title: Pegylated-asparaginase during induction therapy for adult acute lymphoblastic leukaemia: toxicity data from the UKALL14 trial.
abstract: Safety and efficacy data on pegylated asparaginase (PEG-ASP) in adult acute lymphoblastic leukaemia (ALL) induction regimens are limited. The UK National Cancer Research Institute UKALL14 trial NCT01085617 prospectively evaluated the tolerability of 1000 IU/m2PEG-ASP administered on days 4 and 18 as part of a five-drug induction regimen in adults aged 25-65 years with de novo ALL. Median age was 46.5 years. Sixteen of the 90 patients (median age 56 years) suffered treatment-related mortality during initial induction therapy. Eight of the 16 died of sepsis in combination with hepatotoxicity. Age and Philadelphia (Ph) status were independent variables predicting induction death >40 versus ⩽40 years, odds ratio (OR) 18.5 (2.02-169.0), P=0.01; Ph- versus Ph+ disease, OR 13.60 (3.52-52.36), P<0.001. Of the 74 patients who did not die, 37 (50.0%) experienced at least one grade 3/4 PEG-ASP-related adverse event, most commonly hepatotoxicity (36.5%, n=27). A single dose of PEG-ASP achieved trough therapeutic enzyme levels in 42/49 (86%) of the patients tested. Although PEG-ASP delivered prolonged asparaginase activity in adults, it was difficult to administer safely as part of the UKALL14 intensive multiagent regimen to those aged >40 years. It proved extremely toxic in patients with Ph+ ALL, possibly owing to interaction with imatinib.
authors.affiliation: Barts Cancer Institute, The London School of Medicine, Queen Mary University of London, London, UK.
authors.forename: B
authors.initials: B
authors.lastname: Patel
authors.affiliation: CR UK and UCL Cancer Trials Centre, London, UK.
authors.forename: A A
authors.initials: AA
authors.lastname: Kirkwood
authors.affiliation: Cancer Institute, University College London, London, UK.
authors.forename: A
authors.initials: A
authors.lastname: Dey
authors.affiliation: Centre for Clinical Haematology, Nottingham City Hospital, Nottingham, UK.
authors.forename: D I
authors.initials: DI
authors.lastname: Marks
authors.affiliation: United Bristol Healthcare Trust, Bristol, UK.
authors.forename: A K
authors.initials: AK
authors.lastname: McMillan
authors.affiliation: Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.
authors.forename: T F
authors.initials: TF
authors.lastname: Menne
authors.affiliation: CR UK and UCL Cancer Trials Centre, London, UK.
authors.forename: L
authors.initials: L
authors.lastname: Micklewright
authors.affiliation: CR UK and UCL Cancer Trials Centre, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Patrick
authors.affiliation: CR UK and UCL Cancer Trials Centre, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Purnell
authors.affiliation: Cardiff and Vale UHB, London, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Rowntree
authors.affiliation: CR UK and UCL Cancer Trials Centre, London, UK.
authors.forename: P
authors.initials: P
authors.lastname: Smith
authors.affiliation: Cancer Institute, University College London, London, UK.
authors.forename: A K
authors.initials: AK
authors.lastname: Fielding
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity; D001215:Asparaginase / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000401:mortality; D006801:Humans; D060828:Induction Chemotherapy / Q000379:methods; D008875:Middle Aged; D010677:Philadelphia Chromosome; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D018805:Sepsis / Q000139:chemically induced / Q000401:mortality
chemical_list: D000970:Antineoplastic Agents; D011092:Polyethylene Glycols; C042705:pegaspargase; D001215:Asparaginase