BACKGROUND: Tyrosine kinase inhibitors (TKIs) have shown long-term survival benefits in patients with chronic myeloid leukemia (CML). Nevertheless, significant concern has been raised regarding long-term TKI-associated vascular adverse events (VAEs). The objective of this retrospective cohort study was to investigate the incidence of VAEs in Taiwanese patients with CML treated with different TKIs (imatinib, nilotinib, and dasatinib) as well as potential risk factors.
METHODS: We conducted a retrospective cohort study using the Taiwan Cancer Registry Database and National Health Insurance Research Database. Adult patients diagnosed with CML from 2008 to 2016 were identified and categorized into three groups according to their first-line TKI treatment (imatinib, nilotinib, and dasatinib). Propensity score matching was performed to control for potential confounders. Cox regressions were used to estimate the hazard ratio (HR) of VAEs in different TKI groups.
RESULTS: In total, 1,111 patients with CML were included in our study. We found that the risk of VAEs in nilotinib users was significantly higher than that in imatinib users, with an HR of 3.13 (95% confidence interval (CI), 1.30-7.51), whereas dasatinib users also showed a nonsignificant trend for developing VAEs, with an HR of 1.71 (95% CI, 0.71-4.26). In multivariable logistic regression analysis, only nilotinib usage, older age, and history of cerebrovascular diseases were identified as significant risk factors. The annual incidence rate of VAEs was highest within the first year after the initiation of TKIs.
CONCLUSIONS: These findings can support clinicians in making treatment decisions and monitoring VAEs in patients with CML in Taiwan.
CONCLUSIONS: This study found that patients with chronic myeloid leukemia (CML) treated with nilotinib and dasatinib may be exposed to a higher risk of developing vascular adverse events (VAEs) compared with those treated with imatinib. Thus, this study suggests that patients with CML who are older or have a history of cerebrovascular diseases should be under close monitoring of VAEs, particularly within the first year after the initiation of tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) have revolutionized the management and outcomes of chronic myeloid leukemia (CML) patients. Improved disease control and prolonged life expectancy now mandate focus on improving TKIs\' safety profile. Recently, vascular adverse events (VAEs) have emerged as a serious consequence of some of the newer TKIs. In this review, we describe the clinical spectrum of TKI-associated VAE, and examine the unique vascular safety profile of the main TKIs currently used in the treatment of CML: imatinib, nilotinib, dasatinib, bosutinib and ponatinib. The issue of TKI-related platelet dysfunction is discussed as well. We describe the contemporary research findings regarding the possible pathogenesis of the VAE. Finally, the different aspects of TKI-associated VAE management are addressed, including prevention methods, monitoring strategies and treatment options.

An association between tyrosine-kinase inhibitor therapy for chronic myeloid leukemia and vascular adverse events including peripheral arterial disease, coronary artery disease, and pulmonary hypertension has been described. We present a patient who developed isolated pulmonary artery vasculitis resulting in left pulmonary artery stenosis, in addition to left coronary artery stenosis while on nilotinib. While monitoring for cardiovascular events is important, clinicians should also recognize possible drug-induced vasculitis during chronic nilotinib therapy.

