Tyrosine kinase inhibitors (TKI) such as imatinib are not considered curative for chronic myeloid leukemia (CML) – regardless of the significant reduction of disease burden during treatment – since they do not affect the leukemic stem cells (LSC). However, the stochastic nature of hematopoiesis and recent clinical observations suggest that this view must be revisited

We study the natural history of a large cohort of virtual patients with CML under TKI therapy using a computational model of hematopoiesis and CML that takes into account stochastic dynamics within the hematopoietic stem and early progenitor cell pool.  

We find that in the overwhelming majority of patients the LSC population undergoes extinction before disease diagnosis. Hence leukemic progenitors, susceptible to TKI attack, are the natural target for CML treatment. Response dynamics predicted by the model closely match data from clinical trials. We further predict that early diagnosis together with administration of TKI opens the path to CML eradication, leading to the wash out of the aberrant progenitor cells, ameliorating the patient’s condition while lowering the risk of blast transformation and drug resistance.         

TKI therapy can cure CML, although it may have to be prolonged. The depth of response increases with time in the vast majority of patients. These results illustrate the relevance of stochastic effects on the dynamics of acquired HSC disorders and have direct impact on other HSC derived diseases.

see Haematologica