Genetic Heterogeneity in Chronic Myeloid Leukemia: How Clonal Hematopoiesis and Clonal Evolution May Influence Prognosis, Treatment Outcome, and Risk of Cardiovascular Events.

Abstract

Chronic myeloid leukemia (CML) has long been considered as a model of cancer caused by a single-driver genetic lesion (BCR/ABL1 rearrangement) that codes for a unique, gain-of-function, deregulated protein. However, in the last decade, high-throughput sequencing technologies have shed light on a more complex genetic landscape, in which additional mutations may be found in different disease phases, including diagnosis. These genetic lesions may even precede the occurrence of the Philadelphia (Ph) chromosome, pointing to an antecedent premalignant state of clonal hematopoiesis (CH) at least in some patients. Preliminary data support the hypothesis that the most frequent CH-associated mutations (DNMT3A, TET2, and ASXL1) may be associated with a risk of vascular event, but a definitive answer for this topic is still lacking. Moreover, several recent studies have linked a much more complex genetic background in chronic-phase CML, including signs of clonal evolution over time, with depth of treatment responses or with patient survival. In the present review, we address the current state of the art on age-related CH, its association with cardiovascular risk, and its pathophysiology; review the current knowledge on CH that precedes the acquisition of the Ph chromosome in CML patients; and discuss available evidence on the prognostic and predictive value of additional mutations in chronic-phase CML, either as a sign of clonal dynamics under treatment or as markers of an antecedent CH.