Risk factors and mechanisms contributing to TKI-induced vascular events in patients with CML

Abstract

Vascular adverse events (VAE) are an emerging problem in patients with chronic myeloid leukemia (CML) receiving second-generation BCR-ABL1 tyrosine kinase inhibitors (TKI). Relevant VAE comprise peripheral, cerebral, and coronary artery changes in patients receiving nilotinib, venous and arterial occlusive events during ponatinib therapy, and pulmonary hypertension in patients receiving dasatinib. Although each TKI binds to a unique profile of molecular targets in leukemic cells and vascular cells, the exact etiology of drug-induced vasculopathies remains uncertain. Recent data suggest that predisposing molecular factors, pre-existing cardiovascular risk factors as well as certain comorbidities contribute to the etiology of VAE in these patients. In addition, direct effects of these TKI on vascular endothelial cells have been demonstrated and are considered to contribute essentially to VAE evolution. In the current article, we discuss mechanisms underlying the occurrence of VAE in TKI-treated patients with CML, with special emphasis on vascular and perivascular target cells and involved molecular (vascular) targets of VAE-triggering TKI. In addition, we discuss optimal patient selection and drug selection through which the risk of occurrence of cardiovascular events can hopefully be minimized while maintaining optimal anti-leukemic effects in CML, thereby following the principles of personalized medicine.

Arterial occlusive events in chronic myeloid leukemia patients treated with ponatinib in the real‐life practice are predicted by the Systematic Coronary Risk Evaluation (SCORE) chart

“…AOEs represent off‐target relevant complications of TKIs, particularly second‐generation and third‐generation TKIs . Nilotinib and ponatinib interact with a considerable number of clinically relevant vascular targets implicated in endothelial cell survival and angiogenesis …”

“…Cardiovascular profile of 85 patients and management of 26 cardiovascular adverse events Based on sex, age, smoking, systolic pressure, and cholesterol level.AOEs represent off-target relevant complications of TKIs, particularly second-generation and third-generation TKIs. 14 Nilotinib and ponatinib interact with a considerable number of clinically relevant vascular targets implicated in endothelial cell survival and angiogenesis 15. …”

The natural history of vascular and other complications in patients treated with nilotinib for chronic myeloid leukemia

“…9 Strategies to predict the overall likelihood of VAEs have been proposed 1,17,18 and have formed the basis of recommendations for pre-TKI risk assessment and the avoidance of nilotinib where possible in those at higher risk. 2,9 In addition, regular monitoring for risk factors throughout treatment is recommended, with some authors suggesting a role for angiologic testing such as ankle-brachial index assessment 2,19 and computed tomography coronary calcium scores. 9 In line with previous findings, we demonstrated that VAEs were more common in older patients 20 and in those with preexisting cardiovascular risk factors.…”

“…6,7 The incidence of nilotinib-associated VAEs ranges from 0.5% to 35% of patients in published literature. 2,[8][9][10][11] Factors contributing to the variability include inconsistent duration of follow-up, lack of a standardized definition of vascular events, 8 and exclusion of patients with a history of impaired cardiac function in some randomized controlled trials. 3,10 Despite the increasing understanding of the incidence and predisposing risk factors for nilotinib-associated AEs, there is a paucity of data to assist clinicians in their management.…”

A phosphoproteomic signature in endothelial cells predicts vascular toxicity of tyrosine kinase inhibitors used in CML

“…As vascular events can occur years after initiating therapy, long-term follow-up of many CML patients is necessary to distinguish the background risk in this older population (average age, 64 years) from the enhanced risk induced directly by the TKI. 4 Bosutinib was recently approved for first-line treatment of CML, although sufficient long-term vascular safety data are not yet available. A meta-analysis of BCR-ABL TKI trials confirmed the significant increased vascular risk with dasatinib, nilotinib, and ponatinib, but the bosutinib data were limited by insufficient power.…”