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Early Toxicity in Childhood Acute Lymphoblastic Leukemia : A Comparison of NOPHO ALL2008 and ALLTogether Protocols in Sweden

Fermér, Johannes ; van Bunningen, Hannah ; Zhou, Otto ; Abrahamsson, Jonas ; Borssen, Magnus ; Donnér, Isabella ; Heyman, Mats ; Holmqvist, Anna Sällfors LU ; Valind, Anders LU orcid and Vogt, Hartmut , et al. (2026) In Pediatric Blood and Cancer 73(2).
Abstract

Background: The European ALLTogether protocol for childhood acute lymphoblastic leukemia, initiated in Sweden 2019, introduced earlier asparaginase during induction, dexamethasone instead of prednisone for all patients, and omitted anthracyclines from low-risk induction to reduce treatment-related toxicity. Consolidation-1 was based on the Induction 1B-phase developed by the BFM-group, replacing mercaptopurine, methotrexate, and asparaginase used in the previous NOPHO ALL2008 protocol, ALL2008. Following implementation, early treatment toxicity was considered unacceptably high, prompting a protocol amendment. We compared the prevalence of 14 predefined toxicities, the number of inpatient days, and weight changes during induction and... (More)

Background: The European ALLTogether protocol for childhood acute lymphoblastic leukemia, initiated in Sweden 2019, introduced earlier asparaginase during induction, dexamethasone instead of prednisone for all patients, and omitted anthracyclines from low-risk induction to reduce treatment-related toxicity. Consolidation-1 was based on the Induction 1B-phase developed by the BFM-group, replacing mercaptopurine, methotrexate, and asparaginase used in the previous NOPHO ALL2008 protocol, ALL2008. Following implementation, early treatment toxicity was considered unacceptably high, prompting a protocol amendment. We compared the prevalence of 14 predefined toxicities, the number of inpatient days, and weight changes during induction and consolidation-1 between the two protocols. Methods: We conducted a population-based cohort study in Sweden, reviewing patient records from 117 children treated under ALLTogether protocol and 234 matched controls under ALL2008 protocol. Results: The mean number of toxicities per patient was similar between the protocols (2.5 [290/117] vs. 2.3 [547/234]). ALLTogether cohort had significantly greater weight gain, with over 50% experiencing a > 10% increase (p < 0.01). Hyperglycemia (OR 5.17, 95% CI 1.93–13.82) and osteonecrosis (3.4% vs. 0%, p = 0.012) were more common, while liver dysfunction (0.59, 0.38–0.93) was less frequent in the ALLTogether protocol. The number of inpatient days was similar across protocols, except for the initial hospitalization, which was longer in ALLTogether (median 11 vs. 7 days, p < 0.01). Conclusions: The early introduction of asparaginase likely contributed to increased weight gain, hyperglycemia, and osteonecrosis. While overall toxicity burden remained similar between protocols, the shift in toxicity profile may explain the perception of increased early toxicity during treatment with the ALLTogether protocol. Trial Registration: ClinicalTrials.gov identifier: NCT03911128; EudraCT numbers: 2018-001795-38 and 2008-003235-20.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
acute lymphoblastic leukemia, ALLTogether, corticosteroid, pediatric oncology, pegylated asparaginase, treatment toxicity
in
Pediatric Blood and Cancer
volume
73
issue
2
article number
e32168
publisher
John Wiley & Sons Inc.
external identifiers
  • scopus:105022465015
  • pmid:41262029
ISSN
1545-5009
DOI
10.1002/pbc.32168
language
English
LU publication?
yes
id
51180182-93d9-4519-9d91-8521f3643e66
date added to LUP
2026-02-09 15:09:40
date last changed
2026-05-05 04:30:12
@article{51180182-93d9-4519-9d91-8521f3643e66,
  abstract     = {{<p>Background: The European ALLTogether protocol for childhood acute lymphoblastic leukemia, initiated in Sweden 2019, introduced earlier asparaginase during induction, dexamethasone instead of prednisone for all patients, and omitted anthracyclines from low-risk induction to reduce treatment-related toxicity. Consolidation-1 was based on the Induction 1B-phase developed by the BFM-group, replacing mercaptopurine, methotrexate, and asparaginase used in the previous NOPHO ALL2008 protocol, ALL2008. Following implementation, early treatment toxicity was considered unacceptably high, prompting a protocol amendment. We compared the prevalence of 14 predefined toxicities, the number of inpatient days, and weight changes during induction and consolidation-1 between the two protocols. Methods: We conducted a population-based cohort study in Sweden, reviewing patient records from 117 children treated under ALLTogether protocol and 234 matched controls under ALL2008 protocol. Results: The mean number of toxicities per patient was similar between the protocols (2.5 [290/117] vs. 2.3 [547/234]). ALLTogether cohort had significantly greater weight gain, with over 50% experiencing a &gt; 10% increase (p &lt; 0.01). Hyperglycemia (OR 5.17, 95% CI 1.93–13.82) and osteonecrosis (3.4% vs. 0%, p = 0.012) were more common, while liver dysfunction (0.59, 0.38–0.93) was less frequent in the ALLTogether protocol. The number of inpatient days was similar across protocols, except for the initial hospitalization, which was longer in ALLTogether (median 11 vs. 7 days, p &lt; 0.01). Conclusions: The early introduction of asparaginase likely contributed to increased weight gain, hyperglycemia, and osteonecrosis. While overall toxicity burden remained similar between protocols, the shift in toxicity profile may explain the perception of increased early toxicity during treatment with the ALLTogether protocol. Trial Registration: ClinicalTrials.gov identifier: NCT03911128; EudraCT numbers: 2018-001795-38 and 2008-003235-20.</p>}},
  author       = {{Fermér, Johannes and van Bunningen, Hannah and Zhou, Otto and Abrahamsson, Jonas and Borssen, Magnus and Donnér, Isabella and Heyman, Mats and Holmqvist, Anna Sällfors and Valind, Anders and Vogt, Hartmut and Ranta, Susanna and Harila, Arja}},
  issn         = {{1545-5009}},
  keywords     = {{acute lymphoblastic leukemia; ALLTogether; corticosteroid; pediatric oncology; pegylated asparaginase; treatment toxicity}},
  language     = {{eng}},
  number       = {{2}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{Pediatric Blood and Cancer}},
  title        = {{Early Toxicity in Childhood Acute Lymphoblastic Leukemia : A Comparison of NOPHO ALL2008 and ALLTogether Protocols in Sweden}},
  url          = {{http://dx.doi.org/10.1002/pbc.32168}},
  doi          = {{10.1002/pbc.32168}},
  volume       = {{73}},
  year         = {{2026}},
}