Vessel wall magnetic resonance imaging findings and surgical treatment in nilotinib‑associated cerebrovascular disease: A case report

  • Authors:
    • Kohei Suzuki
    • Junkoh Yamamoto
    • Shingo Kakeda
    • Seishiro Takamatsu
    • Ryo Miyaoka
    • Takehiro Kitagawa
    • Takeshi Saito
    • Yoshiteru Nakano
    • Shigeru Nishizawa
  • View Affiliations

  • Published online on: November 30, 2018     https://doi.org/10.3892/mco.2018.1780
  • Pages: 239-243
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Abstract

Nilotinib, a second‑generation tyrosine kinase inhibitor, is considered as one of the most effective drugs for the treatment of chronic myeloid leukemia (CML); however, the use of nilotinib has been reported to be associated with vascular adverse events, such as peripheral arterial occlusive disease and ischemic heart disease. Moreover, there are few reports on cerebral vascular disease associated with nilotinib use. We herein describe the case of a 55‑year‑old male patient with CML, who presented with cerebral infarction and severe cerebrovascular stenosis that developed during nilotinib treatment. The patient was diagnosed with cerebral infarction and severe stenosis of the intracranial arteries associated with nilotinib use. Vessel wall magnetic resonance imaging (VW‑MRI) revealed diffuse concentric thickening of the vessel wall, unlike ordinary patterns of atherosclerosis. The patient underwent direct revascularization (superficial temporal artery to middle cerebral artery bypass) and was successfully treated without recurrence. Based on this rare case, VW‑MRI may be used to detect the morphological changes of the intracranial arteries that are associated with nilotinib use. Moreover, surgical revascularization may improve the prognosis of nilotinib‑associated cerebrovascular diseases, such as severe stenosis or occlusion of the main trunk of the cerebral arteries, that cause brain ischemia.

Introduction

Chronic myeloid leukemia (CML) is caused by uncontrolled proliferation of hematopoietic cells of the myeloid lineage and the presence of the BCR/ABL1 fusion oncogene. Tyrosine kinase inhibitors (TKIs) block the binding of adenosine triphosphate to BCR/ABL1 tyrosine kinase, thus inhibiting its activity (1). Imatinib, a first-generation TKI, has been considered as the standard treatment for CML (2); however, some patients develop resistance to imatinib caused by point mutations of the BCL/ABL1 chromosome. Compared with imatinib, nilotinib, a second-generation TKI, is highly effective and relatively safe for patients with CML (3). Thus, nilotinib has been increasingly used as the gold standard therapy for imatinib-intolerant or -resistant CML and newly diagnosed chronic-phase CML (3). Recently, nilotinib-associated vascular adverse events (VAEs), such as peripheral arterial occlusive disease (PAOD), have been reported (1,4,5). Prospective reports have described an increased rate of VAEs among patients treated with nilotinib compared with imatinib (1,4), although cerebral vascular disease (CVD) associated with nilotinib use is extremely rare (610).

We herein describe a rare case of nilotinib-associated CVD in a patient with CML, and discuss the differential diagnosis and management of this condition.

Case report

A 55-year-old Japanese male patient who had been receiving nilotinib treatment for CML (300 mg twice per day for 3 years) developed transient left-sided weakness of the extremities 2 days prior to presentation (Fig. 1). The symptoms worsened, and the patient was admitted in January 2017 to the University of Occupational and Environmental Health Hospital (Kitakyushu, Japan). The neurological examination revealed mild left-sided hemiparesis, dysarthria and dysphagia. Magnetic resonance imaging (MRI) revealed acute cerebral infarction in the area supplied by the right middle cerebral artery (MCA). Magnetic resonance angiography (MRA) revealed severe stenosis in the right internal carotid artery (ICA) and left MCA (M1), without Moyamoya vessels (Fig. 2). Vessel wall magnetic resonance imaging (VW-MRI) revealed diffuse concentric thickening of the vessel wall of the right intracranial ICA and MCA, and the left MCA. Those findings were different from those of ordinary atherosclerosis, which is characterized by segmental and eccentric wall thickening (Fig. 3A and B). The results of the blood tests demonstrated a mildly elevated low-density lipoprotein (LDL) cholesterol level (139 mg/dl). The results of the serological examination for infectious, collagen and hormonal diseases were unremarkable. The patient had no history of hypertension, arrhythmia, or diabetes mellitus; he occasionally consumed alcohol and had a sporadic smoking habit; he had no family history of stroke or vascular diseases. Thus, the clinical diagnosis was cerebral infarction associated with nilotinib use.

Nilotinib maintenance therapy was terminated and the patient was treated with antiplatelet therapy and a high-potency statin. After 3 months of rehabilitation, his symptoms gradually improved.

