Introduction

The prognosis of patients with chronic myeloid leukemia (CML) has improved with the advent of tyrosine kinase inhibitors (TKIs). TKIs for CML are molecular targeted drugs that induce apoptosis of leukemic cells by inhibiting BCR-ABL tyrosine kinase activity. There are cases in which existing TKIs are ineffective due to genetic mutations, and in which it is difficult to continue taking them due to adverse events. Therefore, second and third generation TKIs are currently mainly administered. However, it has been reported that long-term administration of nilotinib, a second generation, and ponatinib, a third generation TKI cause vascular occlusive adverse events such as myocardial infarction, peripheral arterial disease, and cerebral infarction [1]. In the field of neurosurgery, little is known about the risk of cerebral infarction associated with severe cerebrovascular stenosis as a late complication of TKI. Herein, we report a case of severe intracranial internal carotid artery (ICA) stenosis while taking ponatinib, and a case of multiple severe cerebrovascular stenoses during nilotinib treatment, with superficial temporal artery-middle cerebral artery (STA-MCA) bypass surgery.

Case Presentation

Case 1

A 53-year-old man presented with high serum leukocyte and erythrocyte levels on medical examination 6 years prior and was diagnosed with CML after a detailed examination. He had been treated with dasatinib, a second TKI; however, no molecular response was obtained. Therefore, oral administration of 45 mg ponatinib was initiated 5 years ago and had provided him a molecular response. However, he experienced transient right hemiparesis and dysarthria for about 5 min while working, and was hospitalized. Diffusion-weighted magnetic resonance imaging (MRI) showed only one high-intensity area on the medial side of the left temporal lobe, and magnetic resonance angiography (MRA) showed poor visualization of the left intracranial ICA (Figure 1). Digital subtraction angiography (DSA) revealed severe stenosis of the left ICA and delayed perfusion of the distal portion of the stenosis. The stenosis was diffuse with the lumen narrowing from the terminal portion of the ICA to the entire M1 length (Figure 2). Collateral circulation of the left posterior cerebral artery was well developed. The patient was diagnosed with hemodynamic cerebral ischemia due to severe intracranial ICA stenosis. Antiplatelet therapy with 100 mg aspirin and 75 mg clopidogrel and fluid replacement were initiated. However, his neurological symptoms reappeared 3 days later and gradually worsened. Re-examination of the head MRI revealed an increase in sporadic infarcts in the deep white matter of the left frontal lobe (Figure 3). The patient was resistant to medical therapy; therefore, we performed emergency left STA-MCA bypass surgery. Postoperatively, right hemiparesis improved; however, dysarthria persisted. Although he had hypertension, he had no history of smoking or alcohol consumption, no other atherosclerotic factors or negative immunological serum markers such as vasculitis. As a side effect of TKI was suspected, we consulted a hematologist and decided to discontinue ponatinib therapy. The patient was discharged without symptom recurrence.

Figure 1: DWI shows only one high-intensity area on the medial side of the left temporal lobe (A); however, MRA showed poor visualization of the left intracranial ICA (B). DWI: Diffusion-Weighted Imaging; MRA: Magnetic Resonance Angiography; ICA: Internal Carotid Artery

Figure 2: DSA shows the left ICA severe stenosis and delayed perfusion in the distal portion of the stenosis (A: anteroposterior view, B: lateral view). Three dimensional-DSA shows diffuse stenosis with the lumen narrowing from the terminal portion of the ICA to the entire length of M1 (C). DSA: Digital Subtraction Angiography; ICA: Internal Carotid Artery

Figure 3: Repeated MRI shows an increase in sporadic infarcts in the deep white matter of the left frontal lobe.

MRI: Magnetic Resonance Imaging

Case 2

A 74-year-old man started receiving 800 mg of nilotinib for CML 12 years prior to presentation. He had cerebral infarction due to a left MCA stenosis, 6 years ago. Since then, he has continued to take 75 mg of clopidogrel; however this year, he presented with gait disturbances. Diffusion-weighted MRI revealed multiple infarctions in the right cerebral hemisphere, and MRA revealed severe bilateral intracranial ICA and MCA stenoses that progressed gradually (Figure 4). DSA revealed diffuse stenosis along the entire length of M1. Additionally (Figure 5), North American Symptomatic Carotid Endarterectomy Trial 80% stenosis was observed in the left cervical ICA. N-isopropyl-123I-p-iodoamphetamine-single photon emission computed tomography (IMP-SPECT) showed decreased bilateral cerebrovascular reactivity. We performed a right STA-MCA bypass surgery. During surgery, the STA and MCA stumps were collected for pathological diagnosis. Although the intima of the STA was thickened in the pathological diagnosis, no infiltration of inflammatory cells or macrophages was observed. In addition, the MCA slices were normal (Figure 6). We consulted a hematologist and discontinued nilotinib treatment. Two months after the bypass surgery, carotid artery stenting was performed for the left cervical ICA stenosis (Figure 7). The postoperative course was uneventful and the patient experienced no further cerebral ischemia.

