Alemtuzumab use in clinical practice : recommendations from European multiple sclerosis experts

THERAPY IN PRACTICE Alemtuzumab Use in Clinical Practice: Recommendations from European Multiple Sclerosis Experts Thomas Berger 1 •Irina Elovaara 2 •Sten Fredrikson 3 •Chris McGuigan 4 • Lucia Moiola 5 •Kjell-Morten Myhr 6 •Celia Oreja-Guevara 7 •Igor Stoliarov 8 • Uwe K. Zettl 9 Published online: 23 November 2016 ÓThe Author(s) 2016. This article is published with open access at Springerlink.com Abstract Alemtuzumab (Lemtrada TM ) is a humanized monoclonal antibody approved in more than 50 countries. Within the European Union, alemtuzumab is indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS) with active disease defined by clinical or imaging features; in the USA, the indication states that alemtuzumab should generally be reserved for the treatment of patients with relapsing forms of multiple sclerosis who have had an inadequate response to two or more disease-modifying therapies (DMTs). In clinical trials, alemtuzumab demonstrated efficacy in treatment-naı ¨ve patients with active RRMS and those relapsing on prior DMTs, with a consistent and manageable safety and tolerability profile. The European Union indication provides physicians with significant flexibility regarding treatment decisions, affording the opportunity for individualized treatment. Thus, alemtuzumab may be an appropriate treatment choice across a broad range of patients with RRMS, including, for example, treatment-naı ¨ve patients with active disease, patients with highly active disease, or for patients relapsing on prior DMTs. There are several practicalities to consider when using alemtuzumab, including the unique dosing regimen, administered via intravenous infusion on 5 consecutive days at baseline and on 3 consecutive days 12 months later, and as-needed retreatment (3 consecutive days at least 12 months after the last course) in cases of disease recurrence. Additionally, routine monthly monitoring is required for up to 48 months after the last infusion to promptly identify potentially serious autoimmune adverse events. Given these considerations, it is beneficial to gain insight into how alemtuzumab is being used in the real-world clinical setting. Here, we report recommendations from European multiple sclerosis experts regarding best practices for alemtuzumab treatment, including management of adverse events and compliance with ongoing safety monitoring requirements. &Thomas Berger [email protected] 1 Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria 2 Department of Neurology and Rehabilitation, University of Tampere Medical School and Tampere University Hospital, Tampere, Finland 3 Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden 4 St Vincent’s University Hospital, Dublin, Ireland 5 San Raffaele Scientific Institute, Milan, Italy 6 Haukeland University Hospital and University of Bergen, Bergen, Norway 7 Hospital Clı ´nico San Carlos, Madrid, Spain 8 Institute of the Human Brain, Russian Academy of Sciences, St. Petersburg, Russia 9 Department of Neurology, Neuroimmunological Section, University of Rostock, Rostock, Germany CNS Drugs (2017) 31:33–50 DOI 10.1007/s40263-016-0394-8 Key Points In the European Union (EU), alemtuzumab is indicated for adult patients with relapsing-remitting multiple sclerosis, with active disease defined by clinical or imaging features. It can be considered as an initial therapeutic for treatment-naı ¨ve patients with active disease and for patients relapsing on prior disease-modifying therapy. Healthcare providers should adhere to the alemtuzumab EU label, which gives a broad definition of patient eligibility for treatment; alemtuzumab is not suitable for patients with inactive relapsing-remitting multiple sclerosis, those stable on current therapy, or patients with progressive multiple sclerosis. The Risk Management Program in the EU and other countries in addition to the Risk Evaluation and Mitigation Strategy in the USA are critical to ensure early detection of potential adverse events arising during and after alemtuzumab treatment and to ensure compliance with monitoring requirements. Data from an ongoing extension study, from realworld studies, and from post-marketing safety data will also be important to establish long-term safety of alemtuzumab treatment. 