***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: The Dana-Farber Cancer Institute ( DFCI ) acute lymphoblastic leukemia ( ALL ) Consortium Protocol 91 - 01 was design ed to improve the outcome of children with newly diagnosed ALL while minimizing toxicity . Compared with prior protocol s , post-remission therapy was intensified by substituting dexamethasone for prednisone and prolonging the asparaginase intensification from 20 to 30 weeks .  Between 1991 and 1995 , 377 patients ( age , 0 - 18 years ) were enrolled ; 137 patients were considered st and ard risk ( SR ) , and 240 patients were high risk ( HR ) . Following a 5.0-year median follow-up , the estimated 5-year event-free survival ( EFS ) + /- SE for all patients was 83 % + /- 2 % , which is superior to prior DFCI ALL Consortium protocol s conducted between 1981 and 1991 ( P = .03 ) . There was no significant difference in 5-year EFS based upon risk group ( 87 % + /- 3 % for SR and 81 % + /- 3 % for HR , P = .24 ) . Age at diagnosis was a statistically significant prognostic factor ( P = .03 ) , with inferior outcomes observed in infants and children 9 years or older . Patients who tolerated 25 or fewer weeks of asparaginase had a significantly worse outcome than those who received at least 26 weeks of asparaginase ( P < .01 , both univariate and multivariate ) . Older children ( at least 9 years of age ) were significantly more likely to have tolerated 25 or fewer weeks of asparaginase ( P < .01 ) . Treatment on Protocol 91 - 01 significantly improved the outcome of children with ALL , perhaps due to the prolonged asparaginase intensification and /or the use of dexamethasone . The inferior outcome of older children may be due , in part , to increased intolerance of intensive therapy BACKGROUND l-asparaginase is a universal component of treatment for childhood acute lymphoblastic leukaemia , and is usually administered intramuscularly . Pegylated Escherichia coli asparaginase ( PEG-asparaginase ) has a longer half-life and is potentially less immunogenic than the native Escherichia coli ( E coli ) preparation , and can be more feasibly administered intravenously . The aim of the Dana-Farber Cancer Institute Acute Lymphoblastic Leukaemia Consortium Protocol 05 - 001 ( DFCI 05 - 001 ) was to compare the relative toxicity and efficacy of intravenous PEG-asparaginase and intramuscular native E colil-asparaginase in children with newly diagnosed acute lymphoblastic leukaemia . METHODS DFCI 05 - 001 enrolled patients aged 1 - 18 years with newly diagnosed acute lymphoblastic leukaemia from 11 consortium sites in the USA and Canada . Patients were assigned to an initial risk group on the basis of their baseline characteristics and then underwent 32 days of induction therapy . Those who achieved complete remission after induction therapy were assigned to a final risk group and were eligible to participate in a r and omised comparison of intravenous PEG-asparaginase ( 15 doses of 2500 IU/m(2 ) every 2 weeks ) or intramuscular native E colil-asparaginase ( 30 doses of 25 000 IU/m(2 ) weekly ) , beginning at week 7 after study entry . R and omisation ( 1:1 ) was unmasked , and was done by a statistician-generated allocation sequence using a permuted blocks algorithm ( block size of 4 ) , stratified by final risk group . The primary endpoint of the r and omised comparison was the overall frequency of asparaginase-related toxicities ( defined as allergy , pancreatitis , and thrombotic or bleeding complications ) . Predefined secondary endpoints were disease-free survival , serum asparaginase activity , and quality of life during therapy as assessed by PedsQL surveys . All analyses were done by intention to treat . This study is registered with Clinical Trials.gov , number NCT00400946 . FINDINGS Between April 22 , 2005 , and Feb 12 , 2010 , 551 eligible patients were enrolled . 