Figure 4: DWI shows multiple infarctions on the right cerebral hemisphere (A). MRA shows bilateral intracranial severe stenosis of the ICA and MCA that progressed gradually (B: 12 years ago, C: 6 years ago, D: current). DSA: Digital Subtraction Angiography; MRA: Magnetic Resonance Angiography; ICA: Internal Carotid Artery; MCA: Middle Cerebral Artery

Figure 5: DSA shows bilateral ICA and MCA stenosis (A: right anteroposterior view, B: left anteroposterior view). Three dimensional-DSA shows diffuse stenosis along the entire length of M1 (C). DSA: Digital Subtraction Angiography; ICA: Internal Carotid Artery; MCA: Middle Cerebral Artery

Figure 6: The intima of STA is thickened (A: Elastica van Gieson stain). No infiltration of macrophages was observed on STA (B: CD163 stain). The MCA slice is not thickened (C: Elastica van Gieson stain). STA: Superficial Temporal Artery; MCA: Middle Cerebral Artery

Figure 7: Carotid artery stenting is performed for left cervical ICA stenosis (A: pre, lateral view, B: post, lateral view).

ICA: Internal Cerebral Artery

Discussion

First generation imatinib; second generation dasatinib, bosutinib, nilotinib; and third generation ponatinib are TKIs used to treat CML. TKIs improve the prognosis of CML; however, their long-term use induces mutations such as T315I in the ABL region of BCR-ABL, resulting in acquired resistance to treatment [2]. In recent years, third generation ponatinib has been increasingly selected for patients who have become treatment-resistant owing to genetic mutations or who cannot continue conventional treatment owing to adverse events.

Nilotinib and ponatinib reportedly cause vascular occlusive adverse events [1,3,4]. A few reports of the relationship between these drugs and peripheral arterial disease; however, few reports of myocardial infarction and cerebral infarction. Cerebrovascular stenosis as an adverse event has received little attention in the field of neurosurgery. To the best of our knowledge, only 15 cases of cerebrovascular stenosis caused by nilotinib or ponatinib have been reported (Table 1). In most cases, the stenosis affects multiple intracranial and extracranial cerebrovascular vessels. The average period from TKI administration to cerebral infarction was approximately 5 years. In some cases, invasive interventions are required because of resistance to medical treatment. Although the postoperative course is favorable in most cases, the long-term outcomes are unknown because of the short follow-up period. Case 1 was the first case in which revascularization was performed for cerebrovascular stenosis caused by ponatinib. This patient had not undergone cerebral angiography before starting ponatinib; however, he had no history of smoking or alcohol consumption, arteriosclerotic factors other than hypertension, or immunological serum markers such as vasculitis. Therefore, we diagnosed the patient with ponatinib-induced cerebrovascular disease. In addition, ponatinib itself has the side effect of hypertension [5], and our patient also exhibited hypertension after starting ponatinib treatment.

TKIs for CML primarily target BCR-ABL in leukemic cells. However, TKIs also inhibit various off-target molecules involved in the onset of cardiovascular events such as vascular endothelial cells, platelets, macrophages, and mast cells, thereby altering their functions and causing cardiovascular events [6]. Among TKIs, the likelihood of cardiovascular events varies depending on the differences in the target molecules. TKIs inhibit enzymes, such as SRC kinase, and fibroblast growth factor, platelet-derived growth factor, and vascular endothelial growth factor receptors (VEGFR) [7]. Particularly important for the development of cerebral ischemia, inhibition of VEGFR induces vascular endothelial cell dysfunction and apoptosis [7]. Normal vascular endothelial cells exhibit anti-inflammatory, antithrombotic, and anticoagulant functions and inhibit intimal thickening. Therefore, the inhibition of VEGFR, which occurs as an off-target effect of TKIs, promotes vascular endothelial cell damage, resulting in intimal thickening, thrombus formation, and platelet aggregation [6,8]. Damage to vascular endothelial cells is an important mechanism underlying TKI-induced cerebral infarction. Moreover, various factors such as the expression of inflammatory cytokines are involved. A relationship between TKIs and the expression of adhesion factors that induce arteriosclerosis on the cell surface, such as intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, has also been suggested [9].

Whether cerebrovascular stenosis caused by TKIs is reversible is unknown; however, it is irreversible in peripheral arterial diseases [10]. If cerebrovascular stenosis is irreversible, revascularization should be considered because the discontinuation of TKIs alone does not improve the condition. Invasive intervention is unavoidable, especially in cases of resistance to medical treatment such as antithrombotic therapy. In the present case, the prognosis after revascularization was good. However, the long-term prognosis after revascularization is unknown, and further accumulation of cases is required.

Table 1: Cerebrovascular stenosis with TKIs for leukemia.

Conclusion

Although the prognosis of CML has steadily improved with the advent of new TKIs, systemic complications have become problematic. In the future, reports on cerebrovascular stenosis caused by TKIs in patient with CML may increase. We believe that understanding the pathological mechanism is important in selecting treatment when we are forced to make decisions regarding invasive interventions.

Acknowledgments

None.

Conflict of Interest

None.

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