Inflammation and increased atherothrombotic risk in chronic myeloid leukemia patients during TKI treatment: interim analysis of "Kiaro" prospective multicenter study

Background: Cardiovascular (CV) events, mostly atherothrombotic, in Chronic Myeloid Leukemia (CML) patients (pts) treated with Tyrosine Kinase inhibitors (TKIs) prompted physicians to evaluate CV risk factors (CVRFs) in the choice of TKI. However, the pathogenesis behind CV events during TKIs is still 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 pro-atherothrombotic predisposition, may explain the increased incidence of CV. These data provided the rationale for a multicentric study including CML pts treated with any first line TKI in which clinical, genetic and biochemical pro-atherothrombotic profiles were evaluated at diagnosis and during treatment (KIARO study). Aims: To evaluate prospectively the role of genetic predisposition and pro/anti-inflammatory factors in the atherosclerotic pathogenesis during TKIs. Methods: Pts were studied for: CVRFs, atherothrombotic events, Single Nucleotide Polymorphisms (SNPs) associated to CV risk and levels of pro/anti-inflammatory cytokines. In this interim analysis we focused on LDL, oxidated-LDL (oxLDL), TNF, IL6 and IL10 levels and SNPs of LDLR, LOX1, and IL10 genes. Results: Up to date, 115 CML pts from 16 Italian Hematology Units were enrolled. We report data from the first 43 pts on TKIs for at least 12 months (15 nilotinib,14 imatinib and 14 dasatinib). No CV events were recorded to date. At diagnosis, LDL, oxLDL, TNF, IL6 and IL10 levels were evaluated. No differences were found between the 3 groups. We confirmed a correlation between LDL, oxLDL and IL10 basal levels with the presence/absence of their corresponding detrimental alleles. During TKIs we observed increased levels of LDL and oxLDL only in the nilotinib cohort at 3 and 12 months of treatment, regardless of the concomitant use of CV medications. No differences in TNF and IL6 levels during the first 12 months of TKIs were detected in the 3 cohort. IL10 levels were higher at 3 and 12 months of treatment in the imatinib and dasatinib cohort respect to nilotinib. Discussions: This interim analysis, although preliminary, suggests that in nilotinb pts the high levels of LDL and oxLDL in combination with low levels of IL10, may induce a pro-inflammatory/oxidative status potentially favoring atherothrombotic events. Additional biochemical and genetic data and prolonged clinical observation are needed to confirm this hypothesis.