Modeling Imatinib-Treated Chronic Myelogenous Leukemia and the Immune System

Abstract

Chronic myelogenous leukemia can be considered as a chronic condition thanks to the development of tyrosine kinase inhibitors in the early 2000s. Most CML patients are able to manage the disease, but unending treatment can affect quality of life. The focus of much clinical research has thus transitioned to treatment cessation, where many clinical trials have demonstrated that treatment free remission is possible. While there are a lot of existing questions surrounding the criteria for cessation candidates, much evidence indicates the immune system plays a significant role. Mathematical modeling provides a complementary component to clinical research. Existing models well-describe the dynamics of CML in the first phase of treatment where most patients experience a biphasic decline in the BCR-ABL ratio. The Clapp model is one of the first to incorporate the immune system and capture the often-seen oscillations in the BCR-ABL ratio that occur later in therapy. However, these models are far from capable of being used in a predictive manner and do not fully capture the dynamics surrounding treatment cessation. Based on clinical research demonstrating the importance of immune response, we hypothesize that a mathematical model of CML should include a more detailed description of the immune system. We therefore present a new model that is an extension of the Clapp model. The model is then fit to patient data and determined to be a good qualitative description of CML dynamics. With this model it can be shown that treatment free remission is possible. However, the model introduces new parameters that must be correctly identified in order for it to have predictive power. We next consider the parameter identification problem. Since the dynamics of CML can be considered in two phases, the biphasic decline of and oscillations in the BCR-ABL ratio, we hypothesize that parameter values may differ over the course of treatment and look to identify which parameters are most variable by refitting the model to different windows of data. It is determined that parameters associated with immune response and regulation are most difficult to identify and could be key to selecting good treatment cessation candidates. To increase the predictive power of our model, we consider data assimilation techniques which are successfully used in weather forecasting. The extended Kalman filter is used to assimilate CML patient data. Although we determine that the EKF is not the ideal technique for our model, it is shown that data assimilation methods in general hold promising value to the search for a predictive model of CML. In order to have the most success, new techniques should be considered, data should be collected more frequently, and immune assay data should be made available.