refractory patients with indolent NHL 41% complete remissions, 14% unconfirmed complete remis- reported an ORR of 73%, a complete remission rate of 11%, sions, and 38% partial remissions. Median duration of response and a median remission duration of 16 months, using benda- was 21 months and median PFS was 23 months (31). Similar mustine at 120 mg/m2 ondays1and2every3weeks(21). results were obtained with bendamustine at 90 mg/m2 on days Another study explored the activity of bendamustine given as 1 and 2 combined with 375 mg/m2 rituximab on day 1, for a 5-day cycles of daily 60 mg/m2 in pretreated patients with maximum of four cycles every 4 weeks in patients with relapsed indolent NHL with similar ORR, but the median duration of indolent B-cell NHL or MCL (32). Here, the ORR was 90% with response was 39 months for NHL and 17 months for multiple a complete remission rate of 60%. The median time of PFS was myeloma patients (Table 1; ref. 24). In high-grade NHL, bend- 24 months. In conclusion, the combination of bendamustine amustine was found to be active in relapsed and/or refractory and rituximab is a highly active regimen in relapsed and/or re- patients with an ORR of 44% (25). fractory lymphomas. A German cooperative group randomized A recent U.S. study in rituximab-refractory patients with in- trial compared R-CHOP with the combination of rituximab and dolent NHL explored bendamustine, given at 120 mg/m2 on bendamustine in patients with newly diagnosed, previously un- days 1 and 2 of a 21-day cycle for 6 to 12 cycles (26). Here, treated indolent and (33). The investiga- the authors reported an ORR of 77% with 15% complete remis- tors reported similar response rates in both arms, but lower sions, 19% unconfirmed complete remissions, and 43% partial rates of toxicities for the combination of rituximab and bend- remissions. Comparable data were presented from another amustine, such as alopecia (0% with B-R versus 89% CHOP-R), study in rituximab-refractory NHL patients (27), confirming numbers of infectious complications (25% in the B-R group that bendamustine displays significant activity in this patient versus 37% in CHOP-R group). Hematotoxicity also was less population. In this pivotal single arm, bendamustine was ad- common for the combination of rituximab and bendamustine ministered at 120 mg/m2 on days 1 and 2 of a 21-day treatment (33).

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Bendamustine in B-cell Malignancies

Table 1. Clinical trials of single agent bendamustine in NHL and CLL

Disease Dose mg/m2 No. Percentage ORR Percentage CR RD, mo Reference (days administered)

Rel/ref NHL 120 (d 1, 2) 52 73 11 16 21 Rel/ref NHL 60 (5-d) 77 82 15 39 22 Rel/ref NHL 120 (d 1, 2) 18 44 17 4.5 23 Ritux ref NHL 120 (d 1, 2) 76 77 15 6.7 24 Ritux ref NHL 120 (d 1, 2) 100 74 13 9.2 25 Rel/ref CLL 100 & up, (d 1, 2) 15 60 27 - 32 Rel/ref CLL 100 (d 1, 2) 21 66 29 - 33 Rel/ref CLL 50-60 (5-d) 20 75 30 - 34 Rel/ref CLL 70-100 (d 1, 2) 16 56 13 46 35 Untreated CLL 100 (d 1, 2) 162 68 31 22 1

Abbreviations: Rel, relapsed; ref, refractory; CR, complete remission; RD, response duration; ORR, overall response rate; d, days.

