Speaker
Description
Polycythaemia Vera (PV) is a haematological malignancy characterised by an overproduction of blood cells. Recent clinical studies have shown that combination therapy with interferon-α-2a (IFN-α) and ruxolitinib (RUX) yields substantial reductions in JAK2 V617F variant allele frequency (VAF), a measure of disease burden. Here, we study the mechanisms behind the observed reductions in VAF using mathematical modelling and Bayesian inference. We consider a multi-compartmental ODE model which accounts for the self-renewal, differentiation, and death of mature and immature blood cells in presence and absence of treatment. The cell kinetics depend on non-linear regulatory feedbacks. We combine our previously developed models of single-drug treatment with IFN-α and RUX in order to obtain a model for the combination treatment. Using prior distributions based on the single-drug studies, we fit the model to data from 22 patients and infer the effects of combination treatment. The combination model accurately captures the data, demonstrating that the knowledge of single-drug treatment effects is sufficient for explaining combination treatment data. The combination model suggests an explanation for the observed efficacy of the combination treatment: IFN-α forces malignant stem cells to differentiate, depleting the malignant stem cell pool that drives the disease. RUX targets malignant progenitor and precursor cells which quickly reduces the mutated cell burden.