1 Introduction Alemtuzumab is a humanized monoclonal antibody approved in more than 50 countries [1], including the European Union (EU) for the treatment of adult patients with active relapsing-remitting multiple sclerosis (RRMS) defined by clinical or imaging features, and the USA for the treatment of relapsing forms of multiple sclerosis (MS) [2,3]. In the USA, the indication for alemtuzumab states that it should generally be reserved for patients who have experienced an inadequate response to two or more disease-modifying therapies (DMTs) [3]. Alemtuzumab selectively targets CD52, a protein expressed at high levels on the surface of T and B lymphocytes but at lower levels on natural killer cells and other cell types involved in innate immunity, leading to a selective depletion of circulating T and B cells [4,5], thereby decreasing inflammatory MS disease activity. Following treatment with alemtuzumab, T and B lymphocytes repopulate in a distinctive pattern over time that results in a rebalancing of the immune system over a period of 3–12 months [5,6]. This mechanism allows for a unique dosing regimen of 12-mg intravenous infusions on 5 consecutive days at baseline and on 3 consecutive days 12 months later and may also account for the observed durable efficacy in the absence of continuous treatment, with most patients only requiring these two initial treatment courses [2,7,8]. The safety and efficacy of alemtuzumab have been assessed in phase II and III clinical trials in treatment-naı ¨ve patients (CAMMS223 [NCT00050778]; CARE-MS I [NCT0053034 8]), in patients with active disease despite treatment with another DMT (CARE-MS II [NCT00548405]) (Table 1), and in extension (NCT00930553) and long-term follow-up studies (NCT02255656) that include patients from the phase II, III, and IV trials. The phase II and III studies all included an active comparator arm in which patients were treated with subcutaneous (SC) interferon b-1a (IFNb-1a), a DMT with an established efficacy across standard endpoints in RRMS [9–13]. In CAMMS223 and CARE-MS II, two doses (12 and 24 mg/day) of alemtuzumab were evaluated; however, discussion of data in this article will be restricted to the 12-mg dose as this is the approved and commercially available dose [2,9,12]. 2 Clinical Trial Experience with Alemtuzumab 2.1 Efficacy Data from Clinical Trials As discussed, in the three pivotal clinical trials, SC IFNb1a was included as an active comparator (Table 1); therefore, all subsequent comparisons relate to outcomes for alemtuzumab vs. SC IFNb-1a. Across the CAMMS223 and CARE-MS I and II trials, alemtuzumab significantly reduced the annualized relapse rate (AAR) (co-primary endpoint) and was also associated with significant reductions in 6-month confirmed disability worsening (CDW, co-primary endpoint) in CAMMS223 [9] and CARE-MS II [12], and a non-significant 30% reduction in CARE-MS I [11]. In addition, in a recent analysis of data from the CAMMS223 study, alemtuzumab had greater efficacy than SC IFNb-1a at month 36 in each of the functional systems that make up the Expanded Disability Status Scale (EDSS) score, with the greatest effects being observed in the sensory, pyramidal, and cerebellar systems, which are thought to drive CDW in RRMS [16]. Across all trials, alemtuzumab also demonstrated improvements in several magnetic resonance imaging (MRI) outcomes (lesion volume/load, and brain atrophy) [9,11,12]. In CARE-MS I and II, alemtuzumab-treated patients demonstrated a reduced rate of brain atrophy, as determined by median yearly percentage change in brain 34 T. Berger et al. parenchymal fraction over 2 years [11,17], reaching significance in both CARE-MS I (42% reduction, p\0.0001) and CARE-MS II (24% reduction, p= 0.0121) compared with SC IFNb-1a at year 2. Furthermore, durable efficacy (AAR, disability, and MRI outcomes, including lesions and brain atrophy) was demonstrated throughout the extension studies [7,8,13,17–19], with the majority of patients (68–94%) not requiring retreatment with alemtuzumab or another DMT [17,20]. Key efficacy outcomes from the clinical trial program trials are summarized in Table 2. 