Increase in peg-asparaginase clearance as a predictor for inactivation in patients with acute lymphoblastic leukemia

Merete Dam, Maddalena Centanni, Lena E. Friberg, Daniel Centanni, Mats O. Karlsson, Line Stensig Lynggaard, Inga Maria Johannsdottir, Hilde Skuterud Wik, Johan Malmros, Goda Elizabeta Vaitkeviciene, Laimonas Griskevicius, Helene Hallböök, Ólafur Gísli Jónsson, Ulrik Overgaard, Kjeld Schmiegelow, Stefan Nygaard Hansen, Mats Heyman, Birgitte Klug Albertsen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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.

Original languageEnglish
Pages (from-to)712-719
Number of pages8
JournalLeukemia
Volume38
Issue number4
DOIs
Publication statusPublished - Apr 2024

Bibliographical note

Publisher Copyright:
© 2024, The Author(s).

Other keywords

  • Polyethylene Glycols
  • Hypersensitivity/drug therapy
  • Humans
  • Antineoplastic Agents/therapeutic use
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
  • Asparaginase

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