Lipid peroxidation and inflammatory status during TKI treatment in chronic myeloid leukemia patients: interim analysis of a prospective multicenter study

Background: Evidences of increased cardiovascular (CV) events, mostly atherothrombotic, in Chronic Myeloid Leukemia (CML) patients (pts) treated with some Tyrosine Kinase inhibitors (TKIs) prompted physicians to carefully evaluate CV risk factors (CVRFs) in the choice of TKI. However, the pathogenesis behind CV events during TKIs is still largely unknown and even pts without overt CVRFs incur in CV events. We retrospectively showed that an induced “inflammatory status” during nilotinib treatment, together with genetic proatherothrombotic predisposition, may partly explain the increased incidence of CV (Bocchia, Oncotarget 2016). These data provided the rationale to start a multicentric “Prospective study of TKI induced pro-AtherothROmbotic status in CML. KIARO study” (Grant support: AIRC-ITT) including Chronic Phase CML pts treated with any first line approved TKI in which clinical, genetic and biochemical pro-atherothrombotic profiles were evaluated at diagnosis and during treatment. Aims: This prospective study aims to confirm the possible role of genetic predisposition and behavior of specific pro/anti-inflammatory biochemical parameters in the atherosclerotic pathogenesis during TKIs treatment. Methods: Enrolled pts were prospectively evaluated for: presence of traditional CVRFs, atherothrombotic episodes, presence of Single Nucleotide Polymorphisms (SNPs) associated to CV risk (Cardiokit) and plasma levels of several pro and anti-inflammatory cytokines. In this first interim analysis we focused on levels of LDL, oxidated-LDL (oxLDL), TNFα, IL-6 and IL-10 and the presence of SNPs of LDL-R (rs1122608), LOX-1 (rs3736235), and IL-10 (rs1800896) genes. Results: 12 Italian Hematology Units participated to the study and up to date 95 CML patients were enrolled. We here report data from the first 43 patients on TKI treatment for at least 12 months (15 nilotinib, 14 imatinib and 14 dasatinib). No CV events were recorded to date. At diagnosis, levels of LDL (143.5±13.2), ox-LDL (237.4±99.5), TNFα (3.91±2.51), IL-6 (1.96±0.99) and IL-10 (0.34±0.15) were evaluated for the whole cohort and according to the TKI treatment. No statistically significant differences were found in the expression of these variables between the 3 groups of treatment (p>0.096). Considering the genotype frequency, we confirmed in the whole cohort a correlation between basal levels of LDL, oxLDL and IL10 with the presence/absence of the detrimental G/G allele of LDL-R (H.R. 2.11, p<0.01), LOX-1 (H.R. 2.86, p<0.01) and IL10 (H.R. 1.85, p<0.05) polymorphisms. During TKIs treatment we observed increased levels of LDL (p<0.05) and oxLDL (p<0.05) only in the nilotinib cohort at 3 and 12 months of treatment, regardless of the concomitant use of CV medications. No differences in TNFα and IL6 levels during the first 12 month of treatment were detected in the 3cohort (p<0.079). Interestingly, IL-10 levels were significantly higher at 3 and 12 months of treatment in the imatinib and dasatinib cohort (p<0.01) respect to nilotinib (p=0.094). Summary/Conclusions: This interim analysis, although still very preliminary, suggests that in nilotinb patients the high levels of LDL and oxLDL in combination with low levels of IL10, could induce a persistent pro-inflammatory/oxidative status potentially favoring atherothrombotic events. Additional biochemical and genetic data as well as prolonged clinical observation are needed to confirm this hypothesis. Patients enrolment and monitoring is ongoing.