2.2 Safety Data from Clinical Trials Alemtuzumab has a consistent and manageable safety and tolerability profile as demonstrated across individual clinical trials [9,11,12]), enrolling a total of 1694 patients. Furthermore, a similar safety and tolerability profile was also documented with a long-term follow-up (up to 5 years) in the extension studies [7,8,13]. Nevertheless, several adverse events (AEs) of interest have been reported (Table 3). The most frequently reported AEs in clinical trials were infusion-associated reactions (IARs), experienced by [90% of patients, which peaked immediately following the initial alemtuzumab course and then decreased with subsequent courses [21,22]. Few (B3%) serious IARs were reported [9,11–13,21,23,24]. The incidence of infections (which were mainly mild to moderate in severity) was greatest during the first month following infusion in all three trials [25] but was lower in the CAMMS223 and CARE-MS extensions compared with the core studies, suggesting a reduction in infection risk over time [11–13,15]. Thyroid disease was the most common autoimmune event; however, \1% of patients experienced serious thyroid AEs [2,9,13,26,27]. Immune thrombocytopenic purpura (ITP) was identified as a potential risk in the CAMMS223 study, initially reported in six patients, including the fatal index case in a patient receiving alemtuzumab 24 mg [9,28,29]. Across all clinical trials, ITP incidence was 2% in patients receiving alemtuzumab 12 or 24 mg (1.6% in patients receiving alemtuzumab 12 mg) [11–13,29]. In response to the index case and other autoimmune events, enhanced monitoring and patient education was Table 1 Alemtuzumab clinical trial program CAMMS223 a [2,9,14] CARE-MS I [2,11,14] CARE-MS II a [2,12,14] Patients with active RRMS who were treatment naı ¨ve Patients with active RRMS who relapsed on prior DMT Study duration: 3 years Study duration: 2 years Study duration: 2 years SC IFNb-1a (44 lg TIW) N= 111 Alemtuzumab (12 mg/day) N= 112 SC IFNb-1a (44 lg TIW) N= 187 Alemtuzumab (12 mg/day) N= 376 SC IFNb-1a (44 lg TIW) N= 202 Alemtuzumab (12 mg/day) N= 426 MRI criteria: diagnosis per McDonald 2001 criteria, including brain MRI; C1Gd ? lesion on any of B4 brain scans during B3-month run-in period (including baseline scan) MRI criteria: diagnosis per McDonald 2005 criteria; brain MRI scan demonstrating white matter lesions attributable to MS (within 5 years of screening) MRI criteria: diagnosis per McDonald 2005 criteria; white matter lesions attributable to MS and at least one of the following: C9T 2 lesions C3 mm, any axis; a Gd ? lesion C3 mm, any axis, with C1 brain T 2 lesion; spinal cord lesion with C1 brain T 2 lesion Active MS: C2 relapses in the prior 2 years and C1Gd ? MRI lesion at screening Active MS: C2 relapses in the prior 2 years, with C1 relapse occurring in the year prior to study entry Active MS: C2 relapses in the prior 2 years, with C1 relapse occurring in the year prior to study entry and C1 relapse occurring during prior treatment b Mean age: 32 years Mean age: 33 years Mean age: 35 years EDSS range: 0.0–3.0 (mean 2.0) c EDSS range: 0.0–3.0 (mean 2.0) d EDSS range: 0.0–5.0 (mean 2.7) d Mean/median time since first MS episode: 1.4/ 1.3 years Mean/median time since first MS episode: 2.0/ 1.6 years Mean/median time since first MS episode: 4.5/ 3.8 years Retreatment criteria for CAMMS223 (Sanofi Genzyme, data on file) and CARE-MS extensions [15]: C1 relapse or C2 new or enlarging T 2 and/ or Gd ? brain or spinal lesions, C12 months since the second alemtuzumab course DMT disease-modifying therapy, EDSS Expanded Disability Status Scale, Gd ? gadolinium-enhancing, IFN interferon, MRI magnetic resonance imaging, MS multiple sclerosis, RRMS relapsing-remitting multiple sclerosis, SC subcutaneous, TIW three times per week a A 24-mg/day treatment arm was included in these studies b Treatment with IFNbor glatiramer acetate for C6 months c At screening and baseline visits d At screening Recommendations for Alemtuzumab Use in Clinical Practice 35 Table 2 Overview of the key endpoints from the alemtuzumab clinical trial program CAMMS223 extension [13,20] CARE-MS I [8,11,17,18,33,34] CARE-MS I extension [8,17,18] CARE-MS II [7,12,17,19,35] CARE-MS II extension [7,19] 5-year data Study duration: 2 years Year 4 Study duration: 2 years Year 4 SC IFNb-1a 44 lg TIW Alemtuzumab 12 mg/day SC IFNb-1a 44 lg TIW Alemtuzumab 12 mg/day Alemtuzumab 12 mg/day SC IFNb-1a 44 lg TIW Alemtuzumab 12 mg/day Alemtuzumab 12 mg/day Patients entering study, N111 112 187 376 349 202 426 393 Clinical endpoints ARR 0.35 0.12 0.39 0.18 0.14 0.52 0.26 0.23 ARR relative reduction (alemtuzumab vs. SC IFNb-1a), % 66 (p\0.0001) 55 (p\0.0001) 49 (p\0.0001) Relapse-free patients, a % 4168 5978(p\ 0.0001) 87 47 65 (p\ 0.0001) 79 Patients with 6-month CDW, a % 38 16 11 8 17 (years 0-4) 21 13 24 (years 0-4) CDW relative risk reduction (alemtuzumab vs. SC IFNb-1a), % 69 (p= 0.0005) 30 (p= 0.22) b 42 (p= 0.0084) Patients with 6-month CDI, a % N/A N/A 27 c 23 (p= 0.5192) c 30 (years 0–4) 13 29 (p= 0.0002) 41 (years 0–4) Mean change in EDSS score from baseline 0.46 -0.15 (p= 0.0056) -0.14 -0.14 (p= 0.97) -0.09 (years 0–4) 0.24 -0.17 (p\ 0.0001) 0.00 (years 0–4) MRI endpoints Gd ? lesion free, % 81 93 (p\ 0.0001) 87 78 91 (p\ 0.0001) 89 New/enlarging T 2 lesion free, % 60 78 (p\ 0.0001) 71 48 76 (p\ 0.0001) 70 New T 1 hypointense lesion free, % 82 93 (p= 0.0001) 85 74 93 (p\ 0.0001) 86 MRI activity free, d %5977(p\ 0.0001) 70 47 76 (p\ 0.0001) 70 Brain volume change Median BPF change, % (95% CI) –1.49 -0.87 (p\ 0.0001) (years 0–2) -1.134 c (years 0–4) –0.81 –0.62 (p= 0.0012) (years 0–2) -0.882 c (years 0–4) Reduction in rate of brain volume loss, % 42 24 Disease-free survival Patients with NEDA, e % 273960 143255 36 T. Berger et al. Table 2 continued CAMMS223 extension [13,20] CARE-MS I [8,11,17,18,33,34] CARE-MS I extension [8,17,18] CARE-MS II [7,12,17,19,35] CARE-MS II extension [7,19] 5-year data Study duration: 2 years Year 4 Study duration: 2 years Year 4 SC IFNb-1a 44 lg TIW Alemtuzumab 12 mg/day SC IFNb-1a 44 lg TIW Alemtuzumab 12 mg/day Alemtuzumab 12 mg/day SC IFNb-1a 44 lg TIW Alemtuzumab 12 mg/day Alemtuzumab 12 mg/day Odds ratio 1.75 (p= 0.006) 3.03 (p\0.0001) – Retreatment Patients not requiring retreatment, % N/A 94% N/A N/A 74 N/A N/A 68 ARR annualized relapse rate, BPF brain parenchymal fraction, CI confidence interval, CDI confirmed disability improvement, CDW confirmed disability worsening, EDSS Expanded Disability Status Scale, Gd ? gadolinium-enhancing, IFN interferon, MRI magnetic resonance imaging, N/A not applicable, NEDA no evidence of disease activity, SC subcutaneous, TIW three times per week a Kaplan–Meier estimates b When CAMMS223 and CARE-MS I data were pooled, a significant reduction in risk of 6-month CDW (50%, p= 0.0029), as well as ARR (56%, p\0.0001) was observed, when compared with SC IFNb-1a [36] c Sanofi Genzyme, data on file d MRI activity-free was defined as the absence of both Gd ? lesions and new or enlarging T 2 -hyperintense lesions; clinical disease activity-free was defined as the absence both of relapses and 6-month CDW [8] e Pre-specified tertiary endpoint in CARE-MS I and II. NEDA was defined as patients who were MRI and clinically disease free [8]. NEDA values are per year. For CARE-MS II, the denominator for the percentage of patients with each type of event is the total number of patients with MRIs performed at the given time point (Sanofi Genzyme, data on file) Recommendations for Alemtuzumab Use in Clinical Practice 37 introduced for ongoing trials, which resulted in early identification and management of ITP cases, as well as other autoimmune events (thyroid dysfunction and glomerulonephropathy) in the clinical trials and improved patient outcomes. Subsequently, a Risk Management Program (RMP) and a Risk Evaluation and Mitigation Strategy (REMS) [30] were implemented to ensure early detection of potential AEs in real-world clinical practice. Across the clinical development program, there were four reported cases of immune nephropathy, including one case of antiglomerular basement membrane (anti-GBM) disease (in CAMMS223) reported 39 months after the second alemtuzumab course [13,31]. A single fatal case of progressive multifocal leukoencephalopathy (PML) has been reported in a patient who switched from natalizumab to alemtuzumab. The PML diagnosis was not made until after the patient had received the first course of alemtuzumab; however, retrospective analysis of the MRI data showed that the onset of PML predated alemtuzumab treatment and, therefore, was attributed to natalizumab treatment (Sanofi Genzyme, data on file). The efficacy and safety outcomes from the alemtuzumab clinical trials have also been extensively reported in the literature; for further information, we refer the reader to these publications [9,11–13,32]. 