non - hodgkin s lymphoma ( nhl ) accounts for approximately 3%4% of all cancers worldwide.1 nhl is a growing problem , with the global prevalence projected to rise to more than 0.4 million in 2016 , and estimates suggest that approximately half of new nhl cases will result in death.2 follicular lymphoma ( fl ) is the second most common type of nhl and accounts for 10%20% of all lymphomas.3 the most ubiquitous indolent lymphoma , fl is typically diagnosed in individuals 5560 years of age and is slightly more prevalent in females.3 fl is characterized by painless swelling in several lymph node sites , with bone marrow involvement in approximately 70% of cases.4 approximately 19% of patients present with  b symptoms  , such as fever , weight loss , or night sweats , at the time of diagnosis.3,4 fl predominantly originates from b lymphocytes .
cd20 is a b - cell - specific antigen expressed on both malignant b cells , including fl and healthy cells , and is involved in the proliferation and differentiation of normal b cells.5 as such , targeting cd20 is an optimal therapeutic strategy and plays a central role in the treatment of fl .
rituximab ( rituxan ; genentech , south san francisco , ca , usa / mabthera ; roche , basel , switzerland ) is a chimeric anti - cd20 monoclonal antibody that binds specifically to cd20.6,7 in addition to its role in the treatment of diffuse large b - cell lymphoma ( dlbcl ) in the first - line or relapsed / refractory settings , rituximab is also approved for use in fl as a single agent or in combination with first - line chemotherapy.6,7 given the importance of rituximab across the spectrum of fl treatment and the evolving therapeutic landscape with the emergence of novel agents , the role of rituximab in the future management of fl is described .
the role of rituximab biosimilars in the future of fl treatment and how the introduction of biosimilars can help to relieve this lack of access are also discussed .
the national comprehensive cancer network ( nccn)8 ( table 1 ) and the european society for medical oncology ( esmo ) guidelines9 ( figure 1 ) outline the recommended treatment regimens for patients with fl in the us and europe , respectively . owing to its established long - term efficacy , rituximab is an important component of fl treatment.10 treatment options for patients with limited - stage disease ( stage i / ii ) include radiation,1113  watch - and - wait  approach,14 or rituximab alone or in combination with chemotherapy ( eg , bendamustine plus rituximab [ br ] ; rituximab plus cyclophosphamide , doxorubicin , vincristine , and prednisone [ r - chop ] ; or rituximab plus cyclophosphamide , vincristine , and prednisone [ r - cvp]).15 despite the paucity of randomized clinical trials , radiation therapy is the preferred treatment for patients with non - bulky stage i fl .
patients with grade 3b fl or those undergoing histologic transformation are best treated with chemoimmunotherapy regimens , such as r - chop .
patients with stage ii fl are appropriate candidates for treatment with either rituximab alone or in combination with chemotherapy , depending on their clinical presentation .
in general , the treatment approach for patients with stage ii fl includes  watch - and - wait  , single - agent rituximab vs rituximab plus chemotherapy , or radiation for those with contiguous nodal involvement .
patients with bulky disease or those with an adverse prognosis presenting with b symptoms and/or clinically significant tumor load are candidates for treatment with rituximab plus chemotherapy.8,9 treatment options for patients with advanced - stage ( stage
iii / iv ) fl are similar to those for stage ii fl . for asymptomatic patients with non - bulky disease , the watch- and - wait approach with treatment upon disease progression may be appropriate.16 results from a study by ardeshna et al conducted in asymptomatic patients with advanced - stage low - tumor - burden fl showed that 88% of patients on maintenance treatment with rituximab did not require treatment at 3 years compared with 46% in the watch - and - wait group ( p<0.0001).15 the rituximab induction arm was affected by early closure because of poor accrual .
moreover , there were 18 serious adverse events , possibly as a consequence of treatment with rituximab .
however , this study highlights that rituximab monotherapy is a possible option for patients with asymptomatic , low - tumor - burden fl , particularly for those who may not tolerate chemotherapy or for those with slowly progressive disease.8 patients with advanced - stage fl that is progressive , symptomatic , and/or has associated cytopenias are candidates for chemoimmunotherapy .
recent evidence suggests that br is effective as a first - line regimen in patients with advanced disease . in a randomized phase iii study , treatment with br
resulted in non - inferior clinical response compared with standard rituximab chemotherapy ( r - chop or r - cvp ) , with an acceptable toxicity profile.17 in a prospective , randomized , open - label study in patients with previously untreated indolent lymphoma , first - line therapy with br resulted in greater progression - free survival and fewer toxic effects compared with r - chop.18 patients who respond to induction treatment with r - cvp or r - chop are potential candidates for maintenance therapy with rituximab .
