bendamustine is an anticancer drug , which has recently evolved as an important agent for a number of lymphoid malignancies in europe and the usa .
the drug consists of an alkylating nitrogen mustard group bound to a purine - like benzimidazole ring , and because of this unique bifunctional structure the bendamustine activity profile is significantly different from classical alkylators .
although the precise mechanism of action has not been elucidated yet , it is known that bendamustine induces dna cross - linking and dna breaks and induces cell death by apoptosis through intrinsic and extrinsic pathways , which in turn may deregulate the cell cycle and lead to a 
preclinical studies and clinical observations suggest that bendamustine has limited cross - resistance with other alkylating agents and demonstrates significant synergism with anti - cd20 monoclonal antibody rituximab and purine analogues [ 2 , 3 ] .
based on two multicentre randomised studies , bendamustine has received approval for second - line therapy in relapsed / refractory indolent non - hodgkin lymphoma ( nhl ) [ 4 , 5 ] .
a growing body of evidence suggests good efficacy and acceptable tolerability of bendamustine as the first - line option for indolent lymphoma , mantle cell lymphoma ( mcl ) and selected patients with aggressive lymphoma .
this review presents data for bendamustine use in first - line therapy of nhl , taken from all available relevant articles published in the years 20062013 , supplemented with abstracts from recent haematology and oncology scientific meetings .
a summary of available data , source publications and conference abstracts is presented in tables  1 and 2.table  1bendamustine in first - line treatment for indolent or mantle cell lymphoma  prospective studiesstudypatients ( n)diagnosisorr  % cr  % pfsrefbop versus cop prospective phase iiiherold 2006164fl , lpl , mcl66 versus 7622 versus 205  yrs : 59  % versus 46  % 
 8 
 br versus chopr prospective phase iiirummel 2013 stil study549fl , mcl , lpl , mzl , sll93 versus 9140 versus 3069.5 versus 31.2  months 
 9 
 br versus cvpr or chopr prospective phase iiiflinn 2012 bright study436indolent , mcl94 versus 8431 versus 25 
 10 
 br prospective phase iiluminari 201369mzl , sll , lpl84581  yrs : 90  % 
 14 
 br  +  cytarabine prospective phase iivisco 201320mcl100952  yrs : 95  % 
 19 
 ribvd ( br  +  bortezomib  +  dexamethasone ) prospective phase iigressin 2013 lysa study76 elderlymcl8760 
 22 
 br  +  lenalidomide prospective phase i 
iijerkeman 201351mcl9779not reached in 18-month follow - up 
 21 
 br  +  r maintenance prospective phase iirummel 2012162lpl86 
 9 , 12 
 br prospective phase iisalar 201260malt10098 
 13 
 b  +  ofatumumab prospective phase iifowler 201249indolent9860 
 17 
 br  +  mitoxantrone prospective phase iiboccomini 201276 elderlyfl9675 
 16 

br  +  bortezomib prospective phase iiflinn 201255indolent8947 
 15 
 b  +  ofatumumab  +  dexamethasone prospective ii phasemagni 201219 elderlymcl9489 
 20 

 b ; bendamustine , br ; bendamustine  +  rituximab , bop ; bendamustine  +  vincristine  +  prednisone , cop ; cyclophosphamide  +  vincristine  +  prednisone , cvpr ; cyclophosphamide  +  vincristine  +  prednisone  +  rituximab , chopr ; cyclophosphamide  +  doxorubicin  +  vincristine  +  prednisone  +  rituximab , ribvd ; rituximab  +  bendamustine  +  bortezomib  +  dexamethasone , fl ; follicular lymphoma , lpl ; lymphoplasmacytic lymphoma , mcl ; mantle cell lymphoma , mzl ; marginal zone lymphoma , sll ; small lymphocytic lymphoma , malt ; mucosa - associated lymphoid tissue , orr ; overall response rate , cr ; complete remission , pfs ; progression - free survival , ref ; reference , yrs ; yearstable  2bendamustine in first - line treatment for aggressive lymphomastudypatients ( n ) , diagnosisorr  % cr  % pfs monthsos monthsrefbr , retrospectivehorn 201220 , dlbcl , elderly55208.319.4 
 25 
 br , retrospectivekuntz 201015 , dlbcl463314.123.1 
 27 
 br , retrospectivehammersen 201321 dlbcl mcl9114824 
 28 
 br , retrospectivewalter 201215 ,
dlbcl623869 
 26 
 br , prospective phase iiweidmann 201114 , dlbcl , mcl elderly69547.77.7 
 24 
 br prospective phase iipark 201323 , dlbcl , elderly93609.9 
 29 

 br ; bendamustine  +  rituximab , dlbcl ; diffuse large b - cell lymphoma , mcl ; mantle cell lymphoma , orr ; overall response rate , cr ; complete remission , pfs ; progression - free survival , os ; overall survival , ref ; reference bendamustine in first - line treatment for indolent or mantle cell lymphoma  prospective studies 
