Letter to the Editor
Nilotinib as a risk factor for ischaemic stroke: a series of three cases
Nilotinib como factor de riesgo de ictus isquémico. A propósito de 3 casos
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A) Supratentorial cortical venous flow is diverted to the facial and mastoid emissary veins due to chronic occlusion of the superior longitudinal sinus (note that it is irregular and not filled) and partial obliteration of venous flow from the transverse and sigmoid sinuses. These findings were linked to signs of thrombosis. B) Posterior fossa venous blood flow through the mastoid emissary veins. Below: MRI. C) Contrast T1-weighted MRI sequence showing irregular contrast uptake in the transverse sinuses. D) Post-contrast dynamic TRICK sequence acquired during venous phase showing threadlike uptake in the superior longitudinal sinus and marked congestion of the sinus rectus, linked to signs of chronic thrombosis.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "F. Pérez-Bartolomé, C. Sanz-Pozo, S. Darío Rosati, E. Santos-Bueso, J. Porta-Etessam" "autores" => array:5 [ 0 => array:2 [ "nombre" => "F." "apellidos" => "Pérez-Bartolomé" ] 1 => array:2 [ "nombre" => "C." 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Patients with moderate functional disability displayed more marked improvements in all areas; differences were statistically significant for motor fluctuations (MF), Schwab & England Activities of Daily Living Scale (S&E) rates, Abnormal Involuntary Movement Scale (AIMS) scores, and Hospital Anxiety and Depression Scale (HADS-A and HADS-B).</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "G. Salazar, J. Martín, M. Fragoso, M.A. Font" "autores" => array:4 [ 0 => array:2 [ "nombre" => "G." "apellidos" => "Salazar" ] 1 => array:2 [ "nombre" => "J." "apellidos" => "Martín" ] 2 => array:2 [ "nombre" => "M." 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Gómez-Galván, S. Borrego, N. Tovar, L. Llull" "autores" => array:4 [ 0 => array:3 [ "nombre" => "J.B." "apellidos" => "Gómez-Galván" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:3 [ "nombre" => "S." "apellidos" => "Borrego" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "N." "apellidos" => "Tovar" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:4 [ "nombre" => "L." "apellidos" => "Llull" "email" => array:1 [ 0 => "blllull@clinic.ub.es" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Neurología, Hospital Clínic, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Hematología, Hospital Clínic, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Nilotinib como factor de riesgo de ictus isquémico. A propósito de 3 casos" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 861 "Ancho" => 1400 "Tamanyo" => 111858 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">MRA in patient 3 showed moderate stenosis (> 50%) of the right MCA (A) and right ICA occlusion due to dissection (B).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Nilotinib is a tyrosine kinase inhibitor (TKI) that has been approved as a treatment for chronic myeloid leukaemia (CML). Nilotinib has been associated with increased risk of peripheral artery disease (PAD),<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">1–3</span></a> coronary artery disease, and cerebrovascular events.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">4–6</span></a> We present the cases of 3 patients who experienced ischaemic strokes during long-term treatment with nilotinib. Two of them also presented PAD and intracranial atherosclerosis. The third had dissection of the internal carotid artery (ICA) with no evidence of atheromatosis in the vascular study. At the time of stroke, the 3 patients showed high 10-year cardiovascular risk (CVR) according to the instrument developed by the American Heart Association (AHA).<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">7</span></a></p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Description of the 3 cases</span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Case 1</span><p id="par0010" class="elsevierStylePara elsevierViewall">Our first patient was a 66-year-old man with a history of arterial hypertension and CML; he had been treated with nilotinib 400<span class="elsevierStyleHsp" style=""></span>mg twice daily throughout the previous 8 months. His 10-year risk of atherosclerotic cardiovascular disease (ASCVD) was 9.6%. The patient visited our hospital due to sudden onset of vertigo, diplopia, central facial palsy, and gait ataxia. An MRI scan revealed multiple acute ischaemic lesions in the midbrain, pons, and occipital cortex. MR angiography (MRA) showed occlusion of the vertebral artery and significant intracranial atherosclerosis (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>A). Treatment was changed to dasatinib and oral anticoagulant treatment with acenocoumarol was added. Eight months later, the patient was diagnosed with PAD and had a stent placed in his femoral artery.