PMID- 26549586 OWN - NLM STAT- MEDLINE DCOM- 20160418 LR - 20220321 IS - 1474-5488 (Electronic) IS - 1470-2045 (Linking) VI - 16 IP - 16 DP - 2015 Dec TI - 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. PG - 1677-90 LID - S1470-2045(15)00363-0 [pii] LID - 10.1016/S1470-2045(15)00363-0 [doi] AB - 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. 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 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%]). 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. CI - Copyright (c) 2015 Elsevier Ltd. All rights reserved. FAU - Place, Andrew E AU - Place AE AD - 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. FAU - Stevenson, Kristen E AU - Stevenson KE AD - Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. FAU - Vrooman, Lynda M AU - Vrooman LM AD - 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. FAU - Harris, Marian H AU - Harris MH AD - Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. FAU - Hunt, Sarah K AU - Hunt SK AD - Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. FAU - O'Brien, Jane E AU - O'Brien JE AD - Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. FAU - Supko, Jeffrey G AU - Supko JG AD - Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. FAU - Asselin, Barbara L AU - Asselin BL AD - Department of Pediatrics, Golisano Children's Hospital, University of Rochester Medical Center, Rochester, NY, USA. FAU - Athale, Uma H AU - Athale UH AD - Division of Pediatric Hematology/Oncology, McMaster University, Hamilton, ON, Canada. FAU - Clavell, Luis A AU - Clavell LA AD - Division of Pediatric Oncology, San Jorge Children's Hospital, San Juan, Puerto Rico. FAU - Cole, Peter D AU - Cole PD AD - Division of Pediatric Hematology/Oncology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, NY, USA. FAU - Kelly, Kara M AU - Kelly KM AD - Division of Pediatric Hematology/Oncology/Stem Cell Transplantation, Columbia University Medical Center, New York-Presbyterian Morgan Stanley Children's Hospital New York, NY, USA. FAU - Laverdiere, Caroline AU - Laverdiere C AD - Division of Hematology and Oncology, Hospital Sainte-Justine, University of Montreal, Montreal, Canada. FAU - Leclerc, Jean-Marie AU - Leclerc JM AD - Division of Hematology and Oncology, Hospital Sainte-Justine, University of Montreal, Montreal, Canada. FAU - Michon, Bruno AU - Michon B AD - Division of Hematology-Oncology, Centre Hospitalier Universite de Quebec, Quebec City, Canada. FAU - Schorin, Marshall A AU - Schorin MA AD - Inova Fairfax Hospital for Children, Falls Church, VA, USA. FAU - Welch, Jennifer J G AU - Welch JJ AD - Division of Pediatric Hematology-Oncology, Hasbro Children's Hospital, Warren Alpert Medical School of Brown University, Providence, RI, USA. FAU - Lipshultz, Steven E AU - Lipshultz SE AD - Department of Pediatrics, Wayne State University Medical School, Detroit, MI, USA. FAU - Kutok, Jeffery L AU - Kutok JL AD - Infinity Pharmaceuticals, Cambridge, MA, USA. FAU - Blonquist, Traci M AU - Blonquist TM AD - Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. FAU - Neuberg, Donna S AU - Neuberg DS AD - Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. FAU - Sallan, Stephen E AU - Sallan SE AD - 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. FAU - Silverman, Lewis B AU - Silverman LB AD - 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. LA - eng SI - ClinicalTrials.gov/NCT00400946 GR - 5P01CA068484/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase III PT - Comparative Study PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20151106 PL - England TA - Lancet Oncol JT - The Lancet. Oncology JID - 100957246 RN - 0 (Antineoplastic Agents) RN - 0 (Escherichia coli Proteins) RN - 3WJQ0SDW1A (Polyethylene Glycols) RN - 7D96IR0PPM (pegaspargase) RN - EC 3.5.1.1 (Asparaginase) SB - IM CIN - Lancet Oncol. 2015 Dec;16(16):1580-1. PMID: 26549585 MH - Administration, Intravenous MH - Adolescent MH - Age Factors MH - Antineoplastic Agents/*administration & dosage/adverse effects MH - Asparaginase/*administration & dosage/adverse effects MH - Canada MH - Child MH - Child, Preschool MH - Disease-Free Survival MH - Escherichia coli/*enzymology MH - Escherichia coli Proteins/*administration & dosage/adverse effects MH - Female MH - Humans MH - Infant MH - Injections, Intramuscular MH - Intention to Treat Analysis MH - Kaplan-Meier Estimate MH - Male MH - Polyethylene Glycols/*administration & dosage/adverse effects MH - Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis/*drug therapy/mortality MH - Proportional Hazards Models MH - Quality of Life MH - Risk Factors MH - Surveys and Questionnaires MH - Time Factors MH - Treatment Outcome MH - United States EDAT- 2015/11/10 06:00 MHDA- 2016/04/19 06:00 CRDT- 2015/11/10 06:00 PHST- 2015/08/19 00:00 [received] PHST- 2015/09/19 00:00 [revised] PHST- 2015/09/21 00:00 [accepted] PHST- 2015/11/10 06:00 [entrez] PHST- 2015/11/10 06:00 [pubmed] PHST- 2016/04/19 06:00 [medline] AID - S1470-2045(15)00363-0 [pii] AID - 10.1016/S1470-2045(15)00363-0 [doi] PST - ppublish SO - Lancet Oncol. 2015 Dec;16(16):1677-90. doi: 10.1016/S1470-2045(15)00363-0. Epub 2015 Nov 6.