Staged carotid artery stenting for nilotinib-induced cervical internal carotid artery stenosis: illustrative case

Abstract

BACKGROUND

Nilotinib is known to cause vascular adverse events. No case of staged carotid artery stenting (CAS) for cervical internal carotid artery (ICA) stenosis by nilotinib has been reported. This report describes a case of staged CAS for nilotinib-induced cervical ICA stenosis.

OBSERVATIONS

A 67-year-old man who had been receiving nilotinib for 13 years for chronic myelogenous leukemia (CML) and had undergone stent placement for arteriosclerosis obliterans 10 years after starting nilotinib treatment developed transient right hemiparesis. MRI and MR angiography showed disseminated high-intensity areas in the left hemisphere and severe stenosis of the left cervical ICA. Single-photon emission CT revealed severe steal phenomenon in the left hemisphere. Therefore, a staged CAS was performed. He made good progress to recovery and was discharged a week after the endovascular surgery.

LESSONS

An increasing number of patients are being treated with nilotinib because of its effectiveness in treating CML. Therefore, clinicians should recognize that patients treated with nilotinib may develop adverse vascular events, including those affecting the cervical and intracranial arteries.

https://thejns.org/doi/10.3171/CASE25153

Breakpoint cluster region–Abelson tyrosine kinase inhibitors (TKIs) are used to treat chronic myelogenous leukemia (CML). Second- and third-generation TKIs are more effective than the first-generation inhibitor imatinib for treating CML;¹ however, they are more likely to cause adverse vascular events.^2–4 Nilotinib, a second-generation TKI, is associated with a higher incidence of adverse vascular events compared with imatinib.² Recently, a few cases of cervical internal carotid artery (ICA) stenosis complicated by nilotinib have been reported; however, there are no reported cases with staged carotid artery stenting (CAS) and multiple treatments for different vessels. Here, we report a case of staged CAS for cervical ICA stenosis with arteriosclerosis obliterans (ASO) of the leg treated by stent insertion.

Illustrative Case

A 67-year-old man was diagnosed with CML 15 years prior. He was started on imatinib, but it was discontinued within a month because of myelosuppression. The patient then received dasatinib for 10 months, which was changed to nilotinib 13 years ago owing to the former’s complications, such as liver failure and diarrhea. During the 1st year of nilotinib treatment, he was prescribed 150 mg per day, followed by 300 mg daily for the next 4.5 years. Subsequently, the dose was increased to 600 mg. In addition, the right superficial femoral artery (SFA) was occluded and diagnosed with ASO 10 years after nilotinib treatment. A cardiologist performed the stent placement of the SFA. Transoral administration of 100 mg of aspirin and 75 mg of clopidogrel sulfate was continued thereafter. Regarding comorbidities related to arteriosclerosis, hyperlipidemia was noted, but it was well controlled (low-density lipoprotein cholesterol [LDL-C] 71 mg/dL) with rosuvastatin and ezetimibe. The patient experienced temporary right-sided hemiparesis and visited a local hospital. MRI revealed an acute ischemic stroke in the left cerebral hemisphere (Fig. 1A and B), and MR angiography (MRA) revealed stenosis of the left cervical ICA. The patient was then referred to our hospital for further evaluation and treatment. T1- and T2-weighted MRI and MRA revealed a high-intensity plaque (Fig. 1C–E) in the left cervical ICA, and unstable plaque was suspected. Carotid echography revealed severe stenosis of the left cervical ICA with a peak systolic velocity (PSV) of 651 cm/sec. He had been diagnosed with mild left cervical ICA stenosis 3 years previously with a PSV of 154 cm/sec, and the stenosis developed rapidly. CT angiography (CTA) showed no plaque calcifications (Fig. 1F). Moreover, the cerebrovascular reserve (CVR), quantified using single-photon emission CT (SPECT), demonstrated a severe steal phenomenon in the left cerebral hemisphere (Fig. 2A). Therefore, staged CAS was planned. Nilotinib was discontinued on the first day of the endovascular treatment.

FIG. 1.

Preoperative MRI and 3D-CTA. A and B: Diffusion-weighted images showing disseminated high-intensity areas in the left cerebral hemisphere. C–E:T1- and T2-weighted MR images and MR angiogram showing high-intensity plaque (white arrows). F: Three-dimensional CT angiogram showing severe stenosis of the left ICA and absence of plaque calcification.

FIG. 2.

