Modeling individual time courses of thrombopoiesis during multi-cyclic chemotherapy.

Chemotherapy is ubiquitously used to treat cancer diseases. Due to general toxicity of the drugs, chemotherapy results in a number of side effects especially with respect to blood formation. Here we study the loss of platelets during chemotherapy which is dose limiting in many situations. However, this side-effect greatly varies between patients with respect to both, severity and necessity of clinical countermeasures. We therefore developed a mathematical model to predict the time course of platelets of patients under chemotherapy and to propose possible treatment adaptations in cases of intolerable toxicity. The model is based on available biological knowledge and data of platelet formation and therapeutic effects thereon. As a major result, we could describe individual time series data of 135 patients under chemotherapy. Conversely, the model can be used to make predictions regarding alternative therapy schedules such as postponement of therapy or chemotherapy dose reductions. Our model is intended to support clinical decision making on an individual patient level.

BACKGROUND: Thrombocytopenia is a major side-effect of cytotoxic cancer therapies. The aim of precision medicine is to develop therapy modifications accounting for the individual's risk. METHODOLOGY/PRINCIPLE FINDINGS: To solve this task, we develop an individualized bio-mechanistic model of the dynamics of bone marrow thrombopoiesis, circulating platelets and therapy effects thereon. Comprehensive biological knowledge regarding cell differentiation, amplification, apoptosis rates, transition times and corresponding regulations are translated into ordinary differential equations. A model of osteoblast/osteoclast interactions was incorporated to mechanistically describe bone marrow support of quiescent cell stages. Thrombopoietin (TPO) as a major regulator is explicitly modelled including pharmacokinetics and-dynamics of TPO injections. Effects of cytotoxic drugs are modelled by transient depletions of proliferating cells. To calibrate the model, we used population data from the literature and close-meshed individual data of N = 135 high-grade non-Hodgkin's lymphoma patients treated with CHOP-like chemotherapies. To limit the number of free parameters, several parsimony assumptions were derived from biological data and tested via Likelihood methods. Heterogeneity of patients was explained by a few model parameters. The over-fitting issue of individual parameter estimation was successfully dealt with a virtual participation of each patient in population-based experiments. The model qualitatively and quantitatively explains a number of biological observations such as the role of osteoblasts in explaining long-term toxic effects, megakaryocyte-mediated feedback on stem cells, bi-phasic stimulation of thrombopoiesis by TPO, dynamics of megakaryocyte ploidies and non-exponential platelet degradation. Almost all individual time series could be described with high precision. We demonstrated how the model can be used to provide predictions regarding individual therapy adaptations. CONCLUSIONS: We propose a mechanistic thrombopoiesis model of unprecedented comprehensiveness in both, biological mechanisms considered and experimental data sets explained. Our innovative method of parameter estimation allows robust determinations of individual parameter settings facilitating the development of individual treatment adaptations during chemotherapy.