2023 Volume 10 Pages 61-66
Nilotinib, one of the tyrosine kinase inhibitors, has been used to treat chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Nilotinib-associated cerebral arterial occlusive disease, which is treated with medicine with/without bypass surgery or stenting, has been sporadically reported to occur. The mechanism of the nilotinib-associated cerebral disease has not been clarified and is still controversial. Here we present the case of a 39-year-old woman with Ph+ ALL treated with nilotinib, which led to symptomatic intracranial arterial stenosis. We performed high-flow bypass surgery and observed the arterial stenotic change in the stenotic portion intraoperatively, whose findings strongly supported the theory of atherosclerosis and seemed to be irreversible.
Tyrosine kinase inhibitors (TKI) are molecular targeted drugs. The Breakpoint cluster region-Abelson (BCR-ABL) TKI binds to the oncogenic BCR-ABL protein and inhibits its activity to expand hematopoietic stem cells.1) One such TKI, nilotinib, has been widely used to treat chronic myeloid leukemia (CML) and has begun to be used to treat Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).2,3) Nilotinib is a well-tolerated drug with few side effects.4) However, nilotinib-associated cerebral arterial occlusive disease was reported sporadically in 2013. It has been considered an irreversible arterial stenotic event,5) the mechanism of which has not been fully identified and remains controversial. Most reports suggest that the stenotic change involves atherosclerosis, whereas a few suggest that it may be a quasi-moyamoya disease.5,6) Accordingly, the treatment options have differed among patients and have included antiplatelet medical therapy with percutaneous transluminal angioplasty (PTA), stenting, or direct bypass surgery [superficial temporal artery (STA) to the middle cerebral artery (MCA) ].7,8)
Here, we present the case of a patient with nilotinib-associated symptomatic cerebral arterial disease who was treated with high-flow bypass surgery (external carotid artery to MCA M2 with a radial artery graft). Notably, we were able to evaluate the occlusive point under direct vision during bypass surgery.
A 39-year-old Japanese woman was diagnosed with Ph+ ALL without central nervous system infiltration 6 years prior to her arrival at our hospital, where she received induction therapy and consolidation therapy and achieved a molecular complete response (mCR). After umbilical cord blood transplantation, she experienced central nervous system recurrence and was treated with an intraspinal injection of methotrexate, cytosine arabinoside, and prednisolone and craniospinal irradiation of 40 Gy/10 fractions. Her mCR was maintained under TKI therapy, and she was treated with imatinib and dasatinib, both of which caused gastrointestinal side effects. Next, ponatinib was administered, which led to conjunctival hemorrhage and was switched to nilotinib (800 mg). Three and half years after nilotinib treatment began, she experienced repetitive transient weakness of her left extremities, which lasted for approximately 5 min. Magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) showed acute and subacute infarctions in the right watershed area (Fig. 1a) with multiple arterial stenoses. She was admitted to the hospital, and dual antiplatelet therapy (100 mg/day aspirin and 75 mg/day clopidogrel) was initiated. Digital subtraction angiography revealed severe stenosis in the M1 portion of the right MCA, A1 of the right anterior cerebral artery (ACA), right posterior cerebral artery, right vertebral artery (VA), and left cervical common carotid artery, without moyamoya vessels (Fig. 1b-g). Fast imaging employing steady-state acquisition (FIESTA) showed a preserved external diameter of the right MCA (Fig. 1h), and vessel wall imaging showed asymmetric wall thickening of the right MCA, with a narrowed internal diameter (Fig. 1i-j). Single-photon emission computerized tomography (SPECT) demonstrated severely low blood perfusion in the right MCA area (Fig. 1k). These images suggest that the cerebral infarction was attributed to right MCA stenosis. Her low-density lipoprotein (LDL) levels were mildly elevated (154 mg/dL), and statin therapy was initiated. Notably, the patient was relatively young and had no risk factors for arterial sclerosis, such as hypertension, diabetes mellitus, smoking habit, or family history of moyamoya disease. Lupus anticoagulants and screening tests for other autoimmune diseases were negative. The MRI performed 4 years prior to this event revealed no arterial stenosis (Fig. 1l). Therefore, nilotinib-associated arterial occlusive disease was suspected, which is considered irreversible.8) Nilotinib was terminated, and revascularization surgery was planned because the cerebral blood flow did not recover with medical therapy alone. M1 stenosis had a long segment with many perforating branches, which made it difficult to perform PTA or stenting. Her right STA was too thin to supply enough blood to the MCA with STA-MCA bypass. Therefore, a high-flow bypass was performed (Fig. 2a, b). The left radial artery was harvested endoscopically, whose appearance was normal without an atherosclerotic change intraoperatively, and a cervical external carotid artery to the MCA (M2) bypass with an interposition radial artery graft was performed. The main trunk of the MCA (M1 and M2) was observed under direct vision intraoperatively. The external wall of the artery was not narrowed but was maintained with sporadic yellow, shiny, and firm wall thickening, which corresponded to atherosclerosis (Fig. 2c). We chose a normal appearance portion of M2 for arteriotomy. The procedures of arteriotomies and vascular anastomosis proceeded normally successfully without any problems. Postoperative MRA showed a spastic change in the radial artery graft (Fig. 3), probably because the relatively short length of the harvested graft from her short arm forced us to stretch the graft to make the anastomosis. Chronologically, the spasm gradually improved. She developed no neurological deficits nor new cerebral infarction postoperatively and was discharged home. She has maintained good bypass patency without any symptoms for at least 6 months.
