Alemtuzumab …

K K Jain MD†

Neuroimmunology

Updated 05.28.2021
Released 06.03.2019
Expires For CME 05.28.2024

Alemtuzumab

Author: K K Jain MD†

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Alemtuzumab

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Introduction

Overview

Historical note and terminology

Several monoclonal antibodies have been investigated for use in the treatment of multiple sclerosis, and some of these have already been approved. One of these is the humanized monoclonal antibody alemtuzumab, which was first approved in 2001 for the treatment of chronic lymphocytic leukemia and T-cell lymphoma under the trade name Campath, and later approved for the treatment of multiple sclerosis as Lemtrada. It was the first monoclonal antibody to be proven efficient in comparative phase 3 clinical trials against interferon beta-1a as first-line treatment for patients with relapsing-remitting multiple sclerosis (06). It was approved for multiple sclerosis by the U.S. Food and Drug Administration in 2014. There has been some concern about adverse effects, and the use of some monoclonal antibodies has been discontinued. Studies on well-established, effective monoclonal antibodies such as natalizumab and alemtuzumab focus more on long-term efficacy and safety, risk management, and treatment of complications (08). In April 2019, its use was restricted in Europe pending a safety review by the European Medicines Agency because of reports of intracerebral hemorrhage in patients treated with alemtuzumab for multiple sclerosis (14).

Pharmacology

Alemtuzumab is a recombinant DNA-derived humanized IgG1 kappa monoclonal antibody that is directed against the 21-28 kDa cell surface glycoprotein CD52.

Pharmacodynamics. The beneficial effects of alemtuzumab have been observed clinically, but there is no adequate explanation of its mechanism of action. Treatment with alemtuzumab targets the CD52-bearing T lymphocytes for destruction. The role of high expression of CD52 on T cells in the pathogenesis of multiple sclerosis is not clear, but these cells are rendered susceptible to alemtuzumab-mediated cell lysis, which suppresses neuroinflammatory responses in multiple sclerosis. Depletion of T cells high in CD52 might be of importance in the development of secondary autoimmune disease after alemtuzumab treatment.

Immunomodulatory effects of alemtuzumab may occur through the depletion and repopulation of lymphocytes, increase in regulatory T-cell subsets, and rapid cell cycling of repopulating T cells with enhanced T-cell apoptosis (07).

MRI studies show a decrease of brain parenchymal fraction, as a measure of brain atrophy, in alemtuzumab-treated patients over 2 years indicating a neuroprotective effect, but it is not certain if it reflects an anti-inflammatory action that limits the collateral damage to neurons or is indicative of primary neuroprotective activity associated with increased lymphocytic delivery of neurotrophins to the central nervous system (11).

Pharmacokinetics. Classical biotransformation studies have not been conducted for alemtuzumab, but some features of the pharmacokinetics of alemtuzumab are as follows:

	• According to the pharmacokinetic studies conducted by the drug manufacturer, the population pharmacokinetics of alemtuzumab are best described by a linear, 2-compartment model. The influence of lymphocyte count on systemic clearance is significant, which is consistent with the fact that alemtuzumab targets CD52+ lymphocytes; however, the decrease from cycle 1 to cycle 2 is less than 20%. The central volume of distribution is proportional to body weight and is largely confined to the blood and interstitial space.
	• The highest serum concentration of alemtuzumab is observed following the last infusion of each treatment course as serum concentration increases with each consecutive dose within the course, with mean maximum serum concentration (Cmax) reaching 3014 ng/mL on day 5 of the initial treatment course.
	• The half-life of the drug is about 4 to 5 days in multiple sclerosis patients, but its pharmacodynamic effect lasts considerably longer after dosing.
	• Alemtuzumab concentrations decrease to low or undetectable levels within 1 month.

Pharmacogenetics. Incidence of immune thrombocytopenic purpura increases during treatment with alemtuzumab. A phase 4 study examining DNA extracted from peripheral blood to assess the genetic association of preidentified candidate single-nucleotide polymorphism to alemtuzumab-induced immune thrombocytopenic purpura in relapsing multiple sclerosis patients has been completed (NCT03784898). The results have not been published.

Routes of administration. Alemtuzumab is administered by intravenous infusion.

A phase 1, exploratory, randomized, open-label, 2-arm study is in progress to characterize the pharmacodynamics, pharmacokinetics, safety, and tolerability of alemtuzumab 12 mg administered subcutaneously or intravenously in patients with progressive multiple sclerosis (NCT02583594).

Adverse effects

Mild to moderate infusion-related reactions -- headache, rash, pyrexia, and nausea -- are the most common adverse events, affecting over 90% of patients, and are assumed to be due to the rapid release of the cytokines resulting from target cell lysis and consecutive inflammatory responses (18). These can be prevented by concomitant corticosteroids, antihistamines, and antipyretic drugs.

Alemtuzumab may cause serious, sometimes fatal, autoimmune conditions such as immune thrombocytopenia and anti-glomerular basement membrane disease. Complete blood counts with differential, serum creatinine levels and urinalysis with urine cell counts are recommended at periodic intervals for 48 months after the last dose of alemtuzumab. Alemtuzumab-related secondary autoimmune disorders involving thyroid are frequent and affect the risk-benefit ratio. Standard ThyAb-testing for antithyroid-peroxidase and antithyroglobulin antibodies at baseline is a biomarker of increased risk for clinically manifest thyroid secondary autoimmune disorders and should therefore be used in clinical decisions to initiate treatment with alemtuzumab (19).

