Therapy Resistance and Disease Progression in CML: Mechanistic Links and Therapeutic Strategies.

Abstract

Purpose of review: Despite the adoption of tyrosine kinases inhibitors (TKIs) as molecular targeted therapy in chronic myeloid leukemia, some patients do not respond to treatment and even experience disease progression. This review aims to give a broad summary of advances in understanding of the mechanisms of therapy resistance, as well as management strategies that may overcome or prevent the emergence of drug resistance. Ultimately, the goal of therapy is the cure of CML, which will also require an increased understanding of the leukemia stem cell (LSC).

Recent findings: Resistance to tyrosine kinase inhibitors stems from a range of possible causes. Mutations of the BCR-ABL1 fusion oncoprotein have been well-studied. Other causes range from cell-intrinsic factors, such as the inherent resistance of primitive stem cells to drug treatment, to mechanisms extrinsic to the leukemic compartment that help CML cells evade apoptosis. There exists heterogeneity in TKI response among different hematopoietic populations in CML. The abundances of these TKI-sensitive and TKI-insensitive populations differ from patient to patient and contribute to response heterogeneity. It is becoming clear that targeting the BCR-ABL1 kinase through TKIs is only one part of the equation, and TKI usage alone may not cure the majority of patients with CML. Considerable effort should be devoted to targeting the BCR-ABL1-independent mechanisms of resistance and persistence of CML LSCs.