burkitt lymphoma ( bl ) is a highly aggressive b - cell lymphoma accounting for 1%-5% of all non - hodgkin lymphomas ( nhl ) in adults . bl was first identified as a childhood endemic tumor with a geographical distribution . since then , worldwide and sporadic occurrence of bl has been reported , and bl has become a well - known human immunodeficiency virus ( hiv)associated malignancy . as bl tumor cells are characterized by rapid cellular growth , conventional regimens for nhl have shown disappointing results . on the other hand , dose - intense , multi - fractionated chemotherapeutic regimens have been shown to improve treatment outcomes [ 5 - 7 ] . a recent populationbased study   demonstrated the impact of regimen intensity on treatment outcome of adult bl patients , reporting a 2-year overall survival ( os ) rate of only 38.8% for cyclophosphamide , adriamycin , vincristine , and prednisone ( chop ) or chop - like regimens , whereas survival rates of 68.6% to 82.8% were achieved for dose - intense regimens . atypical bl / burkitt - like lymphoma  by the 2001 world health organization ( who ) classification , and these morphologically similar lymphomas are thought to lie on a continuum between bl and diffuse large b - cell lymphoma ( dlbcl ) . in the 2008 who classfication , classification of these atypical bl / burkitt - like lymphomas was more refined , including a new provisional entity , b - cell lymphoma , unclassifiable , with features intermediate between bl and dlbcl ,  which we define as bl - u in this report . despite these changes in classification , there are no established treatment guidelines for these lymphomas . thus , dose - intense treatment strategies similar to those used for bl are typically used for aggressive lymphomas with overlapping features of bl and dlbcl . among dose - intense treatment regimens , hyper - cvad regimen ( hyper - fractionated cyclophosphamide , adriamycin , vincristine , and dexamethasone alternated with methotrexate plus cytarabine ) has been proposed for treatment of highly aggressive lymphoid malignancies by the md anderson cancer center . since addition of rituximab to hyper - cvad regimen ( rhyper- cvad ) has been shown to improve treatment outcomes , r - hyper - cvad has been used as a primary treatment option for bl . using this approach , a complete remission ( cr ) rate of 86% and 3-year os rate of 89% without any induction death were observed . however , significant toxicity , delayed treatment , and treatment - related early death are not uncommon in actual clinical practice since patient characteristics often differ from those in clinical trials . as elderly and frail patients are commonly treated in clinical practice , information on real - life outcomes of the regimen could be a useful reference for physicians who treat bl . in addition , although ethnic differences might affect drug tolerability and efficacy , outcomes of r - hyper - cvad in asian patients have never been reported . thus , we analyzed the outcomes of adult korean patients with sporadic bl or bl - u treated with r - hyper - cvad regimen   by focusing on tolerability and delivered dose intensity . we reviewed the medical records of 14 hospitals belonging to the consortium for improving survival of lymphoma ( cisl )   and selected patients who fulfilled the following inclusion criteria : 1 ) age  20 years , 2 ) pathologically diagnosed as bl or bl - u according to the 2008 who criteria , and 3 ) treated with at least one cycle of r - hyper - cvad as the first - line systemic treatment . the institutional review boards of each participating center approved this study and waived informed consent since no actual intervention was performed due to its retrospective nature . case report forms ( crf ) for eligible patients were requested from physicians who treated the patients in this retrospective study ( cisl-1201 ) from march 2012 to march 2013 . the crf contained a fill - in section on patient characteristics such as gender , age at diagnosis , anti - hiv antibody status , the international prognostic index ( ipi ) factors , bone marrow involvement , and crucial laboratory data , including complete blood cell counts and serum lactate dehydrogenase , among other values . patient height , weight , accurate dose of each administered drug , and date of drug administration were obtained in order to calculate relative dose intensity ( rdi ) . hematologic toxicity and grade 3 or greater non - hematologic toxicity was reviewed for each cycle in the crf . special events during immunochemotherapy , such as tumor lysis syndrome , cerebellar ataxia due to cytarabine , and infectious episodes , were investigated in detail . the results of the interim and final treatments according to the revised response criteria for malignant lymphomas   were collected along with data on relapse , progression , or death of patients . event - free survival ( efs ) denotes survival free from progressive disease or discontinuation of therapy for any reason . to eliminate the impact of early death on overall treatment outcomes , we also used disease - free survival ( dfs ) , which is the same parameter as efs except that death by any cause other than progression of lymphoma is not considered the kaplan - meier method and log - rank test were used for survival