University of Oulu

Line Stensig Lynggaard, Cecilie Utke Rank, Stefan Nygaard Hansen, Sofie Gottschalk Højfeldt, Louise Tram Henriksen, Kirsten Brunsvig Jarvis, Susanna Ranta, Riitta Niinimäki, Arja Harila-Saari, Benjamin O Wolthers, Thomas L. Frandsen, Mats Heyman, Kjeld Schmiegelow, Birgitte Klug Albertsen; Asparaginase enzyme activity levels and toxicity in childhood acute lymphoblastic leukemia: a NOPHO ALL2008 study. Blood Adv 2022; 6 (1): 138–147. doi:

Asparaginase enzyme activity levels and toxicity in childhood acute lymphoblastic leukemia : a NOPHO ALL2008 study

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Author: Lynggaard, Line Stensig1,2; Rank, Cecilie Utke3; Hansen, Stefan Nygaard4;
Organizations: 1Department of Paediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark
2Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
3Department of Haematology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
4Department of Public Health, Aarhus University, Aarhus, Denmark
5Department of Paediatric Haematology and Oncology, Oslo University Hospital, Oslo, Norway
6Astrid Lindgren Children's Hospital, Karolinska University Hospital and Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
7Department of Paediatrics and Adolescent Medicine, Oulu University Hospital and PEDEGO unit, University of Oulu, Oulu, Finland
8Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden
9Department of Pediatrics and Adolescent Medicine, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
10Novo Nordisk A/S, Søborg, Denmark
11Institute of Clinical Medicine, Faculty of Medicine, University of Copenhagen, Copenhagen, Denmark
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.5 MB)
Persistent link:
Language: English
Published: American Society of Hematology, 2022
Publish Date: 2022-09-19


Asparaginase treatment is a mainstay in contemporary treatment of acute lymphoblastic leukemia (ALL), but substantial asparaginase-related toxicity may lead to jeopardized protocol compliance and compromises survival. We investigated the association between risk of asparaginase-associated toxicities (AspTox) and asparaginase enzyme activity (AEA) levels in 1155 children aged 1.0 to 17.9 years, diagnosed with ALL between July 2008 and March 2016, and treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol. Patients with ≥2 blood samples for AEA measurement drawn 14 ± 2 days after asparaginase administration were included (6944 trough values). AEA was measurable (or >0 IU/L) in 955 patients, whereas 200 patients (17.3%) had asparaginase inactivation and few AspTox recorded. A time-dependent multiple Cox model of time to any first asparaginase-associated toxicity adjusted for sex and age was used. For patients with measurable AEA, we found a hazard ratio (HR) of 1.17 per 100 IU/L increase in median AEA (95% confidence interval [CI], 0.98–1.41; P = 0.09). For pancreatitis, thromboembolism, and osteonecrosis, the HRs were 1.40 (95% CI, 1.12–1.75; P = 0.002), 0.99 (95% CI, 0.70–1.40; P = 0.96), and 1.36 (95% CI, 1.04–1.77; P = 0.02) per 100 IU/L increase in median AEA, respectively. No significant decrease in the risk of leukemic relapse was found: HR 0.88 per 100 IU/L increase in AEA (95% CI, 0.66–1.16; P = 0.35). In conclusion, these results emphasize that overall AspTox and relapse are not associated with AEA levels, yet the risk of pancreatitis and osteonecrosis increases with increasing AEA levels.

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Series: Blood advances
ISSN: 2473-9529
ISSN-E: 2473-9537
ISSN-L: 2473-9529
Volume: 6
Issue: 1
Pages: 138 - 147
DOI: 10.1182/bloodadvances.2021005631
Type of Publication: A1 Journal article – refereed
Field of Science: 3123 Gynaecology and paediatrics
3122 Cancers
Funding: This work was supported by grants from the Danish Childhood Cancer Foundation (B.K.A.), the Swedish Childhood Cancer Foundation (B.K.A.), the Dagmar Marshall’s foundation (L.S.L.), the Arvid Nilsson’s foundation (L.S.L.), Fabrikant Einar Willumsen’s foundation (L.S.L.), Eva and Henry Fraenkel’s foundation (L.S.L.), Jens and Maren Thestrups grant for cancer research (L.S.L.), and Holm’s memorial grant (L.S.L.).
Copyright information: © 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), per- mitting only noncommercial, nonderivative use with attribution. All other rights reserved.