peripheral t - cell lymphomas ( ptcl ) are a rare and heterogeneous group of non - hodgkin s lymphomas ( nhl ) deriving from mature , post - thymic t- and natural killer ( nk- ) cells . ptcl count for approximately 10% of all nhl in europe and north america,13 but present with a higher incidence in east asia and the carib - bean , especially with respect to epstein - barr virus and human t - cell leukemia virus type - i associated entities.46 in contrast to b - cell nhl that are mainly classified into indolent and aggressive subtypes . ptcl are further subdivided primarily according to their site of manifestation . with regard to the current who classification , leukemic , cutaneous , nodal , and extranodal ptcl are distinguished.6 in general , cutaneous and leukemic entities show an indolent clinical course and are separated from the nodal and extranodal subtypes . therefore , following a commonly used closer definition of ptcl , also used in this review , ptcl only include nodal and extranodal ptcl . the most frequent entities are ptcl not otherwise specified ( ptcl , nos ) , angioimmunoblastic t - cell lymphoma ( aitl ) , and anaplastic large cell lymphoma ( alcl ) with or without expression of the anaplastic lymphoma kinase ( alk).7 apart from alk - positive alcl , ptcl have a poor clinical outcome.713 to date , due to the rare incidence and the lack of randomized clinical phase iii trials , there is no consensus on standard therapy either in the upfront setting or for refractory or relapsed ( r / r ) ptcl . as first - line therapy , anthracycline - based conventional ( chop - like ) multi - agent chemotherapy protocols are most commonly used . however , with this approach , long - term remissions are achieved only in a minority of patients , resulting in a median overall survival ( os ) of 9 to 42 months.1416 several prospective series have shown promising results for a consolidation treatment using myeloablative therapy with autologous stem cell transplantation ( autosct ) in patients responding to induction chemotherapy.1721 therefore , this approach is recommended in many centers ; however , randomized data are not available yet . salvage treatment for ptcl is often required because most patients have refractory disease or eventually relapse . several strategies have been investigated to improve the prognosis of patients with r / r ptcl . however , the data are sparse and available studies lack a randomized control arm . in a recently published retrospective analysis mak et al could demonstrate that conventional chemotherapy does not impact on os in r / r ptcl and seems not to be superior to best supportive care alone.22 on the other hand , several series on allogeneic stem cell transplantation ( allosct ) can lead to long - term disease - free survival in a subgroup of patients.2331 however , most of the data on allosct are retrospective , and consequently , the results are biased by patient selection . moreover , this approach is associated with a substantial treatment - related morbidity and mortality and is limited to eligible patients . therefore , with respect to the median age of patients with ptcl , that is , above 60 years , many patients are not candidates for even dose - reduced conditioning regimen - based allosct . in summary , since conventional treatment strategies alone seem to have limited efficacy or are restricted only to subsets of patients , novel targeted agents with a more specific mechanism of action are urgently needed . following decades without any noteworthy progress in the treatment of r / r ptcl , four drugs have been approved worldwide for the treatment of r / r noncutaneous ptcl in the last 6 years . pralatrexate , an antifolate , and romidepsin , a histone deacetylase inhibitor ( hdaci ) , have shown significant efficacy in r / r ptcl , and have therefore been approved by the united states food and drug administration ( fda ) in 2009 and 2011 , respectively.3234 brentuximab vedotin , a cd30-targeted immunoconjugate , has shown a high response rate of 85% in a phase ii study of 58 patients with cd30 + alcl who had experienced at least one prior therapy.35 for r / r alcl , expressing the cd30 antigen brentuximab vedotin was approved by the fda and the european medicines agency ( ema ) in 2011 and 2012 , respectively . this review focuses on belinostat , its current impact on treatment algorithm and its future perspective . histones are proteins that compact dna in the cell nucleus and are modified by acetylation , methylation , or phosphorylation . histone deacetylases ( hdac ) are a class of enzymes that allow tight dna wrapping by removing acetyl groups from an -n - acetyl lysine amino acid on a histone , and thereby regulate dna expression . to date , four classes of hdac are known . unlike other hdaci , belinostat , a hydroxamic acid - derived pan - hdaci , targets class i , ii , and iv hdac , showing antitumor and antiangiogenic properties in a wide range of cancer cell lines with sub to low micromolar potency in vitro.36 in general , hdaci targets the hdac , thereby increasing acetylation of different substrates in the nucleus . however , so far , the exact mechanism of action of hdaci in ptcl is unknown . this could lead to alterations in gene expression effecting cell growth , cell cycle arrest , cell differentiation , and programmed cell death ( apoptosis ) that can be reconstituted by hdaci.37 furthermore , deacetylation of histones can lead to silencing of tumor suppressor genes.38 