title: Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial.
abstract: 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 randomised 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. Randomisation (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 randomised 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 ClinicalTrials.gov, number NCT00400946.
  
  
  RESULTS
  Between April 22, 2005, and Feb 12, 2010, 551 eligible patients were enrolled. 526 patients achieved complete remission after induction, of whom 463 were randomly 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%]).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  National Cancer Institute and Enzon Pharmaceuticals.
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Place
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Stevenson
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Lynda M
authors.initials: LM
authors.lastname: Vrooman
authors.affiliation: Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Marian H
authors.initials: MH
authors.lastname: Harris
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Hunt
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Jane E
authors.initials: JE
authors.lastname: O'Brien
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.affiliation: Department of Pediatrics, Golisano Children's Hospital, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Asselin
authors.affiliation: Division of Pediatric Hematology/Oncology, McMaster University, Hamilton, ON, Canada.
authors.forename: Uma H
authors.initials: UH
authors.lastname: Athale
authors.affiliation: Division of Pediatric Oncology, San Jorge Children's Hospital, San Juan, Puerto Rico.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Clavell
authors.affiliation: Division of Pediatric Hematology/Oncology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Cole
authors.affiliation: Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Medical Center, New York-Presbyterian Morgan Stanley Children's Hospital New York, NY, USA.
authors.forename: Kara M
authors.initials: KM
authors.lastname: Kelly
authors.affiliation: Division of Hematology and Oncology, Hospital Sainte-Justine, University of Montreal, Montreal, Canada.
authors.forename: Caroline
authors.initials: C
authors.lastname: Laverdiere
authors.affiliation: Division of Hematology and Oncology, Hospital Sainte-Justine, University of Montreal, Montreal, Canada.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Leclerc
authors.affiliation: Division of Hematology-Oncology, Centre Hospitalier Universite de Quebec, Quebec City, Canada.
authors.forename: Bruno
authors.initials: B
authors.lastname: Michon
authors.affiliation: Inova Fairfax Hospital for Children, Falls Church, VA, USA.
authors.forename: Marshall A
authors.initials: MA
authors.lastname: Schorin
authors.affiliation: Division of Pediatric Hematology-Oncology, Hasbro Children's Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Jennifer J G
authors.initials: JJ
authors.lastname: Welch
authors.affiliation: Department of Pediatrics, Wayne State University Medical School, Detroit, MI, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Lipshultz
authors.affiliation: Infinity Pharmaceuticals, Cambridge, MA, USA.
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Traci M
authors.initials: TM
authors.lastname: Blonquist
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Electronic address: lewis_silverman@dfci.harvard.edu.
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
mesh_terms: D061605:Administration, Intravenous; D000293:Adolescent; D000367:Age Factors; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001215:Asparaginase / Q000008:administration & dosage* / Q000009:adverse effects; D002170:Canada; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004926:Escherichia coli / Q000201:enzymology*; D029968:Escherichia coli Proteins / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D007223:Infant; D007273:Injections, Intramuscular; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D008297:Male; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000009:adverse effects; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality; D016016:Proportional Hazards Models; D011788:Quality of Life; D012307:Risk Factors; D011795:Surveys and Questionnaires; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
chemical_list: D000970:Antineoplastic Agents; D029968:Escherichia coli Proteins; D011092:Polyethylene Glycols; C042705:pegaspargase; D001215:Asparaginase