Genetic predisposition and induced pro-inflammatory/pro-oxidative status may play a role in increased atherothrombotic events in nilotinib treated chronic myeloid leukemia patients

Abstract

Several reports described an increased risk of cardiovascular (CV) events, mainly atherothrombotic, in Chronic Myeloid Leukemia (CML) patients receiving nilotinib. However, the underlying mechanism remains elusive. The objective of the current cross-sectional retrospective study is to address a potential correlation between Tyrosine Kinase Inhibitors (TKIs) treatment and CV events. One hundred and 10 chronic phase CML patients in complete cytogenetic response during nilotinib or imatinib, were screened for CV events and evaluated for: traditional CV risk factors, pro/anti-inflammatory biochemical parameters and detrimental ORL1 gene polymorphisms (encoding for altered oxidized LDL receptor-1). Multivariate analysis of the whole cohort showed that the cluster of co-existing nilotinib treatment, dyslipidaemia and G allele of LOX-1 polymorphism was the only significant finding associated with CV events. Furthermore, multivariate analysis according to TKI treatment confirmed IVS4-14 G/G LOX-1 polymorphism as the strongest predictive factor for a higher incidence of CV events in nilotinib patients. Biochemical assessment showed an unbalanced pro-inflammatory cytokines network in nilotinib vs imatinib patients. Surprisingly, pre-existing traditional CV risk factors were not always predictive of CV events. We believe that in nilotinib patients an induced “inflammatory/oxidative status”, together with a genetic pro-atherothrombotic predisposition, may favour the increased incidence of CV events. Prospective studies focused on this issue are ongoing.

The hOCT1 and ABCB1 polymorphisms do not influence the pharmacodynamics of nilotinib in chronic myeloid leukemia

“…Nevertheless, the occurrence of the cardiovascular events was similar (8% in the ENESTnd vs 7.5% in our series). Interestingly, in another Italian multicenter “real-life” study on 110 patients, 27% of them experienced cardiovascular events when nilotinib was administered as second-line treatment [ 35 ]. That comparison further strengthens the better tolerability of nilotinib as upfront therapy, despite our study recorded a slight higher discontinuation rate with respect to that reported in the ENESTnd trial (3.8% vs 2.5%, respectively).…”

The use of the tyrosine kinase inhibitor Nilotinib in Spondyloarthritis: does targeting inflammatory pathways with a treatment lead to vascular toxicity?

“…We suggest that authors should take ABI as a safety variable in future trials. In the era of precision medicine and progress in pharmacogenomics, IVS4-14 G/G LOX-1 polymorphism should be investigated before Nilotinib ® introduction, insofar as it constitutes the strongest predictive factor for a higher incidence of CV events [ 27 ].…”

“…In a prospective study including 159 CML patients treated with either Imatinib ® or Nilotinib ® , PAD defined by an abnormal ankle–brachial index (ABI) was more prevalent among patients treated with Nilotinib than among patients on Imatinib ® [ 26 ]. The atherothrombotic vascular events occurring in some Nilotinib ® -treated patients could arise from a combination of genetic and biochemical factors, such as increased lipid peroxidation due to detrimental Lipoxygenase-1 (LOX-1) polymorphism and an imbalance in cytokine-driven inflammation, mainly brought about by the strong reduction in anti-inflammatory cytokine IL-10 levels [ 27 ]. Furthermore, Nilotinib ® is associated with several metabolic disturbances, including hyperglycemia, perhaps via insulin resistance, and dyslipidemia, which can develop within less than 3 months of treatment.…”

From Molecular Mechanisms to Clinical Management of Antineoplastic Drug-Induced Cardiovascular Toxicity: A Translational Overview

“…Recent studies have documented a number of nilotinibinduced effects on endothelium, platelets, and coagulation, which, together with the metabolic effects, enhance the risk of vascular adverse events (4,22).…”