BACKGROUND: Reduced MS disease activity with alemtuzumab versus subcutaneous interferon beta-1a (SC IFNB-1a) in core phase 2/3 studies was accompanied by increased incidence of infections that were mainly nonserious and responsive to treatment. Alemtuzumab efficacy was durable over 6 years. OBJECTIVE: To evaluate infections over 6 years in alemtuzumab-treated patients. METHODS: Three randomized trials (CAMMS223, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I, and CARE-MS II) compared two courses of alemtuzumab 12 mg with SC IFNB-1a 44 μg in patients with active relapsing-remitting MS. An extension study (CAMMS03409) provided further evaluation and as-needed alemtuzumab retreatment. RESULTS: Infections occurred more frequently with alemtuzumab 12 mg than SC IFNB-1a during Years 1 (58.7% vs 41.3%) and 2 (52.6% vs 37.7%), but declined for alemtuzumab-treated patients in Years 3 (46.6%), 4 (42.8%), 5 (40.9%), and 6 (38.1%). Serious infections were uncommon (1.0%-1.9% per year). Infections were predominantly (>95%) mild to moderate and included upper respiratory tract infections, urinary tract infections, and mucocutaneous herpetic infections. Prophylactic acyclovir reduced herpetic infections. Lymphocyte counts after alemtuzumab therapy did not predict infection risk. CONCLUSION: Infections with alemtuzumab were mostly mild to moderate and decreased over time, consistent with preservation of components of protective immunity.

Department of Neurology Medical Faculty Heinrich Heine University Düsseldorf Düsseldorf Germany

Division of Geographic Medicine and Infectious Diseases Tufts Medical Center Boston MA USA

Hope Neurology MS Center Knoxville TN USA

Medical University of Łódź Łódź Poland

Montréal Neurological Institute McGill University Montréal QC Canada

MS Center Department of Neurology 1st Medical Faculty Charles University Prague Czech Republic

Neurological Institute Cleveland Clinic Cleveland OH USA

Sanofi Cambridge MA USA

The Ann Romney Center for Neurologic Diseases Brigham and Women's Hospital Boston MA USA

University of Cambridge School of Clinical Medicine Cambridge UK

Zobrazit více v PubMed

Genzyme Corporation. LEMTRADA (Alemtuzumab), for intravenous injection. Full Prescribing Information, http://products.sanofi.us/lemtrada/lemtrada.pdf (2017, accessed 12 March 2018).

Genzyme Therapeutics Ltd. Lemtrada™ (alemtuzumab 12 mg concentrate for solution for infusion). EU summary of product characteristics, http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/003718/WC500150521.pdf (2018, accessed 12 February 2018).

Hartung HP, Aktas O, Boyko AN. Alemtuzumab: A new therapy for active relapsing-remitting multiple sclerosis. Mult Scler 2015; 21: 22–34. PubMed PMC

Menge T, Stüve O, Kieseier BC, et al. Alemtuzumab: The advantages and challenges of a novel therapy in MS. Neurology 2014; 83: 87–97. PubMed

CAMMS223 Trial Investigators Coles AJ, Compston DA, et al. Alemtuzumab vs. interferon beta-1a in early multiple sclerosis. N Engl J Med 2008; 359: 1786–1801. PubMed

Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: A randomised controlled phase 3 trial. Lancet 2012; 380: 1819–1828. PubMed

Coles AJ, Twyman CL, Arnold DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: A randomised controlled phase 3 trial. Lancet 2012; 380: 1829–1839. PubMed

Coles AJ, Cohen JA, Fox EJ, et al. Alemtuzumab CARE-MS II 5-year follow-up: Efficacy and safety findings. Neurology 2017; 89: 1117–1126. PubMed PMC

Havrdova E, Arnold DL, Cohen JA, et al. Alemtuzumab CARE-MS I 5-year follow-up: Durable efficacy in the absence of continuous MS therapy. Neurology 2017; 89: 1107–1116. PubMed PMC

Ziemssen T, Thomas K. Alemtuzumab in the long-term treatment of relapsing-remitting multiple sclerosis: An update on the clinical trial evidence and data from the real world. Ther Adv Neurol Disord 2017; 10: 343–359. PubMed PMC

Hu Y, Turner MJ, Shields J, et al. Investigation of the mechanism of action of alemtuzumab in a human CD52 transgenic mouse model. Immunology 2009; 128: 260–270. PubMed PMC

Cox AL, Thompson SA, Jones JL, et al. Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis. Eur J Immunol 2005; 35: 3332–3342. PubMed

Kovarova I, Arnold DL, Cohen JA, et al. Alemtuzumab pharmacokinetics and pharmacodynamics in Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS I). In: Proceedings of the 22nd meeting of the European neurological society, Prague, 9–12 June 2012.