</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Case 2</span><p id="par0015" class="elsevierStylePara elsevierViewall">The second patient was a male smoker aged 56 with a history of arterial hypertension and coronary artery disease. Five years before the admission in question, he was diagnosed with CML and treated with nilotinib 300<span class="elsevierStyleHsp" style=""></span>mg twice daily. Sixteen months before being admitted, the patient presented occlusion of the central retinal artery. Treatment with nilotinib was therefore suspended in favour of antiplatelet and lipid-lowering agents. His 10-year ASCVD risk was 14.8%. The patient was admitted following multiple self-limiting episodes of dysarthria, hemiparesis, and hemihypaesthesia. The vascular study showed near occlusion of the left ICA and stenosis of the right ICA and both middle cerebral arteries (MCA). We initiated anticoagulant treatment with intravenous sodium heparin. Despite treatment, the patient showed further symptoms of hemiplegia and aphasia due to left ICA occlusion. Emergency angioplasty and stent placement failed to result in clinical improvement. An ultrasound study 2 days later showed stent occlusion. MR angiography confirmed lack of flow in the left ICA and MCA. The patient remained on anticoagulant treatment with acenocoumarol after discharge. His NIHSS score was 7 in a follow-up assessment completed at 3 months. He had not experienced any new vascular events at that time and we decided to replace acenocoumarol with aspirin.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Case 3</span><p id="par0020" class="elsevierStylePara elsevierViewall">Our third patient was a 66-year-old man with a history of CML treated with nilotinib 300<span class="elsevierStyleHsp" style=""></span>mg twice daily throughout the previous 7 years. The patient visited our department due to 2 transient episodes of hemiparesis and left hemihypaesthesia. His 10-year ASCVD risk was 9.3%. An MRI scan revealed multiple ischaemic lesions in the right frontal and parietal cortex. MR angiography showed ICA dissection and MCA stenosis of more than 50% (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A and B). After suspending treatment with nilotinib, we started treating the patient with lipid-lowering drugs and acenocoumarol as an anticoagulant agent. At 3 months, a follow-up CT angiography showed persistent ICA occlusion and we opted to replace acenocoumarol with aspirin.</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Discussion</span><p id="par0025" class="elsevierStylePara elsevierViewall">Nilotinib has been proven to be an effective treatment for CML.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">8</span></a> Nevertheless, long-term follow-up studies have documented such vascular events as PAD, coronary artery disease, or cerebrovascular disease in a significant percentage of patients receiving this treatment.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">9,10</span></a> Several mechanisms have been proposed to explain this association. The effects of nilotinib on nonhematopoietic cells, such as vascular and perivascular cells, mast cells, or pancreatic cells, might promote development of atherosclerosis, hyperglycaemia, or hypercholesterolaemia.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">2</span></a> Furthermore, the TKI ponatinib has been associated with vascular and cerebral events, which suggests a potential drug class effect.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">1,11</span></a> However, such events have not been described with imatinib or dantinib.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Two of our patients presented pronounced intracranial atherosclerosis. Similar findings have been described previously in patients treated with nilotinib<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">4</span></a> and ponatinib.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">11</span></a> The third patient showed dissection of an extracranial large vessel, a manifestation of vascular involvement that had not previously been described in patients treated with nilotinib.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Some experts have suggested that estimating CVR using such validated scales as those developed by the AHA<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">7</span></a> or the European Society of Cardiology<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">12</span></a> may help identify patients with a higher risk of adverse vascular events.