 b ; bendamustine , br ; bendamustine  +  rituximab , bop ; bendamustine  +  vincristine  +  prednisone , cop ; cyclophosphamide  +  vincristine  +  prednisone , cvpr ; cyclophosphamide  +  vincristine  +  prednisone  +  rituximab , chopr ; cyclophosphamide  +  doxorubicin  +  vincristine  +  prednisone  +  rituximab , ribvd ; rituximab  +  bendamustine  +  bortezomib  +  dexamethasone , fl ; follicular lymphoma , lpl ; lymphoplasmacytic lymphoma , mcl ; mantle cell lymphoma , mzl ; marginal zone lymphoma , sll ; small lymphocytic lymphoma , malt ; mucosa - associated lymphoid tissue , orr ; overall response rate , cr ; complete remission , pfs ; progression - free survival , ref ; reference , yrs ; years bendamustine in first - line treatment for aggressive lymphoma 
 br ; bendamustine  +  rituximab , dlbcl ; diffuse large b - cell lymphoma , mcl ; mantle cell lymphoma , orr ; overall response rate , cr ; complete remission , pfs ; progression - free survival , os ; overall survival , ref ; reference
low - grade lymphoma , considered as an incurable disease , represents about 40  % of all nhls .
rituximab in combination with chemotherapy , usually a chop ( cyclophosphamide , doxorubicin , vincristine , prednisone ) regimen , is a standard first - line treatment , especially in follicular lymphoma subset .
encouraging results of bendamustine in relapsed or refractory indolent nhl have drawn attention to the first - line use of the drug in this setting .
german haematology outpatient centres have reported a continuous increase in the use of bendamustine in combination with rituximab ( br ) as upfront therapy in patients with indolent nhl , despite no european medicines agency ( ema ) approval for this indication .
the first randomised study evaluating the effectiveness of bendamustine in treatment - naive indolent lymphoma patients was published in 2006 . the drug ( bendamustine ) , in combination with vincristine and prednisone ( bop ) ,
was compared with a cop ( cyclophosphamide , vincristine , prednisone ) regimen in 164 patients with follicular lymphoma , mcl and lymphoplasmacytic lymphoma ( lpl ) .
there were no statistically significant differences between groups with respect to overall response rate ( orr ) ( bop vs. cop : 66 vs. 76  % ; p  =  0.1 ) and overall survival ( bop vs. cop : 61 vs. 46  % ; p  =  0.2 ) .
the median time to progression was significantly longer in bop responders ( 84  months ) than in those who responded to the cop regimen ( 28  months ) , p  =  0.0369 , which translated into the probability of 5-year progression - free survival ( pfs ) as 59  % versus 46  % , respectively .
additionally , both haematological and non - haematological complications were less common and less severe in the bop group than in the cop group ( table  3).table  3haematological and non - haematological toxicity of bendamustine - based regimensstudypatients diagnosishaematological toxicity % grade 34non - haematological toxicity % grade 34refbop versus cop prospective phase iiiherold 2006164anaemia10 versus 13alopecia4 versus 48 
 8 
 fl , lplthrombocytopenia19 versus 34vomiting0 versus 1mclleucopenia4 versus 1neuropathy1 versus 0br versus chopr prospective phase iiirummel 2013 stil study549anaemia3 versus 5alopecia*0 versus 100 
 9 
 fl , lplleucopenia37 versus 72neuropathy*7 versus 29mzl , sll , mclthrombocytopenia5 versus 6infection*37 versus 50br versus cvpr or chopr prospective phase iiiflinn 2012 bright study436anaemia*5 versus 5alopecia*4 versus 51 
 10 
 indolentleucopenia*39 versus 87vomiting*29 versus 13mclthrombocytopenia*10 versus 12neuropathy*14 versus 44infection*55 versus 57ribvd prospective phase iigressin 201376anaemia2fatigue5 
 22 
 mclneutropenia21diarrhoea8elderlythrombocytopenia15neuropathy4 *  all grades haematological and non - haematological toxicity of bendamustine - based regimens more recently , an important phase iii study comparing bendamustine with rituximab ( br ) to chopr ( cyclophosphamide , doxorubicine , vincristine , prednisone , rituximab ) regimen was presented . following
the treatment for 549 patients with indolent or mcl , orr was similar for br and chopr groups ( 93 vs. 91  % ) , complete remission ( cr ) was significantly increased in the br group ( 40 vs. 30  % , p  =  0.021 ) and pfs was significantly longer in the br group ( 69.5 vs. 31.2  months , p  <  0.0001 ) .
