Multidimensional Vascular Evaluation in Patients Treated with Tyrosine Kinase Inhibitors (TKIs): From Plaque Formation to Evolution and Follow up on 150 Patients
Authors: Abruzzese Elisabetta , Gloria Rossana , Siani Andrea , Mazzone Carla , Molica Matteo , Dentamaro Teresa , Cupelli Luca , Trawinska Malgorzata Monika , De Fabritiis Paolo 
Published: November 2020

Background
Among the unresolved issues concerning management of chronic myeloid leukemia (CML) patients, the most feared are long-term adverse events due to TKI treatment. Although TKIs have revolutionized CML outcomes, their use has also been associated with severe side effects including cardiovascular events, of which peripheral arterial occlusive disease (PAOD) is the most frequently reported. In 2010 we began a long-term collaboration with local angiologists and vascular surgeons to investigate, screen and follow patients on TKI therapy. Placque formation, evolution and follow up of 150 patients were studied and are presented here.
Methods
We analyzed 143 CML and 7 Ph+ Acute Lymphoid leukemia (ALL) patients, all of whom were treated with TKIs. Careful assessment of cardiovascular risk factors (i.e., age, smoking, obesity, diabetes, high blood pressure, high LDL or low HDL cholesterol levels, family history of heart disease or other cardiovascular disease) were done according to the European Society of Cardiology Systematic Coronary Risk Evaluation (SCORE) risk charts. A complete vascular screening, including physical examination, and a series of instrumental tests were performed for all patients. Tests included doppler echocardiography (US) of supra-aortic arteries with measurement of pre-bulbar IMT, abdominal arteries and inferior limbs arteries and veins (IL), ABI of the posterior tibial artery and digital photoplethysmography (FPG). Patients needing surgical intervention were referred to a surgeon. The team of hematologists, angiologists and surgeons met periodically to discuss results and intervention approaches.
Results
Patients included 76 males and 74 females with a median age of 53.7 yo (range 18-85). All patients were treated with a TKI at diagnosis, 87 (58%) with imatinib, 63 (42%) with other TKIs, including ponatinib (2 LLA), and all received TKI therapy for a minimum of 12 months since 2010. For analyses purposes, patients were divided in 7 different age groups at diagnosis (18-30, 31-40, 41-50, 51-60, 61-70, 71-80 and 81-85 years; patients incidence per group was 6%, 18%, 18.6%, 27.4%, 13.3%, 12.7% and 4%, respectively). Each patient in the study received yearly screening, and this increased to every 3-6 mo if abnormalities occurred.
Of the 150 patients in the study, 10 (7%) developed severe PAOD (grade 3-4) requiring revascularization. Districts involved were: carotid (5), renal (2) and extremities (14 IL, 1 subclavian). Three patients were polyvascular requiring intervention in multiple regions. 18 patients with no malignancies requiring surgery were used as a control group and matched for sex, age, diabetes, smoking, district and intervention to compare patency rates, morbidity and mortality.
At event, these 10 patients were taking imatinib (1), bosutinib (1), nilotinib (5) and ponatinib (3). None of them had a previous PAOD, but all had cardiovascular risk factors (100% were hypertensive). Median age was 66.8 yo (range 46-82) and the median number of PAOD risk factors (age &gt;60, hypertension, diabetes, male gender, nicotine abuse and coronary heart disease) was 2 (range 1-5).
Plaque was deemed significant when stenosis was &gt;30%; at this point it developed very rapidly, with signs of arterial thrombosis within a year, requiring intervention.
IMT scores (measuring thickness of carotid artery wall) and ABI followed by FPG and their variation over time proved predictive for plaque evolution.
No patient died due to complications relating directly to surgical intervention or within 30 days post-surgery. One patient required a major limb amputation at 12 months. Patency rates were similar in the TKI and control group at 12 months (88.2% vs 80%), however the frequency of reintervention (endo or open) was 50% in TKI patients (n=5) and 11% in the control group (n=2; P&lt;0.01).
Discussion
Multidisciplinary evaluation, comorbidity analysis and cardiovascular risk assessment in CML patients are highly recommended, at diagnosis if possible, to implement a tailored treatment strategy and to identify patients who require strict monitoring of risk factors during treatment. Extensive and detailed information on the 150 patients in this study will be presented with a focus on the onset and characteristics of thrombotic arterial events, medical/surgical interventions, analysis of instrumental parameters (ABI, IMT, FPG) and correlation with clinical data.

Disclosures
Abruzzese: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bms: Honoraria.