Infections, mainly of mild-to-moderate severity, were recorded as adverse events in more than 70% of patients in phase 2/3 clinical trials of alemtuzumab. Recommended preventive measures include prophylaxis against herpes virus and tuberculosis, papillomavirus screening, and Listeria-free diet (04).

Intracerebral hemorrhage following alemtuzumab is likely due to hypertension that may occur during the infusion of the drug, and mean systolic blood pressure increases of 20 mmHg or more, or more than 20% throughout the infusion period, are an indication of the need of admission to a hospital for close observation (02).

References

01: Arroyo González R, Kita M, Crayton H, et al. Alemtuzumab improves quality-of-life outcomes compared with subcutaneous interferon beta-1a in patients with active relapsing-remitting multiple sclerosis. Mult Scler 2017;23(10):1367-76. PMID 27885061
02: Azevedo CJ, Kutz C, Dix A, Boster A, Sanossian N, Kaplan J. Intracerebral haemorrhage during alemtuzumab administration. Lancet Neurol 2019;18(4):329-31. PMID 30777657
03: Brecl Jakob G, Barun B, Gomezelj S, et al. Effectiveness and safety of alemtuzumab in the treatment of active relapsing-remitting multiple sclerosis: a multicenter, observational study. Neurol Sci 2021. [Epub ahead of print] PMID 33660157
04: Buonomo AR, Zappulo E, Viceconte G, Scotto R, Borgia G, Gentile I. Risk of opportunistic infections in patients treated with alemtuzumab for multiple sclerosis. Expert Opin Drug Saf 2018;17(7):709-17. PMID 29848085
05: Carandini T, Pietroboni AM, Sacchi L, et al. Alemtuzumab in multiple sclerosis during the COVID-19 pandemic: a mild uncomplicated infection despite intense immunosuppression. Mult Scler 2020;26(10):1268-9. PMID 32463329
06: 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(9856):1819-28. PMID 23122652
07: Freedman MS, Kaplan JM, Markovic-Plese S. Insights into the mechanisms of the therapeutic efficacy of alemtuzumab in multiple sclerosis. J Clin Cell Immunol 2013;4(4). PMID 24363961
08: Graf J, Aktas O, Rejdak K, Hartung HP. Monoclonal antibodies for multiple sclerosis: an update. BioDrugs 2019;33(1):61-78. PMID 30604390
09: 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(11):1107-16. PMID 28835401
10: Horáková D, Boster A, Bertolotto A, et al. Proportion of alemtuzumab-treated patients converting from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis over 6 years. Mult Scler J Exp Transl Clin 2020;6(4):2055217320972137. PMID 33414927
11: Jones JL, Anderson JM, Phuah CL, et al. Improvement in disability after alemtuzumab treatment of multiple sclerosis is associated with neuroprotective autoimmunity. Brain 2010;133(Pt 8):2232-47. PMID 20659956
12: Langer-Gould AM. Pregnancy and family planning in multiple sclerosis. Continuum (Minneap Minn) 2019;25(3):773‐92. PMID 31162316
13: Matías-Guiu J, Montero-Escribano P, Pytel V, Porta-Etessam J, Matias-Guiu JA. Potential COVID-19 infection in patients with severe multiple sclerosis treated with alemtuzumab. Mult Scler Relat Disord 2020;44:102297.** PMID 32554284
14: McCall B. Alemtuzumab to be restricted pending review, says EMA. Lancet 2019;393(10182):1683. PMID 31034363
15: Pfeuffer S, Schmidt R, Straeten FA, et al. Efficacy and safety of alemtuzumab versus fingolimod in RRMS after natalizumab cessation. J Neurol 2019;266(1):165-73. PMID 30446966
16: Prosperini L, Annovazzi P, Boffa L, et al. No evidence of disease activity (NEDA-3) and disability improvement after alemtuzumab treatment for multiple sclerosis: a 36-month real-world study. J Neurol 2018;265(12):2851-60.** PMID 30259178
17: Riera R, Porfírio GJ, Torloni MR. Alemtuzumab for multiple sclerosis. Cochrane Database Syst Rev 2016;4:CD011203. PMID 27082500
18: Ruck T, Bittner S, Wiendl H, Meuth SG. Alemtuzumab in multiple sclerosis: mechanism of action and beyond. Int J Mol Sci 2015;16(7):16414-39. PMID 26204829
19: Ruck T, Schulte-Mecklenbeck A, Pfeuffer S, et al. Pretreatment anti-thyroid autoantibodies indicate increased risk for thyroid autoimmunity secondary to alemtuzumab: a prospective cohort study. EBioMedicine 2019;46:381‐6. PMID 31371192

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Alemtuzumab

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Alemtuzumab …

Alemtuzumab

Introduction

Overview

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview.
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to access the full version.

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Alemtuzumab

Introduction

Overview

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Paraneoplastic syndromes

Anti-IgLON5 disease

Anti-LGI1 encephalitis

Progressive encephalomyelitis with rigidity and myoclonus and glycine receptor antibodies

Giant cell arteritis

Chronic inflammatory demyelinating polyradiculoneuropathy

Autoimmune autonomic neuropathy

HTLV-1 associated myelopathy

This is an article preview.
Start a Free Account
to access the full version.