<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">1,13</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Clinicians should be aware of the association between nilotinib and cerebrovascular events and thus avoid that drug in patients with a high CVR, or else monitor the related metabolic changes that may appear, such as hypercholesterolaemia or hyperglycaemia. Likewise, we recommended informing patients treated with nilotinib about stroke symptoms so that they would know to seek medical attention promptly.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:4 [ 0 => array:3 [ "identificador" => "sec0005" "titulo" => "Description of the 3 cases" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0010" "titulo" => "Case 1" ] 1 => array:2 [ "identificador" => "sec0015" "titulo" => "Case 2" ] 2 => array:2 [ "identificador" => "sec0020" "titulo" => "Case 3" ] ] ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Discussion" ] 2 => array:2 [ "identificador" => "xack289474" "titulo" => "Acknowledgements" ] 3 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Gómez-Galván JB, Borrego S, Tovar N, Llull L. Nilotinib como factor de riesgo de ictus isquémico. A propósito de 3 casos. Neurología. 2017;32:411–413.</p>" ] ] "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 580 "Ancho" => 1750 "Tamanyo" => 133804 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Magnetic resonance angiography (MRA) in patient 1 (A) showed occlusion of the left vertebral artery (VA) and intracranial diffuse atherosclerosis, especially in the right VA, the left MCA, and the right posterior cerebral artery (PCA). The MRA in patient 2 (B) showed a lack of circulation in the left ICA and MCA, with intracranial atherosclerosis predominantly affecting the right MCA and PCA.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 861 "Ancho" => 1400 "Tamanyo" => 111858 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">MRA in patient 3 showed moderate stenosis (> 50%) of the right MCA (A) and right ICA occlusion due to dissection (B).</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:13 [ 0 => array:3 [ "identificador" => "bib0070" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "P. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 7 | 3 | 10 |
| 2024 October | 42 | 11 | 53 |
| 2024 September | 60 | 4 | 64 |
| 2024 August | 47 | 6 | 53 |
| 2024 July | 50 | 3 | 53 |
| 2024 June | 30 | 8 | 38 |
| 2024 May | 35 | 7 | 42 |
| 2024 April | 39 | 6 | 45 |
| 2024 March | 32 | 6 | 38 |
| 2024 February | 47 | 10 | 57 |
| 2024 January | 35 | 14 | 49 |
| 2023 December | 42 | 7 | 49 |
| 2023 November | 35 | 8 | 43 |
| 2023 October | 55 | 7 | 62 |
| 2023 September | 21 | 2 | 23 |
| 2023 August | 30 | 5 | 35 |
| 2023 July | 39 | 6 | 45 |
| 2023 June | 34 | 7 | 41 |
| 2023 May | 57 | 5 | 62 |
| 2023 April | 26 | 0 | 26 |
| 2023 March | 36 | 4 | 40 |
| 2023 February | 39 | 4 | 43 |
| 2023 January | 41 | 3 | 44 |
| 2022 December | 37 | 7 | 44 |
| 2022 November | 42 | 11 | 53 |
| 2022 October | 33 | 9 | 42 |
| 2022 September | 33 | 7 | 40 |
| 2022 August | 37 | 11 | 48 |
| 2022 July | 32 | 5 | 37 |
| 2022 June | 37 | 8 | 45 |
| 2022 May | 34 | 11 | 45 |
| 2022 April | 42 | 19 | 61 |
| 2022 March | 39 | 13 | 52 |
| 2022 February | 67 | 8 | 75 |
| 2022 January | 74 | 9 | 83 |
| 2021 December | 50 | 9 | 59 |
| 2021 November | 44 | 11 | 55 |
| 2021 October | 69 | 8 | 77 |
| 2021 September | 66 | 11 | 77 |
| 2021 August | 73 | 9 | 82 |
| 2021 July | 21 | 11 | 32 |
| 2021 June | 30 | 10 | 40 |
| 2021 May | 29 | 13 | 42 |
| 2021 April | 98 | 16 | 114 |
| 2021 March | 58 | 6 | 64 |
| 2021 February | 27 | 9 | 36 |
| 2021 January | 34 | 7 | 41 |
| 2020 December | 42 | 8 | 50 |
| 2020 November | 34 | 10 | 44 |
| 2020 October | 22 | 5 | 27 |
| 2020 September | 20 | 8 | 28 |
| 2020 August | 20 | 6 | 26 |
| 2020 July | 19 | 6 | 25 |
| 2020 June | 27 | 11 | 38 |
| 2020 May | 26 | 12 | 38 |
| 2020 April | 31 | 6 | 37 |
| 2020 March | 22 | 8 | 30 |
| 2020 February | 19 | 5 | 24 |
| 2020 January | 24 | 11 | 35 |
| 2019 December | 26 | 3 | 29 |
| 2019 November | 14 | 6 | 20 |
| 2019 October | 18 | 2 | 20 |
| 2019 September | 12 | 3 | 15 |
| 2019 August | 6 | 1 | 7 |
| 2019 July | 14 | 12 | 26 |
| 2019 June | 54 | 9 | 63 |
| 2019 May | 116 | 1 | 117 |
| 2019 April | 51 | 9 | 60 |
| 2019 March | 8 | 10 | 18 |
| 2019 February | 11 | 10 | 21 |
| 2019 January | 3 | 4 | 7 |
| 2018 December | 3 | 5 | 8 |
| 2018 November | 10 | 2 | 12 |
| 2018 October | 15 | 11 | 26 |
| 2018 September | 6 | 5 | 11 |
| 2018 August | 10 | 11 | 21 |
| 2018 July | 5 | 10 | 15 |
| 2018 June | 4 | 12 | 16 |
| 2018 May | 3 | 14 | 17 |
| 2018 April | 13 | 5 | 18 |
| 2018 March | 5 | 6 | 11 |
| 2018 February | 2 | 5 | 7 |
| 2018 January | 14 | 12 | 26 |
| 2017 December | 10 | 8 | 18 |
| 2017 November | 8 | 7 | 15 |
| 2017 October | 9 | 1 | 10 |
| 2017 September | 21 | 6 | 27 |
| 2017 August | 29 | 4 | 33 |
| 2017 July | 18 | 4 | 22 |
| 2017 June | 0 | 5 | 5 |
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