Preoperative CVR and DSA. A:SPECT image of CVR demonstrating severe steal phenomenon in the left cerebral hemisphere. B:Digital subtraction angiogram before PTA. C:Digital subtraction angiogram after PTA showing a little expansion of the left cervical carotid artery stenosis.

The initial endovascular treatment was percutaneous transluminal angioplasty (PTA). The severe stenosis was enlarged by balloon catheters, and angiography after PTA demonstrated that the stenosis improved slightly compared to that before PTA (Fig. 2B and C). Carotid echography confirmed that the stenosis improved, with a PSV of 546 cm/sec. CVR showed no steal phenomenon 1 month later (Fig. 3A); therefore, CAS was performed 1 month later (Fig. 3B and C). The patient’s postoperative course was uneventful, and he was discharged on the 10th day without complications, with a modified Rankin Scale score of 0. He is progressing well 6 months after the staged CAS. Dual antiplatelet therapy (aspirin and clopidogrel sulfate) was continued because of stent placement for the ASO. He is in treatment-free remission of CML; therefore, he keeps discontinuing nilotinib.

FIG. 3.

CVR 1 month after PTA, and DSA. A: SPECT image of CVR demonstrating improvement of the steal phenomenon in the left cerebral hemisphere. B: Digital subtraction angiogram before CAS. C: Digital subtraction angiogram after CAS showing improvement of the left cervical carotid artery stenosis.

Informed Consent

The necessary informed consent was obtained in this study.

Discussion

Observations

Cervical ICA stenosis caused by nilotinib has been previously reported. To the best of our knowledge, 4 cases were reported between 2019 and 2024 (Table 1).^5–8 TKIs used for treating CML include imatinib, nilotinib, dasatinib, bosutinib, and ponatinib,¹ all of which, except ponatinib, are used as first-line therapies for CML.⁹ Nilotinib, dasatinib, and bosutinib are more effective than imatinib.^2–4,10 Considering the cost-effectiveness of nilotinib,^11–15 its use may become more frequent; however, nilotinib has caused more arterial occlusive events (AOEs) than imatinib. In particular, more ischemic cerebrovascular events occur when nilotinib is used.^2–4 This may lead to an increase in cervical ICA stenosis induced by nilotinib.

TABLE 1.

Reported cases with cervical ICA stenosis caused by nilotinib

Authors & Year	Age (yrs), Sex	Side	NASCET Stenosis (%)	Plaque	Symptoms	Other Sites of Stenosis	Dosing Period (yrs)	Nilotinib	Tx	FU (mos)
Nakaya et al., 20195	76/M	Lt & rt	84	Stable	Rt hemiparesis	Bilat MCA, lt PCA	7	Nilotinib → bosutinib	CAS	5
Fujiwara et al., 20216	53/F	Lt & rt	NR	Unstable	Disparity in blood pressures in both arms	Bilat SCA, lt VA	5.5	Discontinued	Medication	45
Hirayama et al., 20227	46/F	Lt & rt	85	Stable	None	None	10	Continued	CAS	3
Tokatlı et al., 20248	70/F	Lt & rt	70	NR	Disparity in blood pressures in both arms	Lt SCA, celiac artery	4	Nilotinib → bosutinib	Medication	12
Present case	67/M	Lt	≥90	Unstable	Rt hemiparesis	Rt SFA	13	Discontinued	Staged CAS	6

FU = follow-up; NASCET = North American Symptomatic Carotid Endarterectomy Trial; NR = not reported; PCA = posterior cerebral artery; SCA = subclavian artery; Tx = treatment.

Various perspectives exist regarding the mechanisms by which nilotinib induces AOEs. For example, Hadzijusufovic et al.¹⁶ reported that nilotinib has pro-atherosclerotic and anti-angiogenic effects on human endothelial cells, and these effects might lead to AOEs. Pinheiro et al.¹⁷ reported that nilotinib decreases endothelial cell migration and proliferation. However, it increases the expression of cell surface molecules such as intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin, which induce arteriosclerosis. Nilotinib also downregulates ABL2, thereby suppressing activities by kinase insert domain receptor, which is associated with angiogenesis. In addition, nilotinib inhibits multiple targets such as angiopoietin receptor 1, Janus kinase 1, TEK receptor tyrosine kinase, fibroblast growth factor receptor 3, mitogen-activated protein kinase, and discoidin domain receptor 1 (DDR-1).^16,18 These might lead to AOEs. Patients treated with nilotinib (300 and 400 mg twice daily) experienced AOEs (11.8% and 21.1%, respectively). Among the AOEs, ischemic heart disease, ischemic cerebrovascular disease, and peripheral arterial occlusive diseases were frequent (300 mg twice daily, 5.4%, 3.2%, and 4.1%; respectively; 400 mg twice daily, 11.9%, 7.0%, and 6.6%, respectively). Other AOEs were also detected (1.4% and 1.4% for 300 and 400 mg twice daily, respectively).² However, no case has provided detailed information regarding patients treated with nilotinib who experienced cervical ICA and SFA stenosis.

