A Pharmacokinetic/Pharmacodynamic Model of the Action of Hypomethylating Agents in Chronic Myelomonocytic Leukaemia

Abstract

Chronic myelomonocytic leukaemia (CMML) is a disease that borders between a myelodyplastic syndrome (MDS) and myeloproliferative neoplasia (MPN). It is a progressive condition: about 20% of CMML patients progress to secondary acute myeloid leukaemia (sAML), which has a very poor prognosis. In all cases, normal bone marrow function is compromised with resulting depletion of circulating erythrocytes and platelets. We modelled the dynamics of CMML at two levels: a cytokinetic model was developed that describes bone marrow cell population dynamics for multiple cell lineages, and changes in DNA mutational status that occur in MDS and CMML. This model, in conjunction with pharmacokinetic (PK) models for cytotoxic drugs and hypomethylating agents, was used to study the pharmacodynamics (PD) of these drugs. For the subset of CMML with loss of activity of TET2, our models suggest that TET2 activators may restore normal DNA methylation with a resulting antileukaemic effect. Mouse and human data were used to place bounds on the parameters of our model. Our modelling suggests that both hypomethylation and cytotoxic effects contribute to the antileukaemic activity of decitabine.