Differential response to cytotoxic therapy explains treatment dynamics of AML patients: insights from a mathematical modelling approach

Abstract

AbstractDisease response and durability of remission are very heterogeneous in patients with acute myeloid leukaemia (AML) patients. There is increasing evidence that the individual risk of early relapse can be predicted based on the initial treatment response. However, it is unclear how such a correlation is linked to functional aspects of AML progression and treatment. We suggest a mathematical model in which leukaemia-initiating cells and normal/healthy hematopoietic stem and progenitor cells reversibly change between an active state characterized by proliferation and chemosensitivity and a quiescent state, in which the cells do not divide, but are also insensitive to chemotherapy. Applying this model to 275 molecular time courses of NPM1-mutated patients, we conclude that the differential chemosensitivity of the leukaemia-initiating cells together with the cells’ intrinsic proliferative capacity is sufficient to reproduce both, early relapse as well as long-lasting remission. We can, furthermore, show that the model parameters associated with individual chemosensitivity and proliferative advantage of the leukemic cells are closely linked to the patients’ time to relapse. They can, therefore, be used as a measure of the aggressiveness of the disease. Early assessment of these measures and incorporation into risk stratification schemes will improve risk assessment and individual treatment in AML.