De Mercanti S, Rolla S, Cucci A, et al. Alemtuzumab long-term immunologic effect: Treg suppressor function increases up to 24 months. Neurol Neuroimmunol Neuroinflamm 2016; 3: e194. PubMed PMC

Zhang X, Tao Y, Chopra M, et al. Differential reconstitution of T cell subsets following immunodepleting treatment with alemtuzumab (anti-CD52 monoclonal antibody) in patients with relapsing-remitting multiple sclerosis. J Immunol 2013; 191: 5867–5874. PubMed

Rao SP, Sancho J, Campos-Rivera J, et al. Human peripheral blood mononuclear cells exhibit heterogeneous CD52 expression levels and show differential sensitivity to alemtuzumab mediated cytolysis. PLoS ONE 2012; 7: e39416. PubMed PMC

Gross CC, Ahmetspahic D, Ruck T, et al. Alemtuzumab treatment alters circulating innate immune cells in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm 2016; 3: e289. PubMed PMC

Gilmore W, Lund BT, Traboulsee A, et al. Characteristics of leukocyte recovery following treatment with humanized anti-CD52 (alemtuzumab/LEMTRADA) in multiple sclerosis. Mult Scler 2015; 21: P1045.

Clark RA, Watanabe R, Teague JE, et al. Skin effector memory T cells do not recirculate and provide immune protection in alemtuzumab-treated CTCL patients. Sci Transl Med 2012; 4: 117ra7. PubMed PMC

Coles AJ, Wing M, Smith S, et al. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 1999; 354: 1691–1695. PubMed

Coles AJ, Fox E, Vladic A, et al. Alemtuzumab more effective than interferon β-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology 2012; 78: 1069–1078. PubMed

Liu GF, Wang J, Liu K, et al. Confidence intervals for an exposure adjusted incidence rate difference with applications to clinical trials. Stat Med 2006; 25: 1275–1286. PubMed

Coles AJ, Robertson N, Adnan Al-Araji A, et al. Guidance on the prevention of Listeria infection after alemtuzumab treatment of multiple sclerosis, https://www.theabn.org/media/Guidance%20on%20the%20prevention%20of%20Listeria%20infection%20after%20alemtuzumab%20treatment%20of%20multiple%20sclerosis.pdf (2017, accessed 13 July 2018).

Selmaj KW, Habek M, Bass A, et al. Efficacy and safety of alemtuzumab in patients with RRMS is durable over 10 years: Follow-up from the CAMMS223 study. Neurology 2017; 88: P5338.

Bloomgren G, Richman S, Hotermans C, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012; 366: 1870–1880. PubMed

Food and Drug Administration. FDA Drug Safety Communication: FDA warns about cases of rare brain infection with MS drug Gilenya (fingolimod) in two patients with no prior exposure to immunosuppressant drugs, https://www.fda.gov/Drugs/DrugSafety/ucm456919.htm (accessed 19 July 2017).

McCarthy CL, Tuohy O, Compston DAS, et al. Immune competence after alemtuzumab treatment of multiple sclerosis. Neurology 2013; 81: 872–876. PubMed PMC

Kumar S, Kimlinger TK, Lust JA, et al. Expression of CD52 on plasma cells in plasma cell proliferative disorders. Blood 2003; 102: 1075–1077. PubMed

Turner MJ, Pang PT, Chretien N, et al. Reduction of inflammation and preservation of neurological function by anti-CD52 therapy in murine experimental autoimmune encephalomyelitis. J Neuroimmunol 2015; 285: 4–12. PubMed

Turner MJ, Havari E, Dodge J, et al. Preservation of lymphocyte migratory ability following anti-CD52 therapy. Mult Scler 2013(11 Suppl.): P1207.

Monoclonal Antibodies in the Treatment of Relapsing Multiple Sclerosis: an Overview with Emphasis on Pregnancy, Vaccination, and Risk Management

Secondary Immunodeficiency and Risk of Infection Following Immune Therapies in Neurology

Proportion of alemtuzumab-treated patients converting from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis over 6 years

Managing Risks with Immune Therapies in Multiple Sclerosis