2.3 Additional Long-Term Experience with Alemtuzumab A long-term, investigator-led, observational cohort study has also demonstrated the long-term efficacy and safety of alemtuzumab in patients with active RRMS [37]. In this study, 87 patients (39% having received a prior DMT) were followed for up to 12 years (median follow-up 7 years). The majority of patients (68%) experienced an improvement or stabilization of disability (based upon 6-month CDW) compared with baseline. Retreatment was permitted in the event of a relapse with 52% of patients receiving only the initial two courses, with the remainder receiving three (36%), four (8%), or five (1%) courses. The remaining patients (3%) received only a single treatment course [37]. 3 Use of Alemtuzumab in a Real-World Clinical Setting Real-world data indicate that, in the majority of patients with active or highly active RRMS, alemtuzumab treatment is associated with disease stabilization [37,38]. There is, however, some debate regarding which patients would benefit most from alemtuzumab treatment. The following sections of this article present the opinions and recommendations of European MS experts with regard to identifying the most appropriate patients for alemtuzumab treatment and best practices for treatment and monitoring. 3.1 Alemtuzumab Indication The EU indication for alemtuzumab states that alemtuzumab is suitable for ‘‘adult patients with RRMS with active disease defined by clinical or imaging features’’ [2]. This represents an apparent shift from previous regulatory labeling on the eligibility of patients for a particular DMT and potentially allows physicians to use alemtuzumab as a first-line treatment choice in appropriate patients. EU indications for other DMTs (e.g., fingolimod, natalizumab) are more restrictive, requiring evidence of a specified level of MRI activity, in addition to clinical activity before treatment initiation. Fingolimod and natalizumab are therefore recommended for use in patients with highly active disease who have breakthrough disease activity on a Table 3 Most common AEs observed in clinical trials of alemtuzumab 12 mg CAMMS223 [9,10] N= 108 CARE-MS I [11] N= 376 CARE-MS II [12] N= 435 AEs occurring in [10% of patients, n(%) Infusion-associated reactions 106 (98) 338 (90) 393 (90) Infection 71 (66) 253 (67) 334 (77) Upper respiratory tract 48 (44) 57 (15) 71 (16) Urinary tract 10 (9) 64 (17) 93 (21) Autoimmunity Any autoimmune thyroid-associated event 28 (26) 68 (18) 69 (16) Blood and lymphatic system disorders NR 66 (18) 59 (14) Lymphopenia NR 26 (7) 23 (5) Leukopenia NR 11 (3) NR AEs adverse events, NR not reported 38 T. Berger et al. previous DMT (i.e., as a second-line therapy) or in those with more rapidly evolving severe RRMS [39,40]. 3.2 Is There a Requirement for Specific Patient Profiles? The EU indication for alemtuzumab may provide prescribing physicians with certain challenges when deciding which patients are most suitable for treatment, although it also provides physicians with flexibility, allowing them to use their own clinical experience and judgment to make an informed decision regarding what constitutes active disease and to provide individualized treatment choices in collaboration with their patients. Clinical experience may be more valuable than rigid treatment guidelines, which attempt to define specific patient profiles for treatment eligibility. Furthermore, defining a single specific patient profile for alemtuzumab may not be helpful as this may unintentionally restrict the use of alemtuzumab in certain patients, particularly given that alemtuzumab efficacy has been demonstrated in a broad range of patients and that subgroup analyses have shown that the effects of alemtuzumab remain consistent across most demographic and disease characteristic subgroups [41–43]. Therefore, further studies are required to elucidate the variability and durability of response in patients treated with alemtuzumab to identify reliable biomarkers or clinical characteristics that can assist in the management of MS and further inform treatment decisions. Recently, several groups have investigated the prognostic value of peripheral CD4 ? lymphocyte cell count recovery as a potential biomarker to identify patients who might benefit from retreatment with an additional course of alemtuzumab, although the evidence is conflicting in this regard [44–46]. 