Genetic predisposition and induced pro-inflammatory/pro-oxidative status may explain increased atherothrombotic risk during TKI treatment in chronic myeloid leukemia patients

Introduction: There have been reports of Peripheral Arterial Occlusive Disease (PAOD) in chronic myeloid leukemia (CML) patients (pts) treated with second generation Tyrosine Kinase inhibitor (TKI) nilotinib. To explore a potential correlation between TKIs and mechanisms underlining PAOD or other atherothrombotic events, we investigated genetic and biochemical traits associated with vascular events, in a series of CML pts treated with TKIs. Methods: 75 CML pts, 39 treated with imatinib and 36 with nilotinib (median treatment time 10ys, range 3-13ys and 3 ys, range 2-6ys, respectively), all in complete cytogenetic response and with various degree of molecular response, entered the study. All pts were screened for PAOD a/o other atherothrombotic episodes and evaluated for: classical risk factors (Diabetes Mellitus, Dyslipidemia, Blood Pressure, Body Mass Index, Smoke, Familiarity); sCD40L level and Endogenous Thrombin Potential (ETP) as markers of platelets and coagulation activation; oxidized LDL (oxLDL) level as early stage atherogenesis promoter; IL6, IL10, TNFα cytokines network as indicator of pro/anti-inflammatory balance; 3'UTR/OLR1 polymorphism, encoding for the oxidized LDL receptor 1 (LOX1), as independent genetic predisposition for atherothrombotic events. Results: The distribution of classical risk factors was homogeneous in the 2 groups.On the contrary we noted significant differences in several biochemical parameters evaluated (Fig 1). The incidence of atherothrombotic events was statistically significant difference in the 2 groups with 9/36 (25%) events in the nilotinib group and 3/39 (7.6%) in the imatinib group (p=0.019). Multivariate analysis showed that the most strictly related factors to the increased risk of events in this series of pts were: nilotinib treatment, oxLDL level (O.R.3.8 95% C.I. 1.8-6.9, p< 0.001, β 1.61), IL10 level (O.R.3.3 95% C.I. 1.9-5.1, p< 0.001, β 1.55) and the presence of an intermediate or high risk OLR1 variant allele (O.R.3.1 C.I. 1.6-4.8, p< 0.001, β 1.59). Discussion: Our preliminary data suggest that an unbalance of pro/anti-inflammatory cytokines network observed in nilotinib pts, together with genetic pro-atherothrombotic predisposition conferred by LOX1, may have a role in the increased incidence of vascular events. The pro-inflammatory condition could be responsible of the pro-atherotrombotic activation, mainly by enhanced lipid peroxidation (confirmed by altered sCD40L, ETP and oxLDL levels), despite the use of anti-atherothrombotic drugs. In a condition of potential increased lipid peroxidation due to detrimental SNPs of LOX1, the enhanced inflammatory milieu observed during nilotinib treatment could be an additional factor of accelerate atherothrombosis. Further studies are needed to elucidate the mechanism underlining nilotinib-induced pro-inflammatory status and confirm LOX1 mutations as a useful genetic tool to identify nilotinib-treated pts at potential increased atherothrombotic risk.