analysis . univariate and multivariate analyses were performed by using a backward cox regression model with variables of p < 0.1 in the univariate analysis . all values were two - sided , and statistical significance was accepted at a level of p < 0.05 . we reviewed the medical records of 14 hospitals belonging to the consortium for improving survival of lymphoma ( cisl )   and selected patients who fulfilled the following inclusion criteria : 1 ) age  20 years , 2 ) pathologically diagnosed as bl or bl - u according to the 2008 who criteria , and 3 ) treated with at least one cycle of r - hyper - cvad as the first - line systemic treatment . the institutional review boards of each participating center approved this study and waived informed consent since no actual intervention was performed due to its retrospective nature . case report forms ( crf ) for eligible patients were requested from physicians who treated the patients in this retrospective study ( cisl-1201 ) from march 2012 to march 2013 . the crf contained a fill - in section on patient characteristics such as gender , age at diagnosis , anti - hiv antibody status , the international prognostic index ( ipi ) factors , bone marrow involvement , and crucial laboratory data , including complete blood cell counts and serum lactate dehydrogenase , among other values . patient height , weight , accurate dose of each administered drug , and date of drug administration were obtained in order to calculate relative dose intensity ( rdi ) . hematologic toxicity and grade 3 or greater non - hematologic toxicity was reviewed for each cycle in the crf . special events during immunochemotherapy , such as tumor lysis syndrome , cerebellar ataxia due to cytarabine , and infectious episodes , were investigated in detail . the results of the interim and final treatments according to the revised response criteria for malignant lymphomas   were collected along with data on relapse , progression , or death of patients . event - free survival ( efs ) denotes survival free from progressive disease or discontinuation of therapy for any reason . to eliminate the impact of early death on overall treatment outcomes , we also used disease - free survival ( dfs ) , which is the same parameter as efs except that death by any cause other than progression of lymphoma is not considered the kaplan - meier method and log - rank test were used for survival analysis . univariate and multivariate analyses were performed by using a backward cox regression model with variables of p < 0.1 in the univariate analysis . all values were two - sided , and statistical significance was accepted at a level of p < 0.05 . all patients had sporadic bl or bl - u ( i.e. , no patients had hiv - associated lymphoma ) and were of a median age of 51 years . dates of initial diagnosis ranged from february 2006 to march 2013 , and the majority of patients had advanced diseases at the time of diagnosis . more than half of patients were in ann arbor stage iv ( n=29 , 67.4% ) , had two or more extranodal sites ( n=23 , 53.5% ) , and were at high or high - intermediate risk ( n=25 , 58.1% ) according to the standard ipi . prophylactic measures , doses and intervals of cytotoxic drugs , number of planned cycles , central nervous system ( cns ) prophylaxis , and overall schedule of the regimen were as those in a previous study , except for administration of rituximab ( two patients received 375 mg / m of rituximab on the first and eighth days of each cycle , whereas others received the same dose of rituximab on the first day of each cycle only ) . according to the recommendations of the korean national health insurance guideline , granulocyte - colony stimulating factor ( g - csf ) was administered daily starting the first day patients showed an absolute neutrophil count ( anc ) < 1,000/l until the third consecutive day patients showed an anc > 3,000/l in each cycle . of the 32 evaluable patients , 24 patients ( 75% ) achieved a cr , and six patients experienced disease progression in the final response evaluation ( table 2 ) . seven patients experienced relapse after cr , with two patients experiencing cns involvement and five showing extra - cns sites ( two patients with skin and subcutaneous nodules , two patients with bone marrow involvement , and one patient with right inguinal lymph node involvement ) . after a median follow - up period of 20.0 months , the 2-year dfs , efs , and os rates of patients were 78.6% , 70.9% , and 81.4% , respectively ( fig . 1 ) . according to univariate analysis , bone marrow involvement , an absolute lymphocyte count ( alc ) < 1,200/l , and being a member of the standard ipidefined high - risk group were all associated with poorer efs . among ipi factors , age > 60 years and a poor eastern cooperative oncology group performance status ( ecog ps ) contributed to lower efs , whereas more than one extranodal site , stage iii or iv , and elevated serum lactate dehydrogenase levels did not . according to multivariate analysis , alc < 1,200/l and being a member of the high - risk group were independent risk factors ( table 3 ) . in contrast to the cox regression test for efs , most parameters did not have an impact on dfs ( table 3 ) . early deaths were reported in cycles 1a ( n=2 ; age , 51 and 64 years , respectively ) , 1b ( n=1 ; age , 66 years ) , 2a ( n=2 ; age , 67 and 72 years , respectively ) , and 2b ( n=1 ; age , 47 years ) . five of them ( except for one 47-year - old patient ) had an ecog ps  2 . causes of treatment - related mortality ( trm ) were bacterial septicemia ( n=5 ) and tumor lysis syndrome ( n=1 ; age , 51 years ) . in cycle 1a , four patients ( 9.3% ) experienced tumor lysis syndrome . two patients recovered from tumor lysis syndrome with the support of hemodialysis , one patient recovered with only hydration and oral allopurinol use , and the other patient died of rapidly progressing tumor lysis syndrome during preparation for continuous renal replacement therapy . all of these patients recovered , but re - introduction of cytarabine was limited thereafter , and one patient could not complete r - hyper - cvad . of these patients , 34 patients ( 79.1% ) experienced anemia , 42 patients ( 97.7% ) had neutropenia , and 28 patients ( 86.0% ) had thrombocytopenia . eight patients experienced grade 3 or 4 non - hematologic toxicity , such as alanine transaminase elevation ( n=4 ) , nausea ( n=2 ) , diarrhea ( n=1 ) , and rituximab - induced pneumonitis ( n=1 ) . thirty - nine patients ( 90.7% ) had febrile neutropenia , and bacterial growth was reported in the blood cultures of 16 patients ( 41.0% ) . the median rdis of adriamycin , vincristine , methotrexate , and cytarabine were 64.3% , 65.0% , 66.1% , and 58.9% , respectively . only 10.5% to 23.3% of patients received greater than 80% of the planned doses of chemotherapeutic agents . when we analyzed patients according to age ( > 40 years vs.  40 years , or > 60 years vs.  60 years ) , there were no differences in rdis . however , ps was related to differences in rdis of doxorubicin and methotrexate ( table 4 ) . the median number of days required for a complete cycle of immunochemotherapy for each patient was 31.0 days ( range , 21 to 54.8 days ) . there was no difference in the number of days required for a cycle of r - hyper - cvad among patients  60 years versus > 60 years old ( p=1.000 ) . patients with an ecog ps of  2 tended to have longer cycles compared to those with a ps of 0 or 1 . all patients had sporadic bl or bl - u ( i.e. , no patients had hiv - associated lymphoma ) and were of a median age of 51 years . dates of initial diagnosis ranged from february 2006 to march 2013 , and the majority of patients had advanced diseases at the time of diagnosis . more than half of patients were in ann arbor stage iv ( n=29 , 67.4% ) , had two or more extranodal sites ( n=23 , 53.5% ) , and were at high or high - intermediate risk ( n=25 , 58.1% ) according to the standard ipi . prophylactic measures , doses and intervals of cytotoxic drugs , number of planned cycles , central nervous system ( cns ) prophylaxis , and overall schedule of the regimen were as those in a previous study , except for administration of rituximab ( two patients received 375 mg / m of rituximab on the first and eighth days of each cycle , whereas others received the same dose of rituximab on the first day of each cycle only ) . according to the recommendations of the korean national health insurance guideline , granulocyte - colony stimulating factor ( g - csf ) was administered daily starting the first day patients showed an absolute neutrophil count ( anc ) < 1,000/l until the third consecutive day patients showed an anc > 3,000/l in each cycle . of the 32 evaluable patients , 24 patients ( 75% ) achieved a cr , and six patients experienced disease progression in the final response evaluation ( table 2 ) . seven patients experienced relapse after cr , with two patients experiencing cns involvement and five showing extra - cns sites ( two patients with skin and subcutaneous nodules , two patients with bone marrow involvement , and one patient with right inguinal lymph node involvement ) . after a median follow - up period of 20.0 months , the 2-year dfs , efs , and os rates of patients were 78.6% , 70.9% , and 81.4% , respectively ( fig . 1 ) . according to univariate analysis , bone marrow involvement , an absolute lymphocyte count ( alc ) < 1,200/l , and being a member of the standard ipidefined high - risk group were all associated with poorer efs . among ipi factors , age > 60 years and a poor eastern cooperative oncology group performance status ( ecog ps ) contributed to lower efs , whereas more than one extranodal site , stage iii or iv , and elevated serum lactate dehydrogenase levels did not . according to multivariate analysis , alc < 1,200/l and being a member of the high - risk group were independent risk factors ( table 3 ) . in contrast to the cox regression test for efs , most parameters did not have an impact on dfs ( table 3 ) . early deaths were reported in cycles 1a ( n=2 ; age , 51 and 64 years , respectively ) , 1b ( n=1 ; age , 66 years ) , 2a ( n=2 ; age , 67 and 72 years , respectively ) , and 2b ( n=1 ; age , 47 years ) . five of them ( except for one 47-year - old patient ) had an ecog ps  2 . causes of treatment - related mortality ( trm ) were bacterial septicemia ( n=5 ) and tumor lysis syndrome ( n=1 ; age , 51 years ) . in cycle 1a , two patients recovered from tumor lysis syndrome with the support of hemodialysis , one patient recovered with only hydration and oral allopurinol use , and the