Dynamics and bifurcations in a model of chronic myeloid leukemia with optimal immune response windows.

Abstract

Chronic Myeloid Leukemia is a blood cancer for which standard therapy with Tyrosine-Kinase Inhibitors is successful in the majority of patients. After discontinuation of treatment half of the well-responding patients either present undetectable levels of tumor cells for a long time or exhibit sustained fluctuations of tumor load oscillating at very low levels. Motivated by the consequent question of whether the observed kinetics reflect periodic oscillations emerging from tumor-immune interactions, in this work, we analyze a system of ordinary differential equations describing the immune response to CML where both the functional response against leukemia and the immune recruitment exhibit optimal activation windows. Besides investigating the stability of the equilibrium points, we provide rigorous proofs that the model exhibits at least two types of bifurcations: a transcritical bifurcation around the tumor-free equilibrium point and a Hopf bifurcation around a biologically plausible equilibrium point, providing an affirmative answer to our initial question. Focusing our attention on the Hopf bifurcation, we examine the emergence of limit cycles and analyze their stability through the calculation of Lyapunov coefficients. Then we illustrate our theoretical results with numerical simulations based on clinically relevant parameters. Besides the mathematical interest, our results suggest that the fluctuating levels of low tumor load observed in CML patients may be a consequence of periodic orbits arising from predator-prey-like interactions.