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Characterizing Chemotherapy-Induced Neutropenia and Monocytopenia Through Mathematical Modelling

Abstract

In spite of the recent focus on the development of novel targeted drugs to treat cancer, cytotoxic chemotherapy remains the standard treatment for the vast majority of patients. Unfortunately, chemotherapy is associated with high hematopoietic toxicity that may limit its efficacy. We have previously established potential strategies to mitigate chemotherapy-induced neutropenia (a lack of circulating neutrophils) using a mechanistic model of granulopoiesis to predict the interactions defining the neutrophil response to chemotherapy and to define optimal strategies for concurrent chemotherapy/prophylactic granulocyte colony-stimulating factor (G-CSF). Here, we extend our analyses to include monocyte production by constructing and parameterizing a model of monocytopoiesis. Using data for neutrophil and monocyte concentrations during chemotherapy in a large cohort of childhood acute lymphoblastic leukemia patients, we leveraged our model to determine the relationship between the monocyte and neutrophil nadirs during cyclic chemotherapy. We show that monocytopenia precedes neutropenia by 3 days, and rationalize the use of G-CSF during chemotherapy by establishing that the onset of monocytopenia can be used as a clinical marker for G-CSF dosing post-chemotherapy. This work therefore has important clinical applications as a comprehensive approach to understanding the relationship between monocyte and neutrophils after cyclic chemotherapy with or without G-CSF support.

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Acknowledgements

MCM would like to thank Jim Murray for over 40 years of collegial friendship, and Prof. Dr. Klaus Pawelzik, Universität Bremen, Germany for his hospitality during the time this was written. All authors wish to thank Sanja Glisovic, Drs. Jean-Marie Leclerc, Yves Pastore, and Maja Krajinovic, and the patients enrolled in the ALL study at the CHU Sainte-Justine.

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Correspondence to Morgan Craig.

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The authors declare no conflict of interest.

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TC is grateful to the Natural Sciences and Research Council of Canada (NSERC) for support through the PGS-D program. Portions of this work were performed under the auspices of the U.S. Department of Energy under contract 89233218CNA000001 and funded by NIH grants R01-AI116868 and R01-OD011095. ARH is funded by NSERC Discovery Grant RGPIN-2018-05062. MC is funded by NSERC Discovery Grant and Discovery Launch Supplement RGPIN-2018-04546.

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Cassidy, T., Humphries, A.R., Craig, M. et al. Characterizing Chemotherapy-Induced Neutropenia and Monocytopenia Through Mathematical Modelling. Bull Math Biol 82, 104 (2020). https://doi.org/10.1007/s11538-020-00777-0

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  • DOI: https://doi.org/10.1007/s11538-020-00777-0

Keywords

  • Mathematical modeling
  • Monocytes
  • Neutrophils
  • Cyclic chemotherapy
  • G-CSF
  • Therapy rationalization