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Therapy

Pharmacokinetic, pharmacodynamic and intracellular effects of PEG-asparaginase in newly diagnosed childhood acute lymphoblastic leukemia: results from a single agent window study

Leukemia volume 22, pages 1665–1679 (2008)Cite this article

Abstract

L-asparaginase is an effective drug for treatment of children with acute lymphoblastic leukemia (ALL). The effectiveness is thought to result from depletion of asparagine in serum and cells. We investigated the clinical response in vivo of 1000 IU/m2 pegylated (PEG)-asparaginase and its pharmacokinetic, pharmacodynamic and intracellular effects in children with newly diagnosed ALL before start of combination chemotherapy. The in vivo window response was significantly related to immunophenotype and genotype: 26/38 common/pre B-ALL cases, especially those with hyperdiploidy and TELAML1 rearrangement, demonstrated a good clinical response compared to 8/17 T-ALL (P=0.01) and BCRABL-positive ALL (P=0.04). A poor in vivo clinical window response was related to in vitro resistance to L-asparaginase (P=0.02) and both were prognostic factors for long-term event-free survival (hazard ratio 6.4, P=0.004; hazard ratio 3.7, P=0.01). After administration of one in vivo dose of PEG-asparaginase no changes in apoptotic parameters or in intracellular levels of twenty amino acids in leukemic cells could be measured, in contradiction to the changes found after in vitro exposure. This may be explained by the rapid removal of apoptotic cells from the circulation in vivo. One additional dose of PEG-asparaginase upfront ALL treatment did not lead to other severe toxicities.

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Authors and Affiliations

  1. Department of Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Erasmus University Medical Center, Rotterdam, The Netherlands

    I M Appel, K M Kazemier, J Huijmans, M L den Boer & R Pieters

  2. Department of Pediatric Hematology/Oncology, University Children's Hospital Muenster, Muenster, Germany

    J Boos & C Lanvers

  3. Department of Pediatrics, University Hospital, Vrije Universiteit, Amsterdam, The Netherlands

    A J P Veerman

  4. Dutch Childhood Oncology Group, The Hague, The Netherlands

    A J P Veerman & E van Wering

Authors
  1. I M Appel
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  2. K M Kazemier
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  3. J Boos
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  4. C Lanvers
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  5. J Huijmans
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  6. A J P Veerman
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  7. E van Wering
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  8. M L den Boer
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Correspondence to I M Appel.

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Authorship

IMA designed and analyzed experiments and wrote the paper; KMK performed the research on the laboratory and analyzed the data; JB contributed vital tools for experiments on serum L-asparaginase activity and serum amino-acid analyses; CL performed experiments and contributed vital tools for experiments on serum L-asparaginase activity and serum amino-acid analyses; JH contributed vital tools for experiments on intracellular amino-acid analyses; AJPV is chairman of the DCOG-ALL-9 protocol; EvW contributed vital tools on behalf of the DCOG; MLdB designed and analyzed experiments and contributed to writing the paper; RP designed and analyzed experiments and contributed to writing the paper.

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Appel, I., Kazemier, K., Boos, J. et al. Pharmacokinetic, pharmacodynamic and intracellular effects of PEG-asparaginase in newly diagnosed childhood acute lymphoblastic leukemia: results from a single agent window study. Leukemia 22, 1665–1679 (2008). https://doi.org/10.1038/leu.2008.165

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Keywords

  • PEG-asparaginase
  • intracellular effects
  • window response
  • drug resistance
  • ALL

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