Chronic lymphocytic leukemia. The early trials were con- viewed in ref. 22). Trials of bendamustine as single agent or ducted in pretreated CLL patients, and several phase II studies in combinations are ongoing in myeloma and acute myeloge- indicated that bendamustine induces high response rates in nous leukemia. pretreated or refractory patients that ranged between 65 and Clinical conclusions. Current data indicate that bendamus- 93%, along with a favorable safety profile. Main toxicities were tine as a single agent or in combination with rituximab (BR), hematologic, whereas nonhematologic side effects generally is an effective salvage strategy for patients with CLL and in- were mild and rather uncommon. In these studies (Table 1), dolent B-cell NHL. The role of bendamustine in front-line 100 mg/m2 on days 1 and 2 every 3 weeks (34, 35) or 5-day treatment of these diseases however needs to be better de- cycles of daily 60 mg/m2 (or 50 mg/m2 in patients >70 years fined. In CLL, the recent data from Knauf and colleagues old) every 4 to 6 weeks were given (20, 24, 36). (1) could create a trend toward replacing chlorambucil and The recently reported pivotal European phase III multicenter other drugs used in front-line treatment of CLL with benda- trial compared the efficacy and tolerability of bendamustine mustine, which is not justified at this point. First, because of (100 mg/m2 on days 1 and 2 every 4 weeks) with that of chlor- chlorambucil's notoriously low response rates, it has increas- ambucil (0.8 mg/kg on days 1 and 14 every 4 weeks) in previ- ingly been replaced by fludarabine (F), fludarabine plus cy- ously untreated CLL patients. In a total of 319 patients, the clophosphamide (FC), or the combination of FCR. Trials authors showed that bendamustine induced significantly high- comparing bendamustine or BR with these regimens are on- er response rates and longer PFS than chlorambucil in first-line going or in planning, but data are not yet available. Com- therapy of CLL (1). The ORR was 68% in bendamustine-treated pared with single-agent bendamustine, the fludarabine-based and 31% in chlorambucil-treated patients. The complete remis- FC (38–40) or FCR (41, 42) regimens display higher remis- sion rate with bendamustine, compared with chlorambucil, sion rates and longer remission durations, and therefore we was 31% versus 2%. Bendamustine induced significantly longer will have to wait for the clinical results of bendamustine PFS (21.6 versus 8.3 months) and remission durations (21.8 containing regimes. versus 8.0 months). Grade 3 and 4 adverse events (40% versus Also, we know that response rates in CLL do not necessary 19%), and severe infections events (8% versus 3%) were more translate into improved PFS, remission durations, or overall common with bendamustine (1). These results were basis for survival, a theme that was reinforced by a recent phase III study the FDA approval of bendamustine in CLL and for the recom- comparing chlorambucil with fludarabine as a front-line treat- mended dose of 100 mg/m2 intravenously on days 1 and 2 of a ment for CLL patients older than 65 years. The authors ob- 28-day cycle for up to six cycles.3 served no differences in PFS, and a shorter overall survival in The German CLL study group (GCLLSG) investigated the fludarabine-treated patients (46 versus 64 months in the chlor- combination of bendamustine 70 mg/m2 on days 1 and 2 ambucil arm). Therefore, they concluded that in elderly CLL pa- in combination with rituximab at 375 mg in the first cycle tients first-line therapy with fludarabine does not result in a (and at 500 mg/m2 in subsequent cycles) in relapsed CLL major clinical benefit (43), although trial-inherent issues, such patients (37). In 62 evaluable patients, they noticed an as fludarabine dose reductions and lack of salvage treatment af- ORR 77.4% with CR in 14.5% and PR in 62.9%. Given these ter fludarabine failure explain, at least in part, the low efficacy encouraging results, the GCLLSG is now conducting a phase of fludarabine in this trial. A U.S. intergroup trial comparing III trial to compare immuno-chemotherapy with fludarabine, chlorambucil with fludarabine for initial treatment in CLL con- cyclophosphamide, and rituximab (FCR) to the combination cluded that fludarabine induces higher response rates and lon- of bendamustine and rituximab (BR) in previously untreated ger remission durations and PFS, but the overall survival for CLL patients. both treatments were the same (44). In contrast, younger CLL Bendamustine in other indications. Bendamustine displays patients (<70 years old) have an apparent clinical benefit from significant activity in other B-cell malignancies, such as multi- a regimen that induces high rates of remissions, such as FCR ple myeloma, aggressive B-cell lymphomas, and certain solid (42). In the indolent NHLs, the situation is similar: a longer tumors, such as breast cancer and small-cell (re- follow-up of the front-line trial (33) and subset analysis may

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CCR Drug Update help to better define the pros and cons of bendamustine-based patients (ongoing GCLLSG trial) will help us to better under- therapy, such as BR in the front-line setting when compared stand and compare the activity of bendamustine to other active with the established regimen. agents. Furthermore, once the front-line bendamustine data in CLL (1) and indolent NHLs (33) become more mature, we will Overall Conclusions be updated on how bendamustine impacts overall survival. Fi- nally, metabolism, pharmacokinetics, and detailed mechanistic Collectively, the clinical studies highlight that we first need studies of bendamustine are needed for its optimal dose and better definitions of patient subsets that are likely to benefit schedule and combination with other agents. Collectively, these from bendamustine or bendamustine combinations (BR), and issues will allow us to better define the most appropriate use of second, that we need to better define the clinical endpoints that bendamustine in CLL and other indolent B-cell malignancies. are our goal in treating patients with CLL and indolent NHLs, such as remission rates, survival, and quality of life. Third, side- Disclosure of Potential Conflicts of Interest by-side comparisons of bendamustine with commonly used front-line regimens, such as the FCR regimen in younger CLL V. Gandhi, commercial research grant, Cephalon, Inc.

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Bendamustine in B-cell Malignancies

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Bendamustine in B-Cell Malignancies: The New 46-Year-Old Kid on the Block

Varsha Gandhi and Jan A. Burger

Clin Cancer Res 2009;15:7456-7461. Published OnlineFirst December 8, 2009.

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