Pro-atherothrombotic effect induced by tyrosine-kinase inhibitors for first-line treatment of CML patients: results of a prospective multicenter study (Kiaro trial)

Tyrosine kinase inhibitors (TKI) revolutionized treatment of chronic myeloid leukemia (CML), but some patients (pts) still suffer from potentially severe TKI-related toxicity. Of relevance is cardiovascular (CV) toxicity, mostly associated to Nilotinib (NILO). Previously, we retrospectively confirmed a higher CV risk for pts NILO-treated, particularly if harboring the unfavorable OLR1 polymorphism and we found a NILO-associated pro-inflammatory effect. We now report clinical, genetic and serologic results of a prospective multicenter Italian trial including CML pts treated with first-line TKIs (IMA, NILO, DASA). Aims of the study are: to assess CV toxicity in CML pts in which first-line TKI choice was made according to CV risk guidelines; to assess pts’ genetic predisposition to CV events; to confirm a pro-inflammatory effect NILO-induced. Clinical CV risk Score (S) and Integrated Score (IS), obtained combining clinical and genetic data from Single Nucleotide Polymorphisms (SNPs) associated to CV risk, were calculated. Clinical and biological parameters and plasma samples for IL6, IL10, TNF and oxLDL assessments, were collected at diagnosis and at 1, 3, 6, 12 months (mos) of treatment. 177 naive CML pts starting IMA, NILO or DASA treatment, were enrolled. After a median follow-up of 22.4 mos (range 35 days-5.4 years), a CV event occurred in 5 pts, with a median time to event of 15 mos (range 44 days-31.4 months). NILO treated pts had lower CV risk at diagnosis (S=6.9±2.8) compared to DASA (S=8.1±3.2; p=0.042) or IMA-treated (S=9.9±4.9; p=0.019). 3/57 (5.2%) NILO pts developed CV toxicity, as opposed to 1/83 (1.2%) IMA-treated (HR 2.9, 95% CI 1.8-4.4; p=0.021) and 0 out of 37 DASA-treated pts. A CV event occurred in a pt during IMA 23 mos after being switched to Bosutinib, thus was not attributed to IMA. IL10 levels were higher after 6 and 12 mos of IMA or DASA compared to NILO. Also IL6/IL10 and TNF /IL10 ratios in IMA and DASA treated pts were lower, compared to NILO. OxLDL levels increased after 12 mos of NILO, not during IMA or DASA. This study confirms a higher CV risk for pts treated with NILO, even in a contemporary setting where pts were carefully selected for having a low pre-treatment CV risk. This may be a consequence of the NILO-induced pro-inflammatory status confirmed in this study. The few CV events registered did not allow any correlation between SNPs and increased CV risk; a longer follow-up is necessary to explore a possible genetic role.