other patient died of rapidly progressing tumor lysis syndrome during preparation for continuous renal replacement therapy . all of these patients recovered , but re - introduction of cytarabine was limited thereafter , and one patient could not complete r - hyper - cvad . of these patients , 34 patients ( 79.1% ) experienced anemia , 42 patients ( 97.7% ) had neutropenia , and 28 patients ( 86.0% ) had thrombocytopenia . eight patients experienced grade 3 or 4 non - hematologic toxicity , such as alanine transaminase elevation ( n=4 ) , nausea ( n=2 ) , diarrhea ( n=1 ) , and rituximab - induced pneumonitis ( n=1 ) . thirty - nine patients ( 90.7% ) had febrile neutropenia , and bacterial growth was reported in the blood cultures of 16 patients ( 41.0% ) . the median rdis of adriamycin , vincristine , methotrexate , and cytarabine were 64.3% , 65.0% , 66.1% , and 58.9% , respectively . only 10.5% to 23.3% of patients received greater than 80% of the planned doses of chemotherapeutic agents . when we analyzed patients according to age ( > 40 years vs.  40 years , or > 60 years vs.  60 years ) , there were no differences in rdis . however , ps was related to differences in rdis of doxorubicin and methotrexate ( table 4 ) . the median number of days required for a complete cycle of immunochemotherapy for each patient was 31.0 days ( range , 21 to 54.8 days ) . there was no difference in the number of days required for a cycle of r - hyper - cvad among patients  60 years versus > 60 years old ( p=1.000 ) . patients with an ecog ps of  2 tended to have longer cycles compared to those with a ps of 0 or 1 . in the current study , r - hyper - cvad showed overall treatment outcomes comparable to those of previous retrospective and prospective studies of dose - intense regimens ( table 5 ) . however , the result was not as excellent as a clinical trial reported by thomas et al . : in the current study , a substantial number of patients could not complete immunochemotherapy due to toxicities or impaired ps , including six episodes of trm ( 14.0% ) . in which the patients were relatively younger ( median age , 46 years ) , including three patients ( 9.7% ) with a resected disease , and in particular , there were no patients with an ecog ps of 3 or 4 . these results imply that the treatment outcome of r - hyper - cvad can be affected by patient suitability for dose - intense chemotherapy . similar findings were also reported in a recent population - based analysis of 3,691 patients . in that study , which was outside the context of clinical trials , the surveillance epidemiology and end results ( seer ) data analysis estimated time trends for outcomes of bl in the united states . according to the results , more effective therapies are needed for older patients with bl despite improvements in survival from the 1973 - 2001 era to 2002 - 2008 era . to escape early death , considering an incidence of febrile neutropenia of over 90% with five episodes of death due to bacterial septic shock in the current study , as well as frequent infectious complications in other studies , prophylactic antibiotics and g - csf should be utilized . a gap between dfs and efs in the current study strongly suggests that survival could be substantially improved by reducing early death . therefore , supportive care should be strictly and routinely performed . despite the fact that higher ipi scores and lower alcs were shown to be poor prognostic factors of efs therefore , they might be risk factors for fatal complications of dose - intense treatment , rather than risk factors for treatment failure . however , as the prognostic factors in this study are only exploratory , these findings should be interpreted cautiously . concerns regarding development of peripheral neuropathy and cerebellar ataxia might mitigate the effect of poor ps on the reduced rdis of vincristine and cytarabine . overall , poor ps seems to keep patients from maintaining an adequate rdi of several drugs . since treatment of acute lymphoblastic leukemia is determined according to a patient s age ( adults vs. young and adolescents ) due to tolerability of the protocols , a similar question may be raised in the case of bl . it is reasonable to question whether or not a particular treatment protocol is as suitable for patients in their 20s as those applied to patients older than 60 . considering that age was one of the independent prognostic factors in the current study , r - hyper - cvad might not be an optimal treatment for elderly patients . however , in our study , there were no significant differences in rdi or number of days required for a complete cycle of r - hyper - cvad according to age . these results suggest that some elderly patients can tolerate r - hyper - cvad well . a review article in 2009 on treatment of adult patients with bl   concluded that a part of patients over 40 years of age could have highly favorable outcomes to modern dose - intense , multi - agent chemotherapy . their conclusion is also in line with a previous study on r - hyper - cvad in bl by thomas et al . , in which nine of 31 patients ( 29% ) were  60 years , and all were in continuous cr except for only one episode of later death due to infection . therefore , selection of patients according to chronological age seems not to be an ideal strategy . instead , other tools such as comprehensive geriatric assessment can be performed in patients with bl or burkitt - like lymphoma in the future . for those who are clearly intolerant to dose - intense regimens , alternative therapeutic strategies should be sought . a recent uncontrolled prospective study conducted by dunleavy et al .   