To Cure or Not to Cure: Consequences of Immunological Interactions in CML Treatment.

Affiliation

Instituto de Matemática e Computação, Universidade Federal de Itajubá, Itajubá, Brazil. [Email]

Abstract

Recent clinical findings in chronic myeloid leukemia (CML) patients suggest that the number and function of immune effector cells are modulated by tyrosine kinase inhibitors (TKI) treatment. There is further evidence that the success or failure of treatment cessation at least partly depends on the patients immunological constitution. Here, we propose a general ODE model to functionally describe the interactions between immune effector cells with leukemic cells during the TKI treatment of CML. In total, we consider 20 different sub-models, which assume different functional interactions between immune effector and leukemic cells. We show that quantitative criteria, which are purely based on the quality of model fitting, are not able to identify optimal models. On the other hand, the application of qualitative criteria based on a dynamical system framework allowed us to identify nine of those models as more suitable than the others to describe clinically observed patterns and, thereby, to derive conclusion about the underlying mechanisms. Additionally, including aspects of early CML onset, we can demonstrate that certain critical parameters, such as the strength of immune response or leukemia proliferation rate, need to change during CML growth prior to diagnosis, leading to bifurcations that alter the attractor landscape. Finally, we show that the crucial parameters determining the outcome of treatment cessation are not identifiable with tumor load data only, thereby highlighting the need to measure immune cell number and function to properly derive mathematical models with predictive power.

Keywords

Bifurcations,Chronic myeloid leukemia,Immunological control,Mathematical modeling,Ordinary differential equations,Treatment-free remission,