526 patients achieved complete remission after induction , of whom 463 were r and omly assigned to receive intramuscular native E colil-asparaginase ( n=231 ) or intravenous PEG-asparaginase ( n=232 ) . The two treatment groups did not differ significantly in the overall frequency of asparaginase-related toxicities ( 65 [ 28 % ] of 232 patients in the intravenous PEG-asparaginase group vs 59 [ 26 % ] of 231 patients in the intramuscular native E colil-asparaginase group , p=0·60 ) , or in the individual frequency of allergy ( p=0·36 ) , pancreatitis ( p=0·55 ) , or thrombotic or bleeding complications ( p=0·26 ) . Median follow-up was 6·0 years ( IQR 5·0 - 7·1 ) . 5-year disease-free survival was 90 % ( 95 % CI 86 - 94 ) for patients assigned to intravenous PEG-asparaginase and 89 % ( 85 - 93 ) for those assigned to intramuscular native E colil-asparaginase ( p=0·58 ) . The median nadir serum asparaginase activity was significantly higher in patients who received intravenous PEG-asparaginase than in those who received intramuscular native E colil-asparaginase . Significantly more anxiety was reported by both patients and parent-proxy in the intramuscular native E colil-asparaginase group than in the intravenous PEG-asparaginase group . Scores for other domains were similar between the groups . The most common grade 3 or worse adverse events were bacterial or fungal infections ( 47 [ 20 % ] of 232 in the intravenous PEG-asparaginase group vs 51 [ 22 % ] of 231 patients in the intramuscular E colil-asparaginase group ) and asparaginase-related allergic reactions ( 14 [ 6 % ] vs 6 [ 3 % ] ) . INTERPRETATION Intravenous PEG-asparaginase was not more toxic than , was similarly efficacious to , and was associated with decreased anxiety compared with intramuscular native E colil-asparaginase , supporting its use as the front-line asparaginase preparation in children with newly diagnosed acute lymphoblastic leukaemia . FUNDING National Cancer Institute and Enzon Pharmaceuticals For this study , 118 children with st and ard-risk acute lymphoblastic leukemia ( ALL ) were given r and omized assignments to receive native or pegylated Escherichia coli asparaginase as part of induction and 2 delayed intensification phases . Patients treated with pegaspargase had more rapid clearance of lymphoblasts from day 7 and day 14 bone marrow aspirates and more prolonged asparaginase activity than those treated with native asparaginase . In the first delayed intensification phase , 26 % of native asparaginase patients had high-titer antibodies , whereas 2 % of pegaspargase patients had those levels . High-titer antibodies were associated with low asparaginase activity in the native arm , but not in the pegaspargase arm . Adverse events , infections , and hospitalization were similar between arms . Event-free survival at 3 years was 82 % . A population pharmacodynamic model using the nonlinear mixed effects model ( NONMEM ) program was developed that closely fit the measured enzyme activity and asparagine concentrations . Half-lives of asparaginase were 5.5 days and 26 hours for pegaspargase and native asparaginase , respectively . There was correlation between asparaginase enzymatic activity and depletion of asparagine or glutamine in serum . In cerebrospinal fluid asparagine , depletion was similar with both enzyme preparations . Intensive pegaspargase for newly diagnosed ALL should be tested further in a larger population PURPOSE To improve efficacy and reduce toxicity of treatment for children with acute lymphoblastic leukemia . PATIENTS AND METHODS Patients from all risk groups , including infants and those with T-cell disease , were treated between 1987 and 1991 . St and ard-risk ( SR ) patients did not receive cranial irradiation , whereas high-risk ( HR ) and very high-risk ( VHR ) patients participated in a r and omized comparison of 18 Gy of cranial irradiation conventionally fractionated versus two fractions per day ( hyperfractionated ) . RESULTS At a median follow-up of 9.2 years , the 9-year event-free survival ( EFS + /- SE ) was 75 % + /- 2 % for all 369 patients , 77 % + /- 4 % for the 142 SR patients , and 73 % + /- 3 % for the 227 HR/VHR patients ( P = .37 comparing SR and HR/VHR ) . The CNS , with or without