reported that lower - dose , short - course chemotherapy consisting of infused etoposide , doxorubicin , and cyclophosphamide along with vincristine , prednisone , plus a double dose of rituximab ( sc - epochrr ) showed promising outcomes among 11 patients with hiv - associated bl . in that study , 100% progression - free survival and 90% os were achieved after a median followup time of 73 months , and toxicities were manageable . although patients receiving sc - epoch - rr were older ( median age , 44 years vs. 25 years ; p=0.03 ) than the 19 patients treated with standard dose - adjusted epoch - r , and patients receiving sc - epoch - rr also showed poorer ps ( 55% vs. 16% of patients with ecog ps  2 , p=0.04 ) , the outcomes were comparable . therefore , focusing on exposure - concentration time of drugs rather than peak concentration can be a reasonable strategy , and future studies are warranted , especially in a subgroup of patients who are not suitable for dose - intense chemotherapy . although the activity of rituximab has been demonstrated in most b - cell malignancies , data on the role of rituximab in bl or bl - u are limited . two phase ii studies   and several retrospective studies   have demonstrated that rituximab contributes to the improvement of os in patients with bl or burkitt - like lymphoma . a retrospective population - based study compared os between patients on rituximab ( n=111 ) to those without rituximab therapy ( n=52 ) , and according to their univariate analysis , addition of rituximab confirmed an association with improved os , mainly in the cohort of patients aged 40 - 65 . however , when adjusted for age and chemotherapy regimen , this association failed to maintain significance . compared to the md anderson study , a lower dose of rituximab was administered in the current study due to limitations in national insurance coverage , which might have an impact on outcomes . however , upon assessing the results of previous studies with or without rituximab , the role of rituximab does seems to be , at least , not absolute . rather , more refined patient selection , maximization of supportive care , and efforts to improve dose intensity are more important considerations and future efforts should focus on how to solve these problems . since we did not conduct a central pathologic review and did not analyze outcomes according to fluorescence in situ hybridization due to the scarcity of tested patients , other high - grade mature b - cell lymphomas such as dlbcl may be included in this patient population , and the poor prognosis of double - hit b - cell lymphoma may not be reflected , which is an obvious weakness of this study . notwithstanding , we believe that our assertion on the limitation of r - hyper - cvad in terms of toxicity and its resultant insufficient dose intensity in certain frail patients is still appropriate . r - hyper - cvad is an effective treatment regimen for highly aggressive b - cell lymphomas such as bl . however , due to its significant toxicity and unsatisfactory rdi among more frail korean patients , a more tolerable regimen with preserved efficacy is required for frail patients with bl or burkitt - like lymphomas , even in the rituximab era .
purposethis study was conducted to evaluate outcomes in adult patients with burkitt lymphoma ( bl ) or burkitt - like lymphoma treated with an rituximab plus hyper - cvad ( r - hyper - cvad ) regimen by focusing on tolerability and actual delivered relative dose intensity ( rdi).materials and methodspatients  20 years of age and pathologically diagnosed with bl or burkitt - like lymphoma were treated with at least one cycle of r - hyper - cvad as the first - line treatment in this study . 
 eligible patients case report forms were requested from their physicians to obtain clinical and laboratory data for this retrospective study.resultsforty-three patients ( median age , 51 years ) from 14 medical centers in korea were analyzed , none of which were infected with human immunodeficiency virus . 
 the majority of patients had advanced diseases , and 24 patients achieved a complete response ( 75.0% ) . 
 after a median follow - up period of 20.0 months , 2-year event - free and overall survival rates were 70.9% and 81.4% , respectively . 
 eleven patients ( 25.6% ) were unable to complete the r - hyper - cvad regimen , including six patients due to early death . 
 the rdis of adriamycin , vincristine , methotrexate , and cytarabine were between 60% and 65% , which means less than 25% of patients received greater than 80% of the planned dose of each drug . 
 poor performance status was related to the lower rdis of doxorubicin and methotrexate.conclusionr-hyper-cvad showed excellent treatment outcomes in patients who were suitable for dose - intense chemotherapy . 
 however , management of patients who are intolerant to a dose - intense regimen remains problematic due to the frequent occurrence of treatmentrelated complications .