The Multimodal Approach to Evaluating Cardiovascular Risk in Patients with Chronic Myeloid Leukemia Treated with Tyrosine Kinase Inhibitors- the Role of Endothelial Function

Introduction The severity of endothelial dysfunction may be influenced by: the long-term course of chronic myeloid leukemia (CML), comorbidities, and tyrosine kinase inhibitors (TKIs). In patients with CML the pro-inflammatory profile of endothelium, a pro-thrombotic shift, and a significant increase in permeability were observed compared to the control group's endothelium. This project aims to characterize the profile of endothelial dysfunction in patients diagnosed with CML in chronic phase (CML-CP) treated with various TKIs.

Methods To evaluate the endothelial function, we used: the measurement of flow-mediated dilation (FMD), endothelial function in microcirculation by peripheral artery tonometry (RH-PAT), and flow-mediated skin fluorescence (FMSF) for assessment of vascular circulation and metabolic regulation. Statistical analysis in subgroups and individual analysis were performed for each participant.

Results The study group consisted of 48 patients (pts) (median age 52 years) with CML treated with TKIs (imatinib, bosutinib, nilotinib, ponatinib and asciminib). According to the SCORE scale, 13 (27.08%) patients had high cardiovascular risk. According to prognostic scales - Sokal, Hasford, Eutos, ELTS- most patients had low risk. Endothelial dysfunction was present in 24 pts (50%) measured using FMD, 12pts (25%) measured using RHI, 11 (22.92%) using FMSF. There are no statistically significant differences in FMD% for each TKI, but the median values indicate an impaired endothelial function in each subgroup of TKI. Median RHI (reactive hyperemia index) for TKI subgroups is not indicative of endothelial dysfunction but, in some patients, suggested dysfunction. For FMSF, only for asciminib and bosutinib, the microcirculation score, as hyperemic index (HR index %) parameter, indicates a low and moderate cardiovascular risk, unlike imatinib, nilotinib, and ponatinib, where the risk is high. In the FMD study, we measured different parameters. One of them was shear rate (SR) [sec-1] (measured in the stage of maximal reperfusion, after 30 seconds and 60 seconds of hyperemic response). There were significant differences in levels of SR 60sec (Kruskal test p value: 0.002); in post hoc analysis group treated with nilotinib had higher values of SR 60sec than the group with imatinib (P = 0.03) and ponatinib (P = 0.01). Levels of SR 30s and SR area to 30s seems to be lower in the ponatinib group compared to the nilotinib group however, those differences weren't statistically significant (P = 0.07, P = 0.20).

Group older than 50 years old had lower values of SR max 843.3 (740 - 1121.8) vs 1150.95 (1023.95 - 1470.97); P = 0.0104), lower values of SR 30sec (452.1 (332 - 521.52) vs 575.65 (533.3 - 605); P = 0.0017), lower values of SR 60 sec. Based on those parameters, older patients had a worse endothelium function than younger patients. Median RHI for TKI subgroups is not indicative of endothelial dysfunction but suggested abnormalities in some patients. The microcirculation score indicates a low and moderate cardiovascular risk for FMSF, only for asciminib and bosutinib. For imatinib, nilotinib, and ponatinib, the risk is high.

Follow-up endothelial measurements were routinely performed after three months in 18 patients. Several parameters were significantly higher in follow-up than in the first measurement; namely SR baseline [sec-1], SR Area to 30sec, SR Area to 60sec [sec-1], FMD/SR Area to Maximum diameter [au], FMD/SR Area [au], SR Max/SR Base ratio. We calculated differences (Δ) between the first and second measurements and checked if those differences were bigger or smaller in some subgroups of patients. Δ was significantly lower in female subgroups for SR area to 30s and SR area to 60s.

Conclusions Endothelial dysfunction was observed in CML patients, including those with low cardiovascular risk assessed in SCORE. There are no statistically significant differences in FMD for each TKI, but the median values indicate an impaired endothelial function in each subgroup of TKI. The assessment of endothelial function helps to evaluate better patients’ cardiovascular risk by identifying patients with endothelial dysfunction. It could play a crucial role in the decision-making process of choosing the optimal TKI therapy.

Sacha:Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria; Angelini: Honoraria, Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Honoraria, Speakers Bureau; BMs-Celgene: Honoraria, Speakers Bureau.