The mechanism by which nilotinib-induced plaques develop is unclear. Stable plaques developed in 2 of 4 cases. In 1 of the 4 cases, and in our case, an unstable plaque developed. Nakaya et al.⁵ reported that nilotinib suppresses the function of DDR-1 in macrophages and that this suppression may cause collagenous fibrous and stable plaques. Several reports mentioned stenosis, except for cervical ICA stenosis. Corrêa et al.¹⁹ reported a case of nilotinib-associated cerebrovascular stenosis and an unstable plaque that developed during stenosis. Suzuki et al.²⁰ reported a case in which vessel wall MRI demonstrated a diffuse concentric plaque at the cerebrovascular stenosis induced by nilotinib. Several such cases have been observed, but large-scale studies on the relationship between stenotic plaques and nilotinib have not been reported. Therefore, the effect of nilotinib on plaques is not clear.

There has been no consensus on the standard management of dual antiplatelet therapy for a patient with CML or cervical ICA receiving TKI treatment. CML can lead to both thrombocytopenia and platelet dysfunction. Platelet abnormalities are frequently observed in patients with CML, particularly those with hemorrhagic complications.^21,22 On the other hand, TKIs may contribute to platelet dysfunction.²³ Therefore, careful monitoring is warranted to hemorrhagic complications in patients with CML who receive dual antiplatelet therapy.

The general risk of hyperperfusion syndrome after CAS has been reported to be 0.7%–1.1%, and the frequency is approximately 10 times higher in patients with severe carotid stenosis accompanied by reduced cerebral blood flow reserve with the steal phenomenon.²⁴ For severe carotid stenosis, it has been reported that staged CAS, in which the angioplasty is performed first followed by CAS, reduces the risk of hyperperfusion syndrome.^24,25 It has also been reported that, as in this case, initial angioplasty improves cerebral circulatory reserve, and the frequency of hyperperfusion syndrome after a second CAS is lower than that after the first CAS.²⁶ This report shows that staged CAS may be effective for carotid stenosis caused by nilotinib. No case of carotid endarterectomy has been reported for nilotinib-induced cervical ICA stenosis, and therefore its efficacy in such cases remains unclear. However, CAS for nilotinib-induced stenosis was performed without trouble in previous cases.^5,7 We considered that staged CAS could be performed safely in this case with decreased CVR, as mentioned above.²⁴ Therefore, we performed staged CAS.

Limitations

The patient had hyperlipidemia, which was well controlled. Well-controlled hyperlipidemia might not seriously lead to cervical ICA stenosis, but it is a major risk factor for atherosclerosis and ischemic stroke.²⁷ Ma et al. reported that high small dense LDL-C (sdLDL-C) or a high sdLDL-C/LDL-C ratio increases the risk of cervical ICA stenosis, even if LDL-C is normal.²⁸ However, we were unable to assess sdLDL-C levels, and therefore the causal dependence between cervical ICA stenosis and risk factors of traditional atherosclerosis cannot be completely excluded.

Lessons

We report a case of staged CAS for nilotinib-induced cervical ICA stenosis. However, the mechanisms through which nilotinib causes AOEs and cervical ICA stenosis remain unclear. In addition, only a few cases have been reported; hence, whether nilotinib tends to cause stable or unstable carotid plaques remains unclear. Therefore, additional cases are required to confirm this hypothesis. Neurosurgeons might not be familiar with nilotinib and other TKIs for treating CML, but they need to pay attention to TKI-induced arteriopathies.

Disclosures

The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

Author Contributions

Conception and design: Kamide, Takata. Acquisition of data: Kamide, Kushino, Muranaka, Takata. Analysis and interpretation of data: Kushino, Nogami, Takata. Drafting the article: Kushino, Takata. Critically revising the article: Kamide, Wajima, Nakada. Reviewed submitted version of manuscript: Kamide, Kushino, Hirano, Wajima, Nakada. Approved the final version of the manuscript on behalf of all authors: Kamide. Study supervision: Misaki.

Correspondence

Tomoya Kamide: Kanazawa University, Kanazawa, Ishikawa, Japan. kamide@med.kanazawa-u.ac.jp.