therefore , hdaci might re - express epigenetically silenced tumor suppressor genes and have the potential to reactivate the innate tumor control . the pharmacokinetics data of belinostat have been initially investigated after intravenous or oral administration in rats and dogs . the drug showed two - compartment kinetics with rapid distribution and an elimination half - life of 12 hours . following rapid metabolism to several metabolites , main excretion of belinostat was via the bile and/or feces.39 in a pharmacokinetics and pharmacodynamics study in patients with solid tumors belinostat displays three - compartment pharmacokinetics with an elimination half - life ranging from 0.3 to 1.3 hours independent of dose . with regard to area under the curve ( auc ) and cmax , the drug showed linear ( dose - proportional ) pharmacokinetics without any relevant drug accumulation . the pharmacodynamics studies revealed a defi - nite increase in histone h4 acetylation at the end of infusion at all doses . at doses > 150 mg / m , the increased h4 acetylation was sustained and persists above baseline levels up to 24 hours after the end of infusion . furthermore , the authors revealed a dose - related increase in histone h4 acetylation auc up to approximately 900 mg / m.40 belinostat was first investigated in several phase i trials to determine the maximum tolerated dose ( mtd).4042 in the study by steele et al , in 46 patients with advanced solid tumors , the intravenously given dose ranged from 150 mg / m to 1,200 mg / m . during this dose - escalating phase , dose - limiting toxicities developed at a dose of 600 mg / m in one patient and at a dose of 1,200 mg / m in three patients . after continuing the study at a dose level of 1,000 mg / m without dose - limiting toxicities in all six patients , an additional 18 patients were treated at this dose level . given the results of preliminary studies on pharmacokinetics and pharmacodynamics and the observed toxicities , the mtd was determined to be 1,000 mg / m on days 1 to 5 of every 3-week cycle . dose - limiting toxicities were fatigue , diarrhea , nausea , emesis , and atrial defibrillation.40 in another phase i study in 16 patients with advanced hematologic malignancies , a similar dose of 1,000 mg / m in the same schedule was recommended for future phase ii studies . the most common treatment - related adverse events of all grades were nausea , vomiting , fatigue , and flushing . besides one case of grade 3 lymphopenia , no grade 3 or 4 hematological toxicity was observed . two treatment - related grade 4 adverse events of renal failure occurred in two patients with multiple myeloma.41 in the phase i study by lassen et al , belinostat was investigated in combination with carboplatin and paclitaxel in 23 patients with solid tumors . again grade 3/4 adverse events included leucopenia , neutropenia , thrombocytopenia , anemia , peripheral sensory neuropathy , fatigue , vomiting , and myalgia . importantly , the pharmacokinetics of belinostat , paclitaxel , and carboplatin were not altered by the concurrent administration.41 oral administration of belinostat has also been evaluated using different regimen in advanced solid tumors and hematologic malignancies.4345 however , taking together the available data , the optimal dosing and scheduling of oral belinostat have not been established yet . in the first published phase ii study on belinostat in the treatment of patients with t - cell lymphoma , foss et al evaluated safety and efficacy in 53 patients with cutaneous t - cell lymphoma ( n=29 ) and ptcl ( n=24 ) . this was an open label , international multicenter study conducted in 15 institutions in five countries . the subgroup of patients with ptcl was heavily pretreated and received a median of three prior systemic therapies . the ptcl cohort had a median age of 64 years , with a male predominance of 71% . most subtypes were ptcl , nos ( n=13 , 54% ) , alcl ( n=3 , 13% ) , and aitl ( n=3 , 13% ) . belinostat was given as a 30-minute infusion of 1,000 mg / m on days 1 to 5 of a 3-week cycle . a dose escalation to 1,200 mg/2 for cycle 2 and 1,400 mg2 for cycle 3 was permitted in the absence of grade 2 treatment - related adverse events . responding patients who achieved a partial remission ( pr ) or a stabilization of the disease after cycle 2 were allowed to receive six additional courses or could continue belinostat therapy until disease progression . patients obtaining a complete remission ( cr ) were eligible for retreatment at the time of progression at the investigators discretion . secondary endpoints were duration of response , time to response , time to progression and safety . for the ptcl group , orr was 25% including two complete and four prs . in four patients ( 17% ) , the time to response ranged from 33 days to 431 days , the median duration of response was 109 days , and the median time to progression was 82 days.46 final results from the much larger belief trial , a phase ii study on 129 patients with r / r ptcl were presented by oconnor at the asco meeting 2013.47 patients , who had failed at least one prior therapy , were enrolled in this single - arm study at 62 sites in north america , europe , and africa . further inclusion criteria included measurable lymphoma manifestation , thrombocyte counts of 50,000/l , absence of prior hdaci therapy , adequate organ function , and no relapse following autosct or allosct within 100 days . secondary endpoints were safety , os , progression - free survival ( pfs ) , duration of response , time to response , time to progression , 1-year progression - free rate , and 1-year survival rate . patients were treated until disease progression , unmanageable toxicity , death , or successful bridging to stem cell transplantation . the remaining subtypes included aitl ( n=22 , 18% ) , alcl ( n=15 , 13% ) , and others ( n=6 , 6% ) . previous chop / chop - like regimen had been given to 125 patients ( 96% ) . a total of 27 patients ( 21% ) had undergone prior autosct and two patients ( 2% ) had had an allosct . the median time from first diagnosis to study entry was 12 months and the median time from last disease progression to study entry was 1 month . the median number of cycles administered was two , and the median duration of treatment was 7 weeks . the main reasons for treatment discontinuation were progressive disease ( n=82 ) , death ( n=14 ) , patient decision ( n=11 ) , and adverse events ( n=9 ) . a total of 17 patients ( 13% ) required dose reduction mainly to the first level of dose reduction ( 750 mg / m ) . in terms of efficacy , 13 patients ( 11% ) achieved a cr , 18 patients demonstrated a pr ( 15% ) , resulting in an orr of 26% . in responding patients , the median time to response was 5.6 weeks ( range , 4.350.4 weeks ) . importantly , nine patients ( 7.5% ) were able to proceed to stem cell transplantation . for the subgroup of patients ( n=20 ) with a thrombocyte count < 100,000/l , orr , duration of response , median pfs , os , and time to response were considerably worse compared with patients presenting with a baseline platelet count 100,000/l . in a subgroup analysis presented at the lnternational conference on malignant lymphoma in lugano in 2013 , belinostat treatment resulted in a favorable 45% response rate among the subgroup of 22 patients with r / r aitl . this resulted in a median pfs and os for this cohort of 5.8 and 9.2 , respectively , which seems to be somewhat superior to the results for the entire ptcl group . table 1 summarizes the efficacy data of the two phase ii studies on belinostat.48 recently , a case report was published documenting high efficacy of belinostat in an elderly female patient with ptcl - nos.49 after failing three different chemotherapy regimens , the patient was treated with belinostat and achieved a cr after two cycles . the patient received a total of 28 cycles and maintained a cr for 46 months . the patient relapsed 15 months after the last application of belinostat and died 3 months later due to progressive disease ( personal communication ) . in the phase ii study by foss et al , 23 treatment - emerged adverse events of all grades were documented in 77% of all patients . these included nausea ( 67% ) , constipation ( 38% ) , and vomiting ( 25% ) with the highest incidence . for the ptcl cohort , five grade-3 nonhematologic events ( pneumonitis , paralytic ileus , cellulitis , and two cases of rash ) and one grade-4 event ( thrombocytopenia ) were reported . one patient with a history of left anterior hemiblock died of ventricular fibrillation 6 days after the last dose of belinostat in cycle 2 . however , after assessment of the pre- and post - study ecgs by an independent cardiology review , the fatal arrhythmia was determined unlikely to be related to belinostat exposure . hematologic toxicities grades 3 and 4 were seen in 15 patients ( 63% ) with ptcl . three patients discontinued treatment due to therapy - emerged adverse events . in the belief trial , hematologic toxicity of grade 3/4 was seen in 12% of the patients for anemia , 13% for leukopenia , and 15% for thrombocytopenia . most reported adverse events included dyspnea ( 6% ) , pneumonia ( 5% ) , febrile neutropenia ( 5% ) , and fatigue ( 5% ) . conventional chemotherapy has very limited value and only a minority of patients is eligible to undergo ( allo ) stem cell transplantation . belinostat , a pan - hdaci , has shown conclusive effi - cacy in two phase ii trials . the orr of 26% demonstrated in the belief trial combined with the good safety profile led to an accelerated approval of belinostat for r / r ptcl by the fda in july 2014 . belinostat has been incorporated in the guidelines of the national comprehensive cancer network as salvage therapy for patients with r / r ptcl . the response rate of belinostat in the cited studies is in the range of that reported for romidepsin and pralatrexate , but the toxicity profiles of the three drugs differ . to date , given the limited data , a clear advantage of one drug over the other can not be seen . decision making in favor of one of the drugs should be made on an individual basis , especially considering the differing toxicity profiles . in addition , belinostat may be considered to serve as bridging therapy to achieve a remission prior to potentially definite stem cell transplantation . table 2 summarizes the clinical data of all four fda - approved drugs for r / r ptcl . due to its favorable safety profile and proven efficacy , belinostat seems a very attractive candidate for combination therapies . a phase i clinical trial in combination with chop chemotherapy has been initiated in newly diagnosed ptcl ( nct01839097 ) . this approach might lead to a randomized phase iii study in the future comparing this combination therapy with standard chop therapy in the upfront setting . in addition , belinostat is under investigation in combination strategies and is being evaluated as an oral formulation for solid tumors .