primary rituximab and maintenance ( prima ) was a randomized open - label study to investigate the effect of 2 years of rituximab maintenance therapy ( 375 mg / m every 8 weeks ) after first - line treatment with rituximab plus chemotherapy.19 at a median follow - up of 3 years , progression - free survival was significantly improved in the rituximab maintenance group ( 75% ) compared with the observation group ( 58% ) ( p<0.0001 ) .
furthermore , a significantly greater proportion of patients achieved a complete response with rituximab maintenance therapy than those in the observation group ( 72% vs 52% , respectively ; p=0.0001 ) . however , there was no difference in the overall survival between the 2 groups in this study.19 further investigation is needed to understand the long - term toxicities of rituximab maintenance therapy and to identify the patients most likely to benefit from this treatment regimen . a recent study by kahl et al20 failed to demonstrate a significant clinical benefit from continuing rituximab maintenance treatment in patients with advanced - stage , low - tumor - burden fl after induction with the single - agent rituximab .
although rituximab maintenance therapy should be considered after rituximab plus chemotherapy , it is not recommended after rituximab monotherapy ( table 1 ; figure 1 ) .
furthermore , rituximab maintenance therapy after induction with rituximab monotherapy is of less clinical benefit in patients with low - tumor - burden fl , compared with rituximab re - treatment.20 rituximab is also effective in the re - treatment setting and is used in combination with chemotherapy regimens for the treatment of relapsed / refractory fl .
common chemotherapy regimens include first - line ( br , r - chop , and r - cvp ) and second - line ( fludarabine , cyclophosphamide plus mitoxantrone or fludarabine monotherapy ) regimens ( table 1 ) . in patients with early relapse ( 12 years ) ,
a non - cross - resistant regimen is preferable ( eg , bendamustine before or after chop ) . if patients subsequently experience remission for 6 months , the addition of rituximab should be considered ( table 1).8
following the clinical success of rituximab in the treatment of fl , novel agents are emerging and currently under development .
ibrutinib , an oral , selective , and covalent bruton s tyrosine kinase inhibitor , has been approved by the us food and drug administration ( fda ) for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy,21 chronic lymphocytic leukemia ( cll)/small lymphocytic lymphoma , and waldenstrm s macroglobulinemia.22 ibrutinib has also been approved by the european medicines agency ( ema ) for the treatment of patients with relapsed / refractory mantle cell lymphoma , in the first - line , refractory , and relapsed / refractory settings of cll , for those with waldenstrm s macroglobulinemia who have received at least 1 prior therapy , and in the first - line setting for patients unsuitable for chemoimmunotherapy .
ibrutinib is currently under investigation for use in combination with rituximab ( clinicaltrials.gov , nct01980654 ) and as monotherapy for relapsed / refractory fl ( clinicaltrials.gov , nct01849263 ) .
idelalisib , an oral phosphoinositide 3-kinase - delta inhibitor , has been approved by the fda for the treatment of patients with relapsed / refractory cll and relapsed / refractory fl.24 a phase i / ii study to evaluate the efficacy and safety of idelalisib in patients with previously treated low - grade fl is ongoing ( clinicaltrials.gov , nct01306643 ) .
a phase ii study is planned to explore the efficacy and safety of idelalisib in combination with rituximab in patients with previously untreated fl and small lymphocytic lymphoma ( clinicaltrials.gov , nct02258529 ) .
obinutuzumab is a humanized immunoglobulin g1 monoclonal antibody , with a novel glycoengineered fc region . in combination with chemotherapy
obinutuzumab is approved for use in combination with bendamustine followed by obinutuzumab monotherapy for the treatment of patients with fl who relapsed after , or are refractory to , a rituximab - containing regimen.25 approval was based on an open - label , randomized , phase iii trial in patients with indolent nhl refractory to rituximab.26 in another study , obinutuzumab demonstrated clinical efficacy and an acceptable safety profile in the relapsed / refractory fl setting.27 in a phase iii study , obinutuzumab - based induction and maintenance therapy resulted in small improvements in progressionfree survival in treatment - nave patients with fl ; however , a higher incidence of grades 35 adverse events was observed compared with rituximab.28 a phase i study in patients with nhl or cll showed that induction and maintenance therapy with obinutuzumab offered clinical benefits , with a favorable safety profile.29 similarly , obinutuzumab showed encouraging results in patients with relapsed / refractory nhl.30 lenalidomide , an immunomodulatory agent , has been approved by the fda for the treatment of patients with multiple myeloma , myelodysplastic syndromes , and relapsed / refractory mantle cell lymphoma.31 in a phase ii trial , lenalidomide in combination with rituximab was effective and well tolerated as initial treatment for patients with advanced indolent nhl.32 in light of these promising results , a phase iii study to evaluate the efficacy and safety of rituximab in combination with lenalidomide compared with r - chop , r - cvp , or br in patients with previously untreated fl is ongoing ( clinicaltrials.gov , nct01476787 ) .
