TY - JOUR
T1 - Increase in peg-asparaginase clearance as a predictor for inactivation in patients with acute lymphoblastic leukemia
AU - Dam, Merete
AU - Centanni, Maddalena
AU - Friberg, Lena E
AU - Centanni, Daniel
AU - Karlsson, Mats O
AU - Stensig Lynggaard, Line
AU - Johannsdottir, Inga Maria
AU - Wik, Hilde Skuterud
AU - Malmros, Johan
AU - Vaitkeviciene, Goda Elizabeta
AU - Griskevicius, Laimonas
AU - Hallböök, Helene
AU - Jónsson, Ólafur Gísli
AU - Overgaard, Ulrik
AU - Schmiegelow, Kjeld
AU - Hansen, Stefan Nygaard
AU - Heyman, Mats
AU - Albertsen, Birgitte Klug
N1 - © 2024. The Author(s).
PY - 2024/4
Y1 - 2024/4
N2 - 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.
AB - 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.
KW - Antineoplastic Agents/therapeutic use
KW - Asparaginase
KW - Humans
KW - Hypersensitivity/drug therapy
KW - Polyethylene Glycols
KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
UR - http://www.scopus.com/inward/record.url?scp=85183378578&partnerID=8YFLogxK
U2 - 10.1038/s41375-024-02153-6
DO - 10.1038/s41375-024-02153-6
M3 - Journal article
C2 - 38287133
SN - 0887-6924
VL - 38
SP - 712
EP - 719
JO - Leukemia
JF - Leukemia
IS - 4
ER -