Mathematical models for cytarabine-derived myelosuppression in acute myeloid leukaemia

PLoS One. 2019 Jul 1;14(7):e0204540. doi: 10.1371/journal.pone.0204540. eCollection 2019.

Abstract

We investigate the personalisation and prediction accuracy of mathematical models for white blood cell (WBC) count dynamics during consolidation treatment using intermediate or high-dose cytarabine (Ara-C) in acute myeloid leukaemia (AML). Ara-C is the clinically most relevant cytotoxic agent for AML treatment. We extend a mathematical model of myelosuppression and a pharmacokinetic model of Ara-C with different hypotheses of Ara-C's pharmacodynamic effects. We cross-validate the 12 model variations using dense WBC count measurements from 23 AML patients. Surprisingly, the prediction accuracy remains satisfactory in each of the models despite different modelling hypotheses. Therefore, we compare average clinical and calculated WBC recovery times for different Ara-C schedules as a successful methodology for model discrimination. As a result, a new hypothesis of a secondary pharmacodynamic effect on the proliferation rate seems plausible. Furthermore, we demonstrate the impact of treatment timing on subsequent nadir values based on personalised predictions as a possibility for influencing/controlling myelosuppression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Proliferation / drug effects*
  • Cytarabine* / pharmacokinetics
  • Cytarabine* / pharmacology
  • Humans
  • Leukemia, Myeloid, Acute* / drug therapy
  • Leukemia, Myeloid, Acute* / metabolism
  • Leukemia, Myeloid, Acute* / pathology
  • Models, Biological*

Substances

  • Cytarabine

Grants and funding

This project has received funding from the European Research Council (ERC) under the European Unions Horizon 2020 research and innovation programme (grant agreement No 647573) and from the “International Max Planck Research School (IMPRS) for Advanced Methods in Process and System Engineering” in Magdeburg.