The U.S. Food and Drug Administration (FDA) has issued a black-box warning about a risk of stroke and arterial dissection in patients with multiple sclerosis who have been exposed to alemtuzumab (www.fda.gov/Drugs/DrugSafety/ucm624247.htm?fbclid=IwAR2eBbqp24E0J3VIk8jbUZZ5pet…).  The announcement was issued on November 29, 2018 and a black-box warning was added to the U.S. product label. The Canadian product monograph had not been updated at the time of writing.

Lemtrada (alemtuzumab) was approved by the FDA and Health Canada as an MS drug in 2014. Since that time, 13 cases of ischemic and hemorrhagic stroke or arterial dissection have been identified – 10 cases in the U.S. and three cases in Europe. Additional cases have been recorded in patients receiving Campath for hematologic malignancies.

In 12 of 13 cases, the symptoms occurred within a day of receiving an alemtuzumab infusion; all cases occurred within three days of infusion. The cases were: 7 with hemorrhagic stroke; 1 with hemorrhagic stroke and dissection of both vertebral arteries; 2 with ischemic stroke; 1 with ischemic stroke and dissection of bilateral carotid and right vertebral arteries; 2 with dissection involving the right carotid and left vertebral arteries; and 2 with unspecified stroke. There was one death. Based on overall patient exposure (n=4463), the risk of stroke/dissection has been estimated at 0.74% by the website eHealthMe.com. Risk factors for stroke/arterial dissection have not been identified.

Alemtuzumab is an anti-CD52 monoclonal antibody that was shown in the CARE-MS I and II pivotal trials to be highly effective in MS (Cohen et al. Lancet 2012;380:1819-1828; Coles et al. Lancet 2012;380:1829-1839). While the mechanisms underlying the possible link between alemtuzumab and stroke/dissection have not been determined, the FDA advisory speculated that the problem may be due to cytokine release syndrome due to the timing of the events. A cytokine syndrome can occur over several days following drug infusion and is associated with significant increases in pro-inflammatory cytokines, including TNF-alpha and interferon-gamma (Thomas et al. Neurol Neuroimmunol Neuroinflamm 2016;3:e228; free full text at www.ncbi.nlm.nih.gov/pmc/articles/pmid/27213173/). A cytokine storm was reported in the one patient who died of hemorrhagic stroke. Cytokine syndrome may manifest clinically as pyrexia, headache, malaise and urticarial rash, and may be associated with a transient worsening of neurological symptoms (Moreau et al. Brain 1996;119:225-237). The incidence of cytokine release syndrome with alemtuzumab in MS patients is 1.6%, according to the Canadian Product Monograph.

In its advisory, the FDA recommended emergency medical treatment as soon as possible for patients with symptoms suggestive of stroke/arterial dissection in the 1-3 days following alemtuzumab infusion.