despite an array of novel agents emerging and in clinical development , it is likely that rituximab will remain at the forefront of fl treatment.33 however , patents for many biologics have expired or will lose exclusivity over the coming years ( figure 2 ) .
importantly , the composition - of - matter patent covering rituximab in europe ( mabthera ) expired in 2013 , and its counterpart in the us ( rituxan ) will expire in 2018 . moreover , rituximab is not widely available to physicians and patients in several countries , including the us , mexico , turkey , russia , and brazil . in a recent survey of 450 oncologists and hematologists
, 31% considered rituximab an easily accessible option in brazil . similarly , 25% and 19% reported challenges in getting access to rituximab in mexico and russia , respectively .
issues related to insurance coverage , treatment guidelines , and patient comorbidities were the most common barriers to access or use of rituximab .
indeed , these barriers have the potential to compromise clinical outcomes and patient care across the spectrum of fl treatment , potentially resulting in a change or delay in treatment with rituximab , largely the result of payment issues or patient response .
however , baer et al found physicians who participated in the survey would increase use of rituximab if a more affordable version were available , without compromising efficacy , safety , or patient care.34 another concern in the biologics arena is that these agents are likely to be susceptible to drug shortages as a consequence of sparse active ingredients , coupled with obstacles in manufacture and supply .
in addition , suboptimal compliance with current good manufacturing practice , changes in clinical standards , a greater demand for rituximab , and manufacturing delays are the most common factors that contribute to drug shortages.35 the supply of chemotherapeutics , such as 5-fluorouracil , liposomal doxorubicin , and fludarabine , as well as rituximab , may be adversely affected by looming drug shortages , with potentially pernicious outcomes for patients.36 drug shortages can lead to delays in treatment , use of alternative , potentially less effective treatment , increased case management for health care professionals , and poor availability of more effective , well - tolerated combination therapies.35
the loss of exclusivity and limited access to rituximab has led to the development of well - characterized , safe , and effective biosimilars to rituximab .
biosimilars are defined as biologic products that are highly similar to the reference biologic product , notwithstanding minor differences in clinically inactive components.37 the availability of biosimilars may mitigate the impact of the limited access to rituximab .
biosimilars provide a greater spectrum of treatment choices and may offer efficiencies to the health care system .
in addition , biosimilars increase access to biologics and foster greater use of biologic therapies , which may facilitate improved overall health outcomes at a time when a shortage of biologics may become a barrier to the treatment of patients with fl .
biosimilars have the potential to increase access to therapies by offering more affordable treatment options .
savings with biosimilars could facilitate the reallocation of expenditure to optimize treatment of patients with fl , resulting in patients receiving treatment earlier in therapy , with more patients able to access medicines such as rituximab.37
biosimilars are large , structurally complex molecules developed to be similar to and treat the same condition(s ) , using the same treatment regimens as an existing licensed or approved ( originator or reference ) biologic .
development of biosimilars involves a stepwise approach of physicochemical and biological evaluation , along with a series of comparative nonclinical and clinical studies .
several factors influence the extent of clinical data required for the approval of biosimilars , including the similarity to the originator biologic and strength of preclinical data as well as the molecular complexity .
the ultimate aim of biosimilar development is to demonstrate that there are no clinically meaningful differences based on the  totality of evidence  encompassing all available analytical , nonclinical , and clinical data .
the totality of evidence approach is specifically tailored for biosimilars and applies a different paradigm than the regulation of originator biologics , for which the aim is to establish de novo efficacy and safety .
furthermore , the biosimilar developer is not required to demonstrate efficacy to the reference biologic in each indication , as the extrapolation of clinical data across indications is permitted , and any differences may be considered in the totality of evidence , given appropriate scientific justification.38 the approval of biosimilars is a highly regulated and comprehensive process ( table 2 ) .
the ema and the us fda have published extensive guidance documents with their respective definitions of biosimilars , and the requirement of a series of detailed analytical and similarity assessments , nonclinical in vivo evaluation , and safety and efficacy studies , all in comparison with the reference biologic.38,39 the biosimilars approval pathway was established in the european union ( eu ) , with 8 biosimilars ( under 20 different trade names ) authorized by the ema over the past decade.40 the first biosimilar in the us ( filgrastim - sndz [ zarxio ] ) , a biosimilar version of neupogen , was granted approval in 2015 under the us biologics price competition and innovation act of 2009.41,42 although complex , the regulatory approval process for biosimilars in europe,39 the us,38 and elsewhere43 has been tailored and is often shorter than that required for originator biologics .