An additional examination for brain ischemia was then performed. Cerebral angiography revealed no notable atherosclerosis in the cervical carotid artery and aortic arch, apart from the intracranial lesions previously detected by MRA. Single photon-emission computed tomography imaging revealed poor perfusion of the area supplied by the right MCA around the ischemic core. Subsequently, the patient underwent direct revascularization [superficial temporal artery (STA) to MCA bypass] 5 months after the initial admission.

Thereafter, the patient developed no recurrence of brain ischemia. Follow-up MRI examination 16 months after the initial presentation also revealed no marked changes of the cerebral arteries (Fig. 3C), and the patient was able to resume his daily activities. Nilotinib was replaced with imatinib after the initial admission, and major molecular remission has been maintained as at August 2018.

Discussion

Although PAOD is a well-known nilotinib-associated VAE, nilotinib-associated CVD is extremely rare. To the best of our knowledge, only 8 such cases have been published in the literature to date (Table I). Nilotinib-associated CVD is relatively common in middle-aged men, with development of brain ischemia due to severe stenosis or occlusion in the main trunk of the cerebral arteries. In most cases, the onset of symptoms occurs several months or years after the initiation of nilotinib treatment, except in one case. In addition, almost all the patients had some additional vascular risk factors, which were not all attributable to nilotinib use. Our patient was a middle-aged man with a smoking habit and a mildly elevated LDL cholesterol level, who developed cerebral infarction due to severe stenosis of the major cerebral arteries 3 years after nilotinib treatment initiation, similar to previous cases.

Table I.

Summary of the reported cerebral vascular diseases associated with nilotinib use.

Table I.

Summary of the reported cerebral vascular diseases associated with nilotinib use.

CaseStudy, yearAge/sexClinical presentationArterial stenosisPeriod from TKI onsetVascular risk factorsTreatmentTime to recurrenceRefs.
1Quintás-Cardama et al, 201250/FVasospasmNL48 hNLMedication only48 h(5)
2Coon et al, 201370/FTIA/CIBilateral MCA Right ICA7 years+Medication only1 year(7)
3Jager et al, 201469/FCINL12 months+Medication only3 months(9)
4Alshiekh-Nasany et al, 201650/MTIABilateral MCA5 years+Medication Bil. STA-MCA bypassNo recurrence(6)
5Ozaki et al, 2017 (In press)74/MTIANLNLNL NL(10)
6Ozaki et al, 2017 (In press)66/MCIVA, Left MCA, Right PCA8 months+Medication onlyNL(10)
7Gómez-Galván et al, 201756/MCILeft ICA, Right ICA, Bilateral MCA5 years+Medication stent placement3 months(8)
8Gómez-Galván et al, 201766/MCIICA, MCA7 yearsNLMedication only3 months(8)
9Present study55/MCIRight ICA, Left ICA, MCA and ACA3 years+Medication Rt. STA-MCA bypassNo recurrence

[i] TIA, transient ischemic attack; CI, cerebral infarction; ICA, internal carotid artery; MCA, middle cerebral artery; ACA, anterior cerebral artery; PCA, posterior cerebral artery; STA, superior temporal artery; Bil., bilateral; Rt., right; M, male; F, female; NL, not listed; TKI, tyrosine kinase inhibitor.

The pathogenesis of nilotinib-associated CVD remains unclear. Previous studies have demonstrated that the discoidin domain receptor 1 (DDR1), platelet-derived growth factor receptor (PDGF-R) and C-kit may be associated with systemic VAEs during nilotinib use as off-target activity (1). Among those, DDR1 plays a role in atherosclerosis, and nilotinib has a particularly high affinity for this receptor, compared with that for BCR/ABL1 (4). PDGF-R and C-kit may also potentially provide explanations for the vascular toxicity, since they are both involved in the regulation of vascular and perivascular cells (1,4). Furthermore, previous studies have suggested that nilotinib exerts direct pro-atherogenic and anti-angiogenic effects on endothelial cells (11). An altered endothelial cell function with increased expression of cytoadhesive cell surface molecules and consecutive pro-atherogenic changes in the vessel wall are considered to be a key mechanism underlying the VAE-promoting action of nilotinib (12). In addition, nilotinib exerts metabolic effects, including an increase in cholesterol and fasting glucose levels (1). Thus, previous studies have suggested that nilotinib induces systemic arterial stenosis by its direct pro-atherogenic effects, and inhibits recanalization and reperfusion via its anti-angiogenic effects, thus leading to systemic VAEs.

