Nilotinib treatment‐associated cerebrovascular disease and stroke
Authors: Elizabeth A. Coon, Nicholas L. Zalewski, Ernest Matthew Hoffman, Ayalew Tefferi, Kelly D. Flemming
Journal: American Journal of Hematology (2013)

Treatment of chronic myelogenous leukemia (CML) with nilotinib has been associated with progressive peripheral arterial disease (PAD), but there has been no report of cerebrovascular involvement 1, 2. We describe rapid progression of intra- and extra-cranial atherosclerosis leading to stroke in a previously reported patient with nilotinib-associated PAD 2. A 70-year-old woman presented with acute onset of left-sided weakness and dysarthria. Her past medical history of CML and treatment has been well described 2. Before her CML diagnosis in 1996, she had no history of vascular disease. Her prior treatment regimen included interferon-alpha and low-dose cytarabine followed by imatinib in 2000. After dendritic cell vaccine therapy was unsuccessful, tipifarnib was added in 2004. Due to lack of response and progressive disease, she was switched to nilotinib in 2004 with complete cytogenetic remission. The patient developed symptoms attributable to PAD in 2007 and underwent multiple angioplasty and stenting procedures with recurrent in-stent thromboses. With recurrent claudication symptoms in 2010, she had a superficial femoral to below-knee popliteal artery bypass. Coronary artery disease was diagnosed in 2008, and she underwent percutaneous transluminal coronary angioplasty and stenting followed by four-vessel coronary artery bypass grafting. She has renal artery and mesenteric artery stenosis on angiography. During her course on nilotinib, the patient was diagnosed with hypertension, hyperlipidemia, and prediabetes, which were all controlled on medications. Her medication regimen included aspirin, clopidogrel, and warfarin. In 2008, there was a strong suspicion that her progressive atheromatous disease was attributable to nilotinib with the decision made to continue in the context of imatinib-refractory CML. In 2011, the patient had two episodes of confusion. Magnetic resonance angiography (MRA) showed multifocal narrowing involving both middle cerebral arteries (MCA) and posterior cerebral artery (Fig. 1, top row). There was 50–60% narrowing of the right internal carotid artery (ICA). The episodes were of unclear relationship to the vessel findings. In November 2012, in the setting of postprandial hypotension, she developed acute onset of left-sided weakness with cortical sensory loss of her left upper extremity. An MRI showed a right MCA distribution ischemic stroke. MRA showed diffuse intracranial atherosclerosis (Fig. 1, bottom row) and high-grade stenosis of the extracranial R ICA. A conventional angiogram revealed similar changes and near occlusion (>95%) of the right ICA. The risk of surgical or endovascular carotid intervention was deemed high due to diffuse intracranial disease, and she was maintained on dual antiplatelet therapy and anticoagulation with permissive blood pressure parameters. Nilotinib was shown superior to imatinib for the treatment of CML; however, follow-up was limited to 24 months 3. Further reports have identified rapidly progressive PAD as a significant side effect of nilotinib therapy 1, 2. Our patient had no vascular disease risk factors prior to treatment with nilotinib and developed progressive PAD followed by accelerated atheromatous cerebrovascular disease. Cerebrovascular involvement and stroke have not been previously reported in patients on nilotinib therapy; however, clinicians should be aware of the risk of cerebrovascular events with nilotinib and educate patients on the symptoms of stroke. Elizabeth A. Coon1* Nicholas L. Zalewski2 Ernest Matthew Hoffman1 Ayalew Tefferi3 Kelly D. Flemming4 1Department of Neurology, Mayo Clinic, Rochester, Minnesota 2University of Nebraska Medical Center, Omaha, Nebraska 3Department of Hematology, Mayo Clinic, Rochester, Minnesota