a biosimilar version of rituximab ( truxima ) has recently been granted approval for the treatment of nhl , cll , and rheumatoid arthritis ( ra ) in south korea.44 several potential rituximab biosimilars are currently in development , each in comparison with the originator ( reference ) rituximab ( table 3 ) . a study in patients with newly diagnosed advanced
fl showed pharmacokinetic similarity between a potential biosimilar to rituximab , ct - p10 , and rituximab ( each administered with cvp ) , with similar b - cell kinetics and immunogenicity.45 in another study , ct - p10 and rituximab showed equivalent pharmacokinetics , and comparable efficacy , pharmacodynamics , immunogenicity , and safety in patients with ra.46 a clinical study in patients with previously untreated fl showed therapeutic equivalence in overall response rate between another proposed biosimilar to rituximab , gp-2013 , and rituximab sourced from the eu . in this trial
, similarity was demonstrated for efficacy , pharmacokinetic , and pharmacodynamic parameters , with similar safety findings.47 in addition , the efficacy and safety of another potential biosimilar , bi-695500 , in patients with low - tumor - burden lymphoma is under clinical investigation ( clinicaltrials.gov , nct01950273 ) .
abp 798 , a potential biosimilar to rituximab , is in clinical development in patients with cd20-positive b - cell nhl ( clinicaltrials.gov , nct02747043 ) .
another potential biosimilar to rituximab , mabioncd20 , is in development in patients with cd20-positive dlbcl ( clinicaltrials.gov , nct02617485 ) . in nonclinical studies , pf-05280586 ,
a proposed bio - similar to rituximab , showed the same primary amino acid sequence and similar physicochemical and in vitro functional properties as the licensed originator biologic.48 a study in patients with active ra demonstrated pharmacokinetic similarity of pf-05280586 to rituximab sourced from the eu ( rituximab - eu ) and the us ( rituximab - us ) and that of rituximab - eu to rituximab - us.49 in this trial , all 3 treatments were generally well tolerated , and the incidence of treatment - related adverse events was low .
these encouraging findings support the ongoing development of pf-05280586 as a potential biosimilar to rituximab .
a trial is ongoing to compare the efficacy , safety , pharmacokinetics , and immunogenicity of pf-05280586 to rituximab in patients with low - tumor - burden fl ( clinicaltrials.gov , nct02213263 ) .
debate continues over the optimal treatment strategy for untreated fl : the watch- and - wait approach vs therapeutic intervention .
however , for patients who are candidates for systemic therapy , an anti - cd20 monoclonal antibody alone or in combination with chemotherapy remains at the forefront of the therapeutic landscape .
it is well recognized that rituximab will remain as the cornerstone of therapy in the treatment of patients with fl . the loss of exclusivity of composition - of - matter patents of biologics in recent and coming years , and the lack of access to rituximab in some countries are of particular concern for patients and physicians .
thus , it is relevant , appropriate , and necessary to develop a biosimilar to rituximab with the potential to generate cost savings and efficiencies for health care systems and to increase access to patients worldwide , which can help augment resources for other important aspects of health care
. it will be crucial to engage clinicians on the importance of biosimilars , and moreover , to increase understanding of data that underpin the development of biosimilars and how these data may translate into clinical practice . at present ,
the availability of safe and effective rituximab biosimilars is eagerly anticipated , potentially offering a greater range of therapeutic options and improved clinical benefits to patients with fl .
 follicular lymphoma ( fl ) is the second most common type of non - hodgkin s lymphoma . 
 fl is an incurable disease with treatment options ranging from a  watch - and - wait  approach to localized therapy with radiation or systemic therapy with rituximab in combination with chemotherapy regimens . 
 this review summarizes the role of rituximab across the spectrum of fl treatment and the evolving therapeutic landscape with the emergence of novel agents currently in clinical development . despite the prospect of new agents on the horizon 
 , it is widely accepted that rituximab will remain as the cornerstone of therapy because of its established long - term efficacy . 
 many biologics , including rituximab , have lost exclusivity of composition - of - matter patent or will do so in the next few years , which is a concern for patients and physicians alike . moreover , access to rituximab is challenging , particularly in countries with restricted resources . 
 together , these concerns have fueled the development of safe and effective biosimilars . 
 the term  biosimilar  refers to a biologic product that is highly similar to an approved reference ( or originator ) product , notwithstanding minor differences in clinically inactive components , and for which there are no clinically meaningful differences in purity , potency , or safety . 
 biosimilars are developed to treat the same condition(s ) using the same treatment regimens as an approved reference biologic , and have the potential to increase access to more affordable treatment of fl . 
 herein , we also discuss the potential benefits of eagerly awaited rituximab biosimilars , which may mitigate the impact of the lack of access to rituximab . 