Hands on Alemtuzumab-experience from clinical practice: whom and how to treat

Alemtuzumab is a monoclonal antibody, which was recently approved for the treatment of active relapsing remitting multiple sclerosis. Its main mechanism of action is based on targeting CD52, an antigen of unknown function which is found on B and T lymphocytes, leading to depletion followed by repopulation of these cells. The high efficacy of Alemtuzumab in controlling relapsing remitting MS has been shown in several clinical trials. This new therapy approach is associated with a specific side effects profile requiring regular longterm monitoring. The most important side effects are infusion-associated reactions, a slight increase of infections as well as autoimmune events in almost one third of treated patients. Based on two years of clinical experience in Germany, this review covers the first steps with the careful patient selection to be treated with Alemtuzumab over the preparation steps and the infusion courses up to the longterm monitoring after Alemtuzumab treatment. Background In September 2013, Alemtuzumab was approved in Europe as an additional therapeutic option for active relapsing-remitting Multiple Sclerosis (RRMS). Since its synthesis in the early eighties as the first humanized monoclonal antibody, Alemtuzumab therapeutic potentials were explored for many diseases (eg. Graft versus host disease, transplantation, vasculitis, rheumatoid arthritis, immunologically mediated cytopenia) [1, 2]; it is the first depleting monoclonal antibody which was licensed for the treatment of RRMS. The mechanism of Alemtuzumab differs from immunmodulating and other immunosuppressive treatments in its fundamental approach, which consists of at least two courses of lymphocyte depletion followed by cellular repopulation. The reconstitution of lymphocytes is thought to be of particular importance not only for the beneficial clinical effects, but also for the long-term side effects [3]. Alemtuzumab is introducing a new therapeutic concept of an inductionlike treatment strategy, but without the need of a maintenance treatment in the follow up in most of the treated patients. Such concepts are till now not well established in our clinical practice. Furthermore, other highly efficacious * Correspondence: [email protected] MS Center Dresden, Center of Clinical Neuroscience, Department of Neurology, University Hospital Carl Gustav Carus, Dresden University of Technology, Fetscherstr. 74, 01307 Dresden, Germany © 2016 The Author(s). Open Access This artic International License (http://creativecommons reproduction in any medium, provided you g the Creative Commons license, and indicate if (http://creativecommons.org/publicdomain/ze treatment options such as Natalizumab and Fingolimod are available. No clinical trials have directly compared Alemtuzumab with these medications making the clinical decision not straight forward. Although the role of Alemtuzumab in RRMS was investigated in three active-controlled clinical studies [4–6], using it in clinical practice can be quite challenging as several questions are still to be answered: how to define patients who will most likely profit from Alemtuzumab? Where does Alemtuzumab stand in MS treatment scenario? And then if Alemtuzumab is to be given, how should we switch patients from other specific MS treatments to Alemtuzumab? What other MS medications could be given following Alemtuzumab? How could the infusion management be optimized? Which side effects can be expected and how should they be handled? What is the most applicable monitoring strategy in clinical practice? The aim of this review is to summarize our experience with Alemtuzumab in clinical practice of the last two years following a structured approach starting with treatment selection followed by preparation and infusion management up to the longterm monitoring. The innovative treatment concept of alemtuzumab Alemtuzumab is a monoclonal antibody that selectively binds to CD52, which is a surface glycoprotein molecule le is distributed under the terms of the Creative Commons Attribution 4.0 .org/licenses/by/4.0/), which permits unrestricted use, distribution, and ive appropriate credit to the original author(s) and the source, provide a link to changes were made. The Creative Commons Public Domain Dedication waiver ro/1.0/) applies to the data made available in this article, unless otherwise stated. Hassoun et al. Multiple Sclerosis and Demyelinating Disorders (2016) 1:10 Page 2 of 14 of unknown function [7]. It is expressed on the surface of Tand B-cells and other cell populations but not on the hematological precursors [8]. Alemtuzumab infusion results in rapid depletion of the CD52 positive cells [9], leading to lymphopenia, which lasts for several years [10]. While B-cells recover relatively quickly within a range of 3–8 months, the repopulation of T cells occurs more slowly, as it needs up to 3 years and in another study up to 60 months for CD4+ and 30 months for CD8+ T cells in average [11, 12]. The experimental data using humanized CD52 mice have shown, that the depletion of lymphocytes upon anti-CD52 treatment was predominant in peripheral circulation, while the number of those cells was clearly less affected in spleen, thymus, bone marrow and lymph nodes [13, 14]. This may represent an explanation for the unexpected low rate of infections in patients receiving Alemtuzumab. As mentioned before, the depletion of CD52-positive cell is followed by a recovery phase that can vary between treated patients. However, it was shown that different repopulation kinetics among patients was not able to predict the risk of MS reactivation [14–16]. This process is considered as part of the reprogramming of the dysregulated immune system. Some authors suggest that the observed prolonged effect of Alemtuzumab lies in the slow reconstitution of T lymphocytes after the initial depletion, and not in the depletion itself [3]. The radical approach of Alemtuzumab which leads to its prolonged therapeutical effect is actually also associated with the well-described side effects. In addition to the infusion-associated reactions (IAR), which will be described in more details later, the increased incidence of antibodymediated autoimmune diseases upon Alemtuzumab therapy is remarkable [17]. Taking into consideration the previously described mechanism of immune cells depletion and the potential side effects, the need arises to find appropriate criteria that are useful for patient selection. No biomarker to detect predisposition for secondary autoimmunity has been found yet. IL-21 was previously described as a promising candidate but these results could not be reproduced in another following study, which was attributed to the use of different kits [18, 19]. Different treatment strategies Alemtuzumab therapy consists of two courses with 12 months in between. In spite of this non-frequent intermittent administration of the medication, this approach guarantees a long-term stabilization of the disease activity and to achieve the therapeutic effect, keeping in mind that Alemtuzumab infusions should take place under close monitoring. Until now, all available highly-efficacious therapies as Natalizumab and Fingolimod follow a continuous treatment strategy. After stopping these drugs, disease activity is returning or even overshooting as it has been described for Natalizumab [20, 21] and also even in fewer cases for fingolimod [22–25]. On the other side, treatment switches are easier to perform if a more or less reversible treatment as Fingolimod or Natalizumab is applied. The disadvantage is that the use of other treatment approaches after Alemtuzumab is more complicated due to the effects of irreversible depletion and repopulation, on the other side patient is practically off treatment after the second Alemtuzumab infusion. The rapid onset of Alemtuzumab treatment effects can be explained by depletion of both cells of the acquired and innate immune system, including the impairment in activation as well as cytokine release [9]. Comparing side effects, Alemtuzumab has specific windows where side effects are increased specifically (IARs during infusion, infections directly after infusion, secondary autommunity with a maximum in the third year) [26, 27] which is different to risk of adverse events of eg. Natalizumab presenting an increased PML risk after a certain treatment duration [28]. In the field of MS treatment, we have for the first time different treatment strategies with different efficacy and risk profiles during the treatment duration which should be considered before treatment is selected (Fig. 1). Alemtuzumab presents with characteristics of induction treatment although strategy is not correctly defined by the term induction treatment as in the most cases no maintenance treatment is necessary at least for the 5 year window after treatment start [29]. Patient selection: who is the right patient for