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Article History

Accepted: 24 July 2025

First Online: 19 August 2025

Declarations

:

: The therapeutic drug monitoring program performed in the international AIEOP-BFM ALL 2009 trial has been in part supported by an unrestricted grant from the company Servier (and previously from medac GmBH, Sigma-Tau, Baxalta, and Shire, who have marketed the drug during the present study period). Analytical procedures have been supported by Servier Deutschland GmbH as well as medac GmbH. Anti-E. coli-ASNase and anti-PEG-ASNase antibodies have been analyzed by medac GmbH. Assay development and monitoring of anti-PEG antibodies within the AIEOP-BFM ALL 2009 trial was supported by Deutsche José Carreras Leukämie-Stiftung e.V. (DJCLSR 13/01). Additional funding was provided by Servier Deutschland GmbH to perform the population pharmacokinetic analysis described here. Christa E. Nath is supported by the Cancer Centre for Children at The Children’s Hospital at Westmead, Australia. Asparaginase monitoring in Australia was supported by funding from The Kids Cancer Alliance, a translational cancer research center of the Cancer Institute of New South Wales. No sources of funding were used to assist with the preparation of this manuscript.

: C.L.K. held invited talks for Sigma tau, Erytech, Jazz Pharma, and Servier and received honoraria for consultancy from Erytech and a travel grant from Servier. C.R.’s relationships with the companies Jazz Pharmaceuticals, Clinigen, and Servier marketing different asparaginase products have occurred throughout several years, in particular since when the study 2009 was started and was characterized by the introduction, in the clinical practice of the drug PEG-asparaginase as a first-line product and the Erwinia product as second line. The AIEOP-BFM ALL 2009 study was in any case an independent investigator-initiated study. The companies never interfered with his clinical, laboratory, and scientific activities regarding talks, or lectures or events when findings related to the abovementioned study were reported. M.S. and the ALL-BFM Study Center received funding from medac, Shire, Sigma-Tau, Servier, and Jazz Pharmaceuticals for research, and for functions in advisory boards. J.B. served personally as a consultant for the medac GmbH and Servier. He participated in advisory as well as on safety boards for the medac GmbH. He received support for travel from Eusa Pharma, Jazz Pharmaceuticals, Baxalta, Shire, and Servier. For medac GmbH, Eusa Pharma, Jazz Pharmaceuticals, Baxalta, Servier, Shire, and Sigma-Tau, he held invited lectures. For the Satellite meeting SIOP 2021, payment was to the university. In addition, institutional grants in the context of ASNase drug monitoring from more or less all ASNase providers contributed to the therapeutic drug monitoring program, including medac GmbH, Eusa Pharma, Jazz Pharmaceuticals, Baxalta, Servier, Shire, and Sigma-Tau (all representing the varying marketing authorization holders of E. coli ASNase, PEG-ASNase, and Erwinase).CS, CM, PS, CN and GW declare no conflicts of interest.

: The data sets generated and/or analyzed during the current study are not publicly available due to data protection rules and the fact that the complexity of the data does not allow for full anonymization.

: The AIEOP-BFM ALL 2009 trial (EudraCT No: 2007-004270-43) was approved by each national and local review board and was conducted in accordance with the Declaration of Helsinki and applicable national legislation. Informed consent was obtained from the parents or guardians of each patient included in the study. As the analysis described here extended the original informed consent, an additional ethics committee vote was obtained (Ethics Committee of the Medical Association Westfalen-Lippe and the University of Münster; reference number 2021-071-f-S).

: Informed consent was obtained from the parents or legal representative of each patient included in the study.

: Not applicable.

: The NONMEM codes for the final popPK models are provided on request.

: C.S., G.W., C.L.K., and J.B. designed the research. C.M., C.R., C.N., P.S., and M.S. collected the data. C.S., G.W., C.L.K., and J.B. performed and discussed the pharmacokinetic analysis. Results were discussed and interpreted by all authors during scientific meetings of the Asparaginase Working Party. G.W. and J.B. wrote the manuscript; all authors reviewed the manuscript and approved the final version of the manuscript.