Article, 2024
Increase in peg-asparaginase clearance as a predictor for inactivation in patients with acute lymphoblastic leukemia
Leukemia,
ISSN
1476-5551,
0887-6924,
Volume 38,
4,
Pages 712-719,
10.1038/s41375-024-02153-6
Contributors
Dam, Merete Eybye
0000-0002-8857-8629
[1]
[2]
Centanni, Maddalena
0000-0001-6594-9813
[3]
Friberg, Lena E
0000-0002-2979-679X
[3]
Centanni, Daniel
[3]
Karlsson, Mats O
0000-0003-1258-8297
[3]
Stensig Lynggaard, Line
[2]
Johannsdottir, Inga Maria Rinvoll
[4]
Wik, Hilde Skuterud
0000-0002-1035-5521
[4]
Malmros, Johan
[5]
[6]
Vaitkeviciene, Goda Elizabeta
0000-0001-6724-8164
[7]
Griskevicius, Laimonas
[7]
Hallböök, Helene
[3]
Jónsson, Ólafur Gísli
[8]
Overgaard, Ulrik Malthe
[9]
[10]
Schmiegelow, Kjeld
0000-0002-0829-4993
[9]
[10]
Hansen, Stefan Nygaard
[1]
Heyman, Mats Marshall
[5]
[6]
Albertsen, Birgitte Klug
0000-0002-3902-3694
(Corresponding author)
[1]
[2]
Affiliations
- [1]
Aarhus University
[NORA names:
AU Aarhus University; University; Denmark; Europe, EU; Nordic; OECD];
- [2]
Aarhus University Hospital
[NORA names:
Central Denmark Region; Hospital; Denmark; Europe, EU; Nordic; OECD];
- [3]
Uppsala University
[NORA names:
Sweden; Europe, EU; Nordic; OECD];
- [4]
Oslo University Hospital
[NORA names:
Norway; Europe, Non-EU; Nordic; OECD];
- [5]
Karolinska Institutet
[NORA names:
Sweden; Europe, EU; Nordic; OECD];
(... more)
- [6]
Karolinska University Hospital
[NORA names:
Sweden; Europe, EU; Nordic; OECD];
- [7]
Vilnius University Hospital Santariskiu Klinikos
[NORA names:
Lithuania; Europe, EU; OECD];
- [8]
National University Hospital of Iceland
[NORA names:
Iceland; Europe, Non-EU; Nordic; OECD];
- [9]
Rigshospitalet
[NORA names:
Capital Region of Denmark;
Hospital; Denmark; Europe, EU; Nordic; OECD];
- [10]
University of Copenhagen
[NORA names:
KU University of Copenhagen;
University; Denmark; Europe, EU; Nordic; OECD]
(less)
Abstract
Asparaginase is an essential component of acute lymphoblastic leukemia (ALL) therapy, yet its associated toxicities often lead to treatment discontinuation, increasing the risk of relapse. Hypersensitivity reactions include clinical allergies, silent inactivation, or allergy-like responses. We hypothesized that even moderate increases in asparaginase clearance are related to later inactivation. We therefore explored mandatory monitoring of asparaginase enzyme activity (AEA) in patients with ALL aged 1–45 years treated according to the ALLTogether pilot protocol in the Nordic and Baltic countries to relate mean AEA to inactivation, to build a pharmacokinetic model to better characterize the pharmacokinetics of peg-asparaginase and assess whether an increased clearance relates to subsequent inactivation. The study analyzed 1631 real-time AEA samples from 253 patients, identifying inactivation in 18.2% of the patients. This inactivation presented as mild allergy (28.3%), severe allergy (50.0%), or silent inactivation (21.7%). A pharmacokinetic transit compartment model was used to describe AEA-time profiles, revealing that 93% of patients with inactivation exhibited prior increased clearance, whereas 86% of patients without hypersensitivity maintained stable clearance throughout asparaginase treatment. These findings enable prediction of inactivation and options for either dose increments or a shift to alternative asparaginase formulations to optimize ALL treatment strategies.
Keywords
Baltic countries,
Nordic,
PEG-asparaginase,
activity,
acute lymphoblastic leukemia,
acute lymphoblastic leukemia aged 1,
aged 1,
allergy,
alltogether,
asparaginase,
asparaginase enzyme activity,
asparaginase formulations,
asparaginase treatment,
clearance,
clinical allergy,
compartment model,
countries,
discontinuation,
dose,
dose increments,
enzyme activity,
findings,
formulation,
hypersensitivity,
hypersensitivity reactions,
inactivation,
increase,
increased clearance,
increment,
leukemia,
lymphoblastic leukemia,
mild allergy,
model,
moderate increase,
monitoring,
options,
patients,
pharmacokinetic model,
pharmacokinetics,
pilot protocol,
prediction,
predictors,
profile,
protocol,
reaction,
relapse,
response,
risk,
risk of relapse,
samples,
severe allergy,
shift,
silent inactivation,
strategies,
study,
therapy,
toxicity,
transit compartment model,
treatment,
treatment discontinuation,
treatment strategies,
years
Funders
Data Provider: Digital Science