another randomised study compared results of br therapy with cvpr ( cyclophosphamide , vincristine , prednisone , rituximab ) or chopr in the treatment for 436 patients with indolent nhl or mcl [ 10 , 11 ] .
orr was 94  % after br in comparison with 84  % after cvpr or chopr regimen , and cr rate was higher for the br group ( 31 vs. 25  % , p  =  0.0225 ) .
analysis indicated that adverse reactions were reported for both br and cvpr or chopr therapy ( table  3 ) .
subgroup analysis for indolent lymphoma ( mcl excluded ) , revealed similar results with respect to cr rate for br and cvpr or chopr regimens ( 28 vs. 25  % ) .
br is effective in the treatment for patients with lpl , as was seen in the stil study and confirmed by rummel in a phase ii trial with 86  % of orr , where br therapy was followed by rituximab maintenance therapy [ 9 , 12 ] .
another subgroup of nhl patients with mucosa - associated lymphoid tissue ( malt ) lymphoma , treated in a spanish study with br , achieved 98  % cr rate , and overall response was observed in 100  % .
a number of ongoing and recently finished clinical trials investigating bendamustine in combination with other drugs ( mitoxantrone , lenalidomide , bortezomib ) reveal promising orr and cr in the indolent lymphoma setting [ 1317 ] .
these results translate into prolonged progression - free survival , which today is considered a treatment success in low - grade nhl patients .
bendamustine has not yet been approved as a first - line therapy of nhl in europe , but as the preliminary reports on its use in treatment - nave patients are encouraging , there are an increasing number of centres using bendamustine as a compassionate drug [ 7 , 18 ] .
a retrospective multicentre analysis of the spanish registry of indolent nhl patients revealed high effectiveness , with an orr of 95  % and cr of 66.5  % , and favourable tolerance profile of br regimen in newly diagnosed indolent lymphoma patients .
young and fit patients are usually treated with intensive therapy followed by autologous stem cell transplantation .
a growing body of data indicates a high response rate after bendamustine in patients with mcl , not only in rescue therapy but also as upfront treatment . in a phase ii study with bendamustine in combination with cytarabine and rituximab in untreated mcl patients ,
subgroup analysis of prospective , randomised studies has also shown superiority of br regimen in comparison to chopr - like treatment .
the cr rate in the bright study was 27  % for br versus 50  % for chopr or cvpr regimen , and pfs ( progression - free survival ) in the stil study for br was 35.4  months versus 22.1  months for chopr ( p  =  0.0044 ) .
ongoing clinical studies are evaluating bendamustine in combination with lenalidomide , ibrutinib , temsirolimus or ofatumumab in mcl therapy [ 2022 ] .
preliminary results from the lysa trial , including 76 elderly patients newly diagnosed with mcl , indicated that 4 cycles of rituximab , bendamustine , bortezomib , dexamethasone ( rivbd ) yielded 87  % orr rate and 60  % cr rate .
fifty - one elderly patients ( > 65  years ) with previously untreated mcl grade ii 
following six cycles of the treatment , the orr was 97  % , cr was 79  % and os after 2  years amounted to 87  % .
the results of clinical studies published thus far , assessing the use of bendamustine in upfront treatment for mcl , seem to indicate a risk - stratified approach , based on the mcl international prognostic index ( mipi ) .
bendamustine in combination with rituximab could be recommended as a first - line therapy in elderly mcl patients with high or intermediate mipi risk .
the combination of rituximab and cyclophosphamide , doxorubicin , vincristine and prednisone is the standard first - line treatment regimen in patients with diffuse large b - cell lymphoma ( dlbcl ) ; however , the available data do not apply to elderly or frail patients .