concomitant bone marrow involvement , was the first site of relapse in 19 ( 13 % ) of the 142 SR patients : 16 ( 20 % ) of 79 SR boys and three ( 5 % ) of 63 SR girls . This high incidence of relapses necessitated a recall of SR boys for additional therapy . CNS relapse occurred in only two ( 1 % ) of 227 HR and VHR patients . There were no outcome differences found among r and omized treatment groups . Nine-year overall survival was 84 % + /- 2 % for the entire population , 93 % + /- 2 % for SR children , and 79 % + /- 3 % for HR and VHR children ( P < .01 comparing SR and HR/VHR ) . CONCLUSION A high overall survival outcome was obtained for SR patients despite the high risk of CNS relapse for SR boys , which was presumed to be associated with eliminating cranial radiation without intensifying systemic or intrathecal chemotherapy . For HR/VHR patients , inability to salvage after relapse ( nearly all of which were in the bone marrow ) remains a significant clinical problem Background . L‐asparaginase has been a mainstay of therapy along with vincristine and prednisone in the treatment of acute lymphoblastic leukemia ( ALL ) in children for almost 30 years . Because L‐asparaginase is a foreign protein , the potential exists for severe , dose‐limiting hypersensitivity reactions . To reduce this toxicity , L‐asparaginase has been linked with polyethylene glycol ( PEG ) Background : Administration of L-asparaginase is limited by hypersensitivity reactions mediated by anti-asparaginase antibodies . To overcome this problem , native Escherichia coli L-asparaginase was conjugated to polyethylene glycol ( PEG ) to formulate PEG-L-asparaginase , a preparation with decreased immunogenicity and increased circulating half-life . In early trials , PEG-L-asparaginase was tolerated by patients known to be hypersensitive to the native E. coli product . Methods : The Pediatric Oncology Group conducted a phase II , r and omized trial to compare the efficacy and toxicity of PEG-L-asparaginase compared with native E. coli asparaginase in children with acute lymphoblastic leukemia in second bone marrow relapse . All patients ( n=76 ) received st and ard doses of vincristine and prednisone .  Nonhypersensitive patients ( n=34 ) were r and omized to receive either PEG-L-asparaginase of 2500 IU/m2/dose intramuscularly on days 1 and 15 ( treatment I ) or native E. coli asparaginase of 10,000 IU/m2/dose intramuscularly on days 1 , 3 , 5 , 8 , 10 , 12 , 15 , 17 , 19 , 22 , 24 , and 26 ( treatment II ) . Patients with a clinical history of an allergic reaction to unmodified asparaginase were directly assigned to treatment with PEG-L-asparaginase ( n=42 ) . Asparaginase levels and anti-asparaginase antibody titers were monitored in all patients . Response and toxicity were scored using conventional criteria . Results : The complete response rate for the total study population was 41 % . There was no difference in complete response between patients r and omized to PEG ( 47 % ) and native asparaginase ( 41 % ) . PEG was well tolerated even in patients with prior allergic reactions to native asparaginase . PEG half-life was shorter in patients with prior allergy . Conclusions : PEG asparaginase is a useful agent in patients with allergic reactions to native asparaginase The Dana-Farber Cancer Institute ( DFCI ) Childhood ALL Consortium Protocol 95 - 01 was design ed to minimize therapy-related morbidity for children with newly diagnosed ALL without compromising efficacy . Patients participated in r and omized comparisons of ( 1 ) doxorubicin given with or without dexrazoxane , a cardioprotectant ( high-risk patients ) , ( 2 
    Output:
    
Evidence is insufficient to assess the effects on health outcomes because of the limited number and power of studies and important flaws in their design or conduct in classifying PEG-asparaginase as a superior drug or not , in the pharmacotherapy of ALL in children and adolescents .
PEG-asparaginase can be used as a substitute for native E. coli L-asparaginase , demonstrating similar efficacy and safety .