Preoperative images.
Preoperative images after infarctions (a–k) and for years prior to infarctions (l). a Diffusion-weighted image of the brain MRI showing acute infarctions within the right cerebral hemisphere in watershed distribution. b–g Catheter angiograms showing stenosis of the right MCA M1 (b), ACA A1 (b–c), VA (d), and cervical common carotid artery to the external carotid artery (f). Catheter angiograms of the right external carotid artery in the lateral view showing a very thin STA, which was insufficient for use as a graft in bypass surgery (e). Abdominal aortography showing moderate stenosis of the bilateral renal arteries (g). h FIESTA showing the preserved external diameter of the right MCA M1 (arrow). i–j A coronal slice (i) and a sagittal slice (j) of vessel wall imaging showing asymmetric wall thickening of the right MCA, with a narrowed internal diameter (arrow). k N-isopropyl-p-[123I]iodoamphetamine (123I-IMP) -SPECT showing hypoperfusion of the right hemisphere with rest (left) and acetazolamide (ACZ) stress (middle). Cerebrovascular reserve (CVR) showing a low degree of autoregulatory vasodilation in the right hemisphere (right). l MRA 4 years before infarctions showing no intracranial arterial stenosis.
Intraoperative images.
a, b Intraoperative cerebral angiogram in the lateral view (a) and three-dimensional reconstruction (b) showing good bypass flow through the radial artery graft. c MCA M1–M2–M3 appearance in the Sylvian fissure, whose external artery wall was not narrowed but was maintained, with sporadic yellow, shiny, and firm wall thickening that corresponded to atherosclerosis.
Postoperative image.
MRA showing good patency of the radial artery and right MCA M2 anastomosis.
BCR-ABL TKIs are a class of molecular targeted drugs for leukemia that inhibit BCR-ABL tyrosine kinase activity. Imatinib, a first-generation TKI, was first approved for CML treatment. Many studies have shown the efficacy of imatinib. However, some patients fail to respond to imatinib therapy because of resistance caused by point mutations in the BCR-ABL kinase domain. Nilotinib is a second-generation TKI that was designed to overcome imatinib resistance.9) Its efficacy is high, but side effects have been reported, such as QT long syndrome and blood cholesterol and glucose level elevations.10) Nilotinib-associated peripheral arterial occlusive disease was reported for the first time in 2011.4) Subsequently, cerebral ischemic events with arterial stenosis in a nilotinib user were first reported in 2013,11) with a total of 14 similar cases, including our patient, reported to date (Table 1). The ages of the reported patients ranged from 39 to 76 years, with our patient being the youngest. Ten of the 14 patients were male, and the location of arterial stenosis was mainly the MCA (8/12 cases). Eight of 12 patients did not have any risk factors for atherosclerosis, which suggests that stenotic changes are associated with nilotinib use. The median period of nilotinib treatment was 5 years (range, 8 months to 7.5 years). Among the 14 patients, PTA alone was performed in one,8) intracranial stenting in two,12,13) cervical stenting in one,14) STA-MCA bypass in two,6,7) and high-flow bypass in one, which was our patient. Follow-up imaging in the published reports has showed no improvement in arterial stenosis despite the termination of nilotinib use, which suggests that the stenotic change in the arteries is irreversible.6) Therefore, surgical intervention along with the termination of nilotinib use is considered a reasonable treatment approach.
