Atherothrombotic Risk and TKIs Treatment In Chronic Myeloid Leukemia Patients: A Role For Genetic Predisposition and Pro-Inflammatory/Pro-Oxidative Status?

Recently there have been some reports of Peripheral Arterial Occlusive Disease (PAOD) in chronic myeloid leukemia (CML) patients treated with second generation Tyrosine Kinase inhibitor (TKI) nilotinib. PAOD is mainly caused by atherosclerosis, which is a multifactorial disease of the vessels involving lipid accumulation, thrombogenic components, cell death and inflammatory responses in the arterial wall. With the intent to elucidate a potential correlation between TKIs treatment and mechanisms underlining PAOD or other atherotrombotic events, we investigated a previously described (and confirmed in different settings) genetic and biochemical trait associated with vascular events, in a series of CML patients treated in with TKIs.

Seventy-five CML patients referring to three Italian Hematology Centers (Siena, Pisa and Firenze), of which 39 treated with imatinib and 36 with nilotinib (median treatment time 10 years, range 3-13ys and 3 years, range 2-6ys, respectively), all in complete cytogenetic response and with various degree of molecular response, entered the study. During a routine follow-up visit the patients were evaluated for: classical risk factors (Diabetes Mellitus, Dyslipidemia, Arterial Hypertension, Body Mass Index, Cigarette Smoking, 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 polymorphism of OLR1, encoding for the oxidized LDL receptor 1 (LOX-1), as independent genetic predisposition for atherotrombotic events. In addition the patients were screened for PAOD a/o other atherotrombotic episodes.

The distribution of classical risk factors was homogeneous in the two groups of patients. On the contrary we noted significant differences in several biochemical parameters evaluated (Table 1).

Evaluation of events (i.e. PAOD, Acute Coronary Syndrome and Cerebral Ischemia) showed a statistically significant difference in the two groups with 9/36 (25%) atherotrombotic events occurring in the nilotinib group and 3/39 (7.6%) events occurring 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 CML patients 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).

These preliminary data suggest that an unbalance of pro/anti-inflammatory cytokines network observed in nilotinib treated patients, together with genetic pro-atherothrombotic predisposition conferred by LOX-1, 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, as confirmed by altered sCD40L, ETP and oxLDL levels, despite the use of anti-atherothrombotic drugs. The link between pro-inflammatory stimuli and lipid peroxidation is a well established trigger of accelerated atherogenesis in the general population. As such, in a condition of potential increased lipid peroxidation as described in carriers of detrimental SNPs of LOX-1, the enhanced inflammatory milieu observed during nilotinib treatment could be an additional factor of accelerate atherothrombosis. Further studies are needed to both elucidate the mechanism underlining nilotinib-induced pro-inflammatory status and confirm LOX-1 mutations as a useful genetic tool to identify nilotinib-treated patients at potential increased atherothrombotic risk.

Galimberti:Novartis and Bristol Mayer Squibb: Honoraria. Gozzini:Novartis and Bristol Mayer Squibb: Honoraria. Baratè:Novartis and Bristol Mayer Squibb: Honoraria. Scappini:Novartis and Bristol Mayer Squibb: Honoraria. Bosi:Novartis and Bristol Mayer Squibb: Honoraria. Petrini:Novartis and Bristol Mayer Squibb: Honoraria. Bocchia:Novartis and Bristol Mayer Squibb: Honoraria.