Alemtuzumab Linked to CNS Inflammation

January 26, 2017

Two cases of what is suggested to be "the first recognised cases of severely exacerbated CNS [central nervous system] inflammation after alemtuzumab therapy in multiple sclerosis" have been published.

Writing in a letter in the February issue of The Lancet Neurology, a group of German and British multiple sclerosis (MS) experts describe two patients who developed severe apparent acute deterioration of their MS and several new ring-enhancing lesions on MRI a few months after their first course of alemtuzumab (Lemtrada, Genzyme) therapy.

Both patients experienced marked improvement after plasmapheresis and the B cell–depleting antibody rituximab therapy, which the authors suggest indicate a predominantly B cell–driven pathology.

"Alemtuzumab dependent, B-cell-mediated autoimmune diseases have been identified for several tissues other than the CNS," the authors, with corresponding author Ralf Gold, MD, Department of Neurology of the Ruhr-University Bochum at St Josef-Hospital, Bochum, Germany, write.

"The exacerbated inflammation seen in our patients is consistent with the time frame in which B-cell repopulation and peripheral expansion occur following alemtuzumab treatment. Thus, it remains to be determined if the disease observed in these two patients after treatment is due to worsening of multiple sclerosis or to the development of secondary CNS-directed autoimmunity."

They add that a rare genetic or infectious cause was not found, as evaluated by whole genome analyses, suggesting that further cases might be identified, and that apparent relapses after alemtuzumab treatment should be promptly evaluated by MRI for the presence of ring-enhancing lesions. A specific rescue therapy comprising plasma exchange with consecutive B cell depletion can then be initiated to help prevent irreversible disability.

The first patient described was a 41-year-old man diagnosed with MS in 2004. Despite receiving many different immunomodulatory therapies during the following decade, he had several relapses and displayed continuing MRI activity. A first course of alemtuzumab was given in July 2015, but in December 2015, the patient presented with severe dysarthria, marked cognitive symptoms, apraxia, and left-dominant tetraparesis, and MRI revealed 20 new contrast-enhancing T1 lesions, most of which were ring-enhancing.

The patient was unresponsive to steroids, but plasmapheresis and one cycle of immunoadsorption led to marked improvement of clinical symptoms and lesion restitution by MRI. Subsequent treatment with rituximab resulted in a near absence of contrast-enhancing lesions, and by September 2016 the patient was almost free of the symptoms that prompted admission 9 months earlier.

The second patient, a 25-year-old woman, was diagnosed with MS in 2011 and had received several different treatments since diagnosis, including interferon β-1a, natalizumab, and fingolimod. Because of continued disease activity, she received an initial course of alemtuzumab in December 2014, and she presented with tetraparesis predominantly affecting the legs in July 2015.

Methylprednisolone improved symptoms but not completely, and in September she developed newly occurring left-sided hemiataxia and hemihypesthesia. She received more methylprednisolone and plasma exchange. The symptoms recurred in November and were treated with a higher methylprednisolone dose.

Subsequent MRI revealed several contrast-enhancing lesions, including some with ring-enhancing characteristics. Both symptoms and MRI measures improved after treatment with rituximab.

Dr Gold received speaker's fees and board honoraria from Baxter, Bayer Schering, Biogen Idec, Chugai, CLB Behring, Genzyme, Merck Serono, Novartis, Talecris, TEVA, and Wyeth. His department received grant support from Bayer, Schering, Biogen Idec, Genzyme, Merck Serono, Novartis, and TEVA.

Lancet Neurol. 2017;16:104-106. Full text

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