only a few smaller studies have investigated the role of bendamustine in this setting . a phase ii study demonstrated a cr rate of 54  % in elderly patients treated with br as first - line therapy with a good safety profile .
results are acceptable and manageable for toxicity ; however , they seem to be generally unacceptable for pfs and overall survival [ 2527 ] .
defining prognostic factors as gcb - subtype of dlbcl might predict a better outcome in bendamustine treated patients .
performance and comorbidity assessment have a great impact on the outcome of frail patients with aggressive lymphoma .
the clinical studies published so far have reported fairly low or mild toxicity of bendamustine - containing regimens .
the adverse events ( ae ) observed in lymphoma patients treated with bendamustine are summarised in table  3 . in general
, bendamustine seems to present a favourable toxicity profile , and the most common complications involve haematological events such as anaemia , leucopenia , neutropenia or thrombocytopenia . despite being reversible ,
these toxicities are common , with as much as a 94  % occurrence rate for all grade events .
the most frequently reported non - haematological toxicities related to bendamustine treatment include nausea , infections , fatigue , constipation , diarrhoea , headache and vomiting . a multicentre phase iii clinical trial comparing first - line br versus chopr revealed a much lower rate of serious ae in the br arm than in chopr treated patients ( 49 vs. 74 ) . moreover , a granulocyte colony - stimulating factor ( g - csf ) was used only in 4  % of the patients receiving br and in 20  % of those receiving chopr treatment .
similarly , non - haematological aes were of lower grade or incidence in the br group than in the chopr arm .
a meta - analysis of randomised , controlled trials comparing the bendamustine - containing regimen to any other regimen demonstrated no effect of bendamustine on the rate of infection when compared to either alkylating agents or fludarabine in haematological , as well as in solid , malignancies despite , remarkably , lymphopenia .
a few case studies were published reporting on the safety and effectiveness of the br regimen in dlbcl patients with severe liver impairment .
low toxicity of bendamustine , even in these unfavourable settings , makes the drug safe and effective in special patient populations .
the exact mechanism behind bendamustine s low toxicity remains not fully understood , and additional basic research aimed at its elucidation is required .
it also seems advisable to assess long - term bendamustine toxicity and its potential interactions with other second - line treatments .
increasing interest in bendamustine as an upfront therapy has prompted a cost - effectiveness analysis of this drug . when compared to chopr or cvpr regimens ,
the br was found to be cost - effective , and due to its more favourable toxicity profile it incurred lower costs related to ae management .
the remarkably low toxicity profile and high efficacy of bendamustine provide a basis for the use of this drug in the treatment for a variety of lymphoma subsets .
recent preclinical data and clinical studies have confirmed the activity of bendamustine in heavily pretreated patients with hodgkin lymphoma or peripheral t - cell lymphoma .
the efficacy of bendamustine has been evaluated in treatment for multiple myeloma , with encouraging results [ 35 , 36 ] .
these impressive observations may lead to the design of prospective trials evaluating bendamustine in upfront therapy in selected patients in these settings .
it was demonstrated that bendamustine provided clinical benefits when combined with other agents , i.e. monoclonal antibodies , purine analogues or more modern drugs such as lenalidomide , bortezomib , ibrutinib or idelalisib .
there are a number of clinical trials , expected to be completed in 2014 and 2015 , that are assessing the dose - limited toxicity and maximum tolerated dose of bendamustine in combination with those and other drugs .
 recently , bendamustine has become an important agent in the treatment for patients with lymphoid malignancies . 
 although the drug has received approval for second - line therapy in indolent lymphoma , a growing body of evidence suggests its efficacy and safety in first - line use . 
 the results of randomised and observational studies with bendamustine as front - line therapy in non - hodgkin lymphoma ( nhl ) with emphasis on efficacy and toxicity are presented . 
 furthermore , completed and ongoing clinical trials evaluating upfront bendamustine effectiveness in combination with other agents are discussed . 
 the review refers mainly to indolent lymphoma , mantle cell lymphoma and aggressive lymphoma , as the most commonly diagnosed nhl types . 
 finally , we elaborated on the safety profile of bendamustine and the perspectives of using the drug as a first - line therapy . 
Introduction
Indolent lymphoma
Mantle cell lymphoma
Aggressive lymphoma
Bendamustine safety profile
Perspectives