Characterizing chemotherapy-induced neutropenia and monocytopenia through mathematical modelling

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.