The present study aimed to evaluate the safety of high-intensity focused ultrasound (HIFU) treatment on peripancreatic arterial and venous blood vessels in patients with pancreatic cancer. This trial included 15 patients with pancreatic cancer (9 females and 6 males; age, 39-81 years; median age, 62 years). All patients underwent preoperative computed tomography (CT) or magnetic resonance imaging (MRI) and color Doppler flow imaging (CDFI) to assess the vascular hemodynamics of peripancreatic arterial and venous blood vessels pre-treatment. These patients were re-examined within 1 week post-HIFU treatment. Then, vascular adverse events were observed and followed up clinically. Prior to HIFU treatment, vessel involvement was recorded in 13 patients, including tumor lesions invading 19 veins and 14 arteries, which refers to the growth of pancreatic tumor lesions surrounding blood vessels, or tumor growth into blood vessels. In addition, 9 veins and 13 arteries were <1 cm from the lesions. The hemodynamic parameters of peripancreatic vessels were measured using CDFI, including mean blood flow velocity, peak systolic blood flow velocity, vascular resistance index, vascular pulsatility index, vascular diameter, vascular blood flow and other indicators, to assess vascular perfusion in CT/MRI. There were no significant differences in preoperative and postoperative hemodynamic data (P>0.05). Overall, HIFU demonstrated no negative effects on peripancreatic arterial and venous blood vessels in patients with pancreatic cancer, even with tumor lesions wrapped in blood vessels. In addition, no complications of vascular stenosis and vascular adverse events were observed in the present study.

Ponatinib is a multi-targeted third generation tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukemia (CML) patients harboring the Abelson (Abl)-breakpoint cluster region (Bcr) T315I mutation. In spite of having superb clinical efficacy, ponatinib triggers severe vascular adverse events (VAEs) that significantly limit its therapeutic potential. On vascular endothelial cells (ECs), ponatinib promotes EC dysfunction and apoptosis, and inhibits angiogenesis. Furthermore, ponatinib-mediated anti-angiogenic effect has been suggested to play a partial role in systemic and pulmonary hypertension via inhibition of vascular endothelial growth factor receptor 2 (VEGFR2). Even though ponatinib-associated VAEs are well documented, their etiology remains largely unknown, making it difficult to efficiently counteract treatment-related adversities. Therefore, a better understanding of the mechanisms by which ponatinib mediates VAEs is critical. In cultured human aortic ECs (HAECs) treated with ponatinib, we found an increase in nuclear factor NF-kB/p65 phosphorylation and NF-kB activity, inflammatory gene expression, cell permeability, and cell apoptosis. Mechanistically, ponatinib abolished extracellular signal-regulated kinase 5 (ERK5) transcriptional activity even under activation by its upstream kinase mitogen-activated protein kinase kinase 5α (CA-MEK5α). Ponatinib also diminished expression of ERK5 responsive genes such as Krüppel-like Factor 2/4 (klf2/4) and eNOS. Because ERK5 SUMOylation counteracts its transcriptional activity, we examined the effect of ponatinib on ERK5 SUMOylation, and found that ERK5 SUMOylation is increased by ponatinib. We also found that ponatibib-mediated increased inflammatory gene expression and decreased anti-inflammatory gene expression were reversed when ERK5 SUMOylation was inhibited endogenously or exogenously. Overall, we propose a novel mechanism by which ponatinib up-regulates endothelial ERK5 SUMOylation and shifts ECs to an inflammatory phenotype, disrupting vascular homeostasis.

This study investigated the incidence rate and features of vascular adverse events (VAEs) in Japanese patients with chronic myeloid leukemia (CML) who were treated with tyrosine kinase inhibitors (TKIs). The analysis included 369 CML patients in the chronic or accelerated phases, selected from the CML Cooperative Study Group database; 25 events in 23 (6.2%) of these patients were VAEs. At the time of VAE incidence, nine patients were on treatment with imatinib, 12 with nilotinib, three with dasatinib, and one with bosutinib. VAE incidence comprised 13 cases of ischemic heart disease (IHD), eight of cerebral infarction (CI), and four of peripheral arterial occlusive disease (PAOD). IHD incidence rate in the study population was higher than that in the age-matched general population, particularly in nilotinib-treated patients, while CI incidence rate was almost equivalent. Compared with the Suita score, the SCORE chart and the Framingham score risk assessment tools detected more patients with high or very high risk of VAEs. In conclusion, incidence of IHD requires closer monitoring in nilotinib-treated patients. More detailed investigations for determining the most useful tool to predict VAE incidence and long-term analysis of therapy-related VAE cases are needed for improving safety during TKI therapy.