VW-MRI can provide information on vessel wall changes to distinguish among different CVDs. In atherosclerosis, the atherosclerotic plaques tend to appear as asymmetrical vascular wall thickenings (eccentricity) relative to other vascular pathologies. Conversely, symmetrically thickened walls are usually observed in vasculitis, Moyamoya disease, and reversible cerebral vasoconstriction syndrome (13). In the present case, VW-MRI revealed diffuse concentric thickening of the vessel wall of the right intracranial ICA and MCA, and the left MCA. Additionally, the eccentricity index [calculated as (maximal thickness - minimal thickness)/maximal thickness] was 0.1–0.2; if the index exceeds 0.5, the lesion is defined as an eccentric plaque (13). The findings of follow-up MRI did not match the future development of Moyamoya disease, which is characterized by progressiveness. These findings in the present case indicated that the morphological changes of the vessel wall were inconsistent with those of ordinary simple atherosclerotic disease. We could not perform pathological examination of the intracranial arteries, which exhibited severe stenosis, due to the clinical and surgical limitations. Instead, the pathological study of the STA, which was retrieved during surgery, revealed no notable atherosclerotic and inflammatory changes or wall thickening. Nilotinib induces vasculitis and/or severe atherosclerotic changes in the entire circumference of the main trunk of the cerebral arteries under certain conditions, such as smoking, diabetes mellitus, hypertension and hypercholesterolemia. The findings on VW-MRI in the present case suggested that those morphological changes were potentially caused by ordinary atherosclerosis and vasculitis, as CVDs associated with nilotinib use were limited to the intracranial arteries.

Patients who develop nilotinib-associated CVD are generally managed by anticoagulant or antiplatelet therapy, elimination of risk factors, a reduced TKI dose and conversion to another TKI (59). Yet, the majority of the patients experienced recurrent CVD within 1 year after their initial symptoms. Only 2 patients, including our patient, underwent STA-MCA bypass surgery with medical treatment and experienced no recurrence of CVD. The number of similar cases and follow-up period are limited; however, in the present case, the severe stenosis in the MCA and ICA was not progressed and the patient's neurological status was not changed, as indicated by follow-up MRI. Thus, surgical revascularization may improve prognosis in patients with nilotinib-associated CVD, which manifests with any critical and symptomatic intracranial arterial stenosis.

In conclusion, nilotinib-associated CVD is rare, but its incidence may increase as the use of nilotinib increases among patients with CML. Thus, clinicians should be aware of the risk factors of nilotinib-associated CVD and perform careful long-term follow-up of patients for several years. As regards the management of nilotinib-associated CDV, surgical revascularization may improve the prognosis of such patients.

Acknowledgements

Not applicable.

Funding

No funding was received.

Availability of data and materials

Not applicable.

Authors' contributions

KS drafted the manuscript. JY, TS and YN revised the content and advised constructive feedbacks. KS, JY, RM and TK performed this surgery. SK and ST analysed all images and drafted parts of the manuscript. SN wrote the final draft. All the authors have read and approved the final version of this manuscript.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Informed consent was obtained from the patient about the publication of the case details and any associated images.

Competing interests

The authors declare that they have no competing interests.

Glossary

Abbreviations

Abbreviations:

CML

chronic myeloid leukemia

CVD

cerebral vascular disease

DDR1

discoidin domain receptor 1

ICA

internal carotid artery

LDL

low-density lipoprotein

MCA

middle cerebral artery

MMR

major molecular remission

MRA

magnetic resonance angiography

MRI

magnetic resonance imaging

PAOD

peripheral arterial occlusive disease

PDGF-R

platelet-derived growth factor receptor

STA

superficial temporal artery

SPECT

single photon-emission computed tomography

TKI

tyrosine kinase inhibitor

VAE

vascular adverse event

VW-MRI

vessel wall magnetic resonance imaging

References

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Spandidos Publications style
Suzuki K, Yamamoto J, Kakeda S, Takamatsu S, Miyaoka R, Kitagawa T, Saito T, Nakano Y and Nishizawa S: Vessel wall magnetic resonance imaging findings and surgical treatment in nilotinib‑associated cerebrovascular disease: A case report. Mol Clin Oncol 10: 239-243, 2019
APA
Suzuki, K., Yamamoto, J., Kakeda, S., Takamatsu, S., Miyaoka, R., Kitagawa, T. ... Nishizawa, S. (2019). Vessel wall magnetic resonance imaging findings and surgical treatment in nilotinib‑associated cerebrovascular disease: A case report. Molecular and Clinical Oncology, 10, 239-243. https://doi.org/10.3892/mco.2018.1780
MLA
Suzuki, K., Yamamoto, J., Kakeda, S., Takamatsu, S., Miyaoka, R., Kitagawa, T., Saito, T., Nakano, Y., Nishizawa, S."Vessel wall magnetic resonance imaging findings and surgical treatment in nilotinib‑associated cerebrovascular disease: A case report". Molecular and Clinical Oncology 10.2 (2019): 239-243.
Chicago
Suzuki, K., Yamamoto, J., Kakeda, S., Takamatsu, S., Miyaoka, R., Kitagawa, T., Saito, T., Nakano, Y., Nishizawa, S."Vessel wall magnetic resonance imaging findings and surgical treatment in nilotinib‑associated cerebrovascular disease: A case report". Molecular and Clinical Oncology 10, no. 2 (2019): 239-243. https://doi.org/10.3892/mco.2018.1780