The Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: An Overview

The introduction in the clinical practice during the last decade of the tyrosine kinase inhibitors (TKI) have signifi cantly improved the outcome of patients affected by chronic myeloid leukemia (CML). Nevertheless, about one third of them still must stop or change treatment because of toxicity or resistance. Resistance could be “primary”, when patients don’t reach the established goals at the fi xed timepoints (see ELN or NCCN guidelines), or “secondary”, when patients lose the previously achieved hematological, cytogenetic or molecular response. At the basis of resistance many different mechanisms can be considered: the ABL1 mutations (rare at diagnosis but increasing at the progression, especially the T315I), the chromosomal adjunctive aberrations, but also the activation of other pathways able to sustain the growth of the progenitor leukemic stem cell, such as the Wnt, catenin, Scr, PI3K, and Hedgehog pathways. Moreover, also the epigenetic control of disease must be considered as a cause of resistance (such as that exerted by the Polycomb family). Finally, TKIs are often substrates of different transmembrane transporters; their polymorphisms and expression would explain either their possible lower effi cacy or higher toxicities. All these causes of resistance to TKIs are discussed in this paper.