Characterizing Chemotherapy-Induced Neutropenia and Monocytopenia Through Mathematical Modelling
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Characterizing Chemotherapy-Induced Neutropenia and Monocytopenia Through Mathematical Modelling Tyler Cassidy1 · Antony R. Humphries2,3 · Morgan Craig4,5 Michael C. Mackey6,7,8
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Received: 1 April 2020 / Accepted: 11 July 2020 © Society for Mathematical Biology 2020
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. Keywords Mathematical modeling · Monocytes · Neutrophils · Cyclic chemotherapy · G-CSF · Therapy rationalization
Morgan Craig and Michael C. Mackey are co-senior authors. 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. Extended author information available on the last page of the article 0123456789().: V,-vol
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1 Introduction In humans, approximately 100,000 hematopoietic stem cells (HSCs) produce 100 billion blood cells a day (Lee-Six et al. 2018). This astonishing hyper-productivity accounts for the hematopoietic system being one of the most intensively studied and best understood stem cell systems (Mackey 2001). All terminal blood cells originate from HSCs that differentiate, proliferate, and mature along many lineages before reaching the circulation to perform their multitude of functions, including oxygenating the body (red blood cells), clotting and w
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