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

Y1 - 2024

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 - Humans

KW - Asparaginase

KW - Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy

KW - Polyethylene Glycols

KW - Hypersensitivity/drug therapy

KW - Antineoplastic Agents/therapeutic use

U2 - 10.1038/s41375-024-02153-6

DO - 10.1038/s41375-024-02153-6

M3 - Journal article

C2 - 38287133

VL - 38

SP - 712

EP - 719

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 4

ER -