| Author, year | Age/sex | Disease | Risk factor | Clinical presentation | Symptoms | Arterial stenosis | Period of nilotinib use | Treatment |
|---|---|---|---|---|---|---|---|---|
| ND, not described; M, male; F, female; CML, chronic myeloid leukemia; CI, cerebral infarction; TIA, transient ischemic attack; rt, right; lt, left; bil, bilateral; MCA, middle cerebral artery; ACA, anterior cerebral artery; VA, vertebral artery; ICA, internal carotid artery; ECA, external carotid artery; APT, antiplatelet medical therapy; CAS, carotid artery stenting; PTA, percutaneous transluminal angioplasty; RA, radial artery | ||||||||
| Coon, 201311) | 70/F | CML | None | CI | Lt hemiparesis, dysarthria | Bil. MCA, bil. PCA, rt. intracranial ICA, rt ACA A1 | 7 years | APT |
| Jager, 201421) | 69/F | CML | None | CI | Aphasia, paresis, epilepsy | ND | 12 months | APT |
| Alshiekh-nasany, 20167) | 50/M | CML | None | TIA | Rt. hemiparesis | Bil. MCA | ND | APT, bil. STA-MCA bypass |
| Ozaki, 201712) | 74/M | CML | ND | TIA | Transient hemiplegea | Lt. intracranial ICA, BA | 2.5 years | APT, stent |
| Gomez-galvan, 201722) | 66/M | CML | Hypertension | CI | Vertigo, diplopia, central facial palsy, gait ataxia | VA, and intracranial ND | 8 months | APT |
| 56/M | CML | Hypertension | CI | Dysarthria, hemiparesis, hemiparesthesia | Lt. ICA, rt. ICA, bil. MCA | 5 years | APT, stent | |
| 66/M | CML | None | CI | Hemiparesis, hemiparesthesia | ICA, MCA | 7 years | APT | |
| Chen, 201813) | 49/F | CML | Type 2 diabetes mellitus, hyperlipidemia | TIA | Rt. hemiparesis | Lt. intracranial ICA | 1 year | APT, stent |
| Suzuki, 20186) | 55/M | CML | ND | CI | Transient lt. sided weakness | Rt. ICA, lt. ICA, MCA and ACA | 3 years | APT, rt. STA-MCA bypass |
| Nakaya, 201914) | 76/M | CML | None | CI | Rt. hemiparesis | Bil. Cervical ICA | 7 years | APT, CAS |
| Uemura, 20205) | 62/M | CML | None | CI | Dysesthesia | Rt. MCA, lt. ACA, lt. PCA | 9 years | APT |
| 59/M | CML | Hypertension | CI | Hoarseness, dysarthria, lt. hemiparesis | Lt. MCA, BA | 7.5 years | APT | |
| Fujiwara, 20218) | 53/M | CML | None | None | Disparity in blood pressures in both arms | Bil. subclavian artery, lt. VA, bil. cervical ICA | 5.5 years | APT, PTA |
| Our case | 39/F | Ph+ALL | None | CI | Rt. hemiparesis | Rt. MCA, rt. ACA A1, VA, lt. cervical ECA | 4 years | Med, rt. ECA-RA-MCA bypass |
Although studies on nilotinib-associated intracranial arterial occlusive disease have been increasingly reported, as well as peripheral, coronary, and pulmonary artery stenosis,15,16) the mechanism of occlusive disease has not yet been clarified. Nilotinib binds to BCR-ABL and discoidin domain receptor 1 (DDR1).17) DDR1 is a collagen receptor expressed on smooth muscle cells and macrophages and is implicated in plaque formation in atherosclerosis.18) Thus, DDR1 inhibition by nilotinib is considered to accelerate plaque formation. Nilotinib also binds to platelet-derived growth factor receptor and KIT receptor kinases, which regulate various vascular and perivascular cells.17) KIT is essential for the development and survival of mast cells,19) which contain heparin, histamine, and tissue plasminogen activator (tPA). Notably, these factors are produced and released in a KIT-dependent manner,20) and nilotinib can lead to thrombophilia by inhibiting KIT. Another study showed that nilotinib exerts direct proatherogenic and antiangiogenic effects on vascular endothelial cells in vitro and in vivo.4) Moreover, nilotinib elevates blood LDL and glucose levels, which can contribute to atherosclerotic changes and ischemic events. Therefore, nilotinib-associated arterial occlusive disease has been implicated in atherosclerosis.
Conversely, another prior study identified, using vessel wall MRI, diffuse concentric thickening of the stenotic artery, which differed from ordinary simple atherosclerosis and represented a type of quasi-moyamoya disease.6)
In summary, this is the first report to observe the intracranial artery directly. The arterial appearance during surgery was atherosclerotic, with asymmetrical, sporadic, yellow firm wall thickening. This finding strongly supports the theory of atherosclerotic changes. The appearance of MCA M1-M2-M3 revealed an atherosclerotic change intraoperatively. However, we cannot firmly conclude this finding because we did not confirm the pathology. We also report only one patient, and thus, we can only draw limited conclusions. More cases are needed to understand the pathobiology of this disease.
Nilotinib has been associated with cerebral arterial occlusive disease, which can cause cerebral ischemic events. Occlusive and irreversible changes are implicated in atherosclerosis. Therefore, in addition to the termination of nilotinib use, the correction of hyperlipidemia and hyperglycemia, and antiplatelet therapy, revascularization surgery should be considered to properly treat patients with this condition.
We thank Dr. Naoyuki Uchida and Dr. Mitsuhiro Yuasa at the Department of Hematology, Toranomon Hospital, for their hematological treatment and consultation.
The patient provided written informed consent.
All authors have no conflict of interest, and they have registered online self-reported COI Disclosure Statement Forms through the website for JNS members.
