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Activity and toxicity of intramuscular 1000 iu/m² polyethylene glycol-E. coli L-asparaginase in the UKALL 2003 and UKALL 2011 clinical trials

Sidhu, J; Masurekar, AN; Gogoi, MP; Fong, C; Ioannou, T; Lodhi, T; Parker, C; ... Krishnan, S; + view all (2022) Activity and toxicity of intramuscular 1000 iu/m² polyethylene glycol-E. coli L-asparaginase in the UKALL 2003 and UKALL 2011 clinical trials. British Journal of Haematology 10.1111/bjh.18158. (In press). Green open access

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Abstract

In successive UK clinical trials (UKALL 2003, UKALL 2011) for paediatric acute lymphoblastic leukaemia (ALL), polyethylene glycol-conjugated E. coli L-asparaginase (PEG-EcASNase) 1000 iu/m2 was administered intramuscularly with risk-stratified treatment. In induction, patients received two PEG-EcASNase doses, 14 days apart. Post-induction, non-high-risk patients (Regimens A, B) received 1–2 doses in delayed intensification (DI) while high-risk Regimen C patients received 6–10 PEG-EcASNase doses, including two in DI. Trial substudies monitored asparaginase (ASNase) activity, ASNase-related toxicity and ASNase-associated antibodies (total, 1112 patients). Median (interquartile range) trough plasma ASNase activity (14 ± 2 days post dose) following first and second induction doses and first DI dose was respectively 217 iu/l (144–307 iu/l), 265 iu/l (165–401 iu/l) and 292 iu/l (194–386 iu/l); 15% (138/910) samples showed subthreshold ASNase activity (<100 iu/l) at any trough time point. Older age was associated with lower (regression coefficient −9.5; p < 0.0001) and DI time point with higher ASNase activity (regression coefficient 29.9; p < 0.0001). Clinical hypersensitivity was observed in 3.8% (UKALL 2003) and 6% (UKALL 2011) of patients, and in 90% or more in Regimen C. A 7% (10/149) silent inactivation rate was observed in UKALL 2003. PEG-EcASNase schedule in UKALL paediatric trials is associated with low toxicity but wide interpatient variability. Therapeutic drug monitoring potentially permits optimisation through individualised asparaginase dosing.

Type: Article
Title: Activity and toxicity of intramuscular 1000 iu/m² polyethylene glycol-E. coli L-asparaginase in the UKALL 2003 and UKALL 2011 clinical trials
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/bjh.18158
Publisher version: https://doi.org/10.1111/bjh.18158
Language: English
Additional information: Copyright © 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: PEG-asparaginase, acute lymphoblastic leukaemia, children
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > CRUK Cancer Trials Centre
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10147006
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