3.3 Personal Experience with Alemtuzumab in Routine Clinical Practice In the absence of specific patient profiles and validated biomarkers, personal clinical experience will inevitably influence alemtuzumab-related treatment decisions. Collectively, we have treated 181 patients with alemtuzumab, either as a first-line or as an escalation therapy in patients with breakthrough disease activity on a previous DMT (Table 4). Most of our patients initiated treatment with alemtuzumab owing to breakthrough disease (i.e., having only a partial response to, or not responding to, other therapies). In general, these patients had experienced one or more relapses within the previous 12 months and demonstrated recent inflammatory disease activity (as evidenced either by gadolinium enhancement (Gd ? ) or by an obvious increase in T 2 lesion load) on a brain MRI. Thus, alemtuzumab use in this group of patients was consistent with a treatment escalation paradigm. There was a consensus that more favorable treatment outcomes are typically observed in these patients if alemtuzumab treatment can be initiated early on in the disease course, particularly in patients who are younger, have highly active disease, and have low levels of disability at the start of treatment. Nevertheless, in clinical practice, we have also found alemtuzumab is efficacious in patients with already accumulating disability, particularly when used as a rescue therapy to stabilize disease and prevent further disability worsening if inflammatory disease activity (either clinically or on MRI) is still overt. We, therefore, recommend the use of alemtuzumab in patients with active RRMS, regardless of their level of disability. However, 15% of our patients represented a very important treatment group, namely those who were treatment naı ¨ve but who presented with early, highly active disease. Compared with patients receiving alemtuzumab as an escalation therapy, these patients were generally younger and had a shorter, but more active disease course, usually with two or more relapses in the preceding 3–6 months (cluster of relapses). We feel that alemtuzumab may represent an effective treatment option in treatmentnaı ¨ve patients with rapidly evolving MS (or a clinical relapse accompanied by an increase in the number of T 2 lesions and/or ongoing evidence of Gd ? T 1 lesions), and, as experience grows and the favorable outcomes associated with early intervention with alemtuzumab become evident, alemtuzumab use in this patient population will increase. In CARE-MS I, alemtuzumab significantly reduced the rate of Table 4 Summary of author experiences with alemtuzumab National approval/reimbursement period September 2013–May 2015 Patients treated, N181 Female, n(%) 129 (71) Age, mean (range), years 35 (17–66) Alemtuzumab as: First-line therapy, n(%) 27 (15) Escalation therapy, n(%) 154 (85) Data provided courtesy of the authors and represents a summary of the experiences in Austria, Finland, Germany, Ireland, Italy, Norway, and Spain Recommendations for Alemtuzumab Use in Clinical Practice 39 brain volume loss in treatment-naı ¨ve patients with MS by 42% compared with SC IFNb-1a [34], and, given the correlation between brain volume loss and disability and cognitive worsening [47,48], early treatment with alemtuzumab may be more favorable than delaying treatment (discussed in Sect. 3.4). Indeed, we feel that initiating alemtuzumab in treatment-naı ¨ve patients may be advantageous, as lymphocyte levels have not been affected by use of prior DMTs. In our experience, alemtuzumab has a place in routine clinical practice for the treatment of patients relapsing on prior treatments, as well as those who are treatment naı ¨ve. Postponing treatment in favor of escalating patients through alternative DMTs, in effect retaining alemtuzumab as a last resort, is not advised, and we feel that initiating alemtuzumab as soon as possible, particularly in patients with low levels of disability, will be associated with the most favorable outcomes. 3.4 Alemtuzumab Early in Multiple Sclerosis The importance of treating MS early in the disease course to prevent inflammatory processes that lead to irreversible brain loss is well established [49–52]. Traditionally, the treatment paradigm is one of escalation therapy, during which drugs with greater efficacy (often with distinct mechanisms of action) but with increasing risk are used as disease progresses, with the most efficacious drugs (e.g., natalizumab, often considered following failure of one or more DMTs [53,54]) used as the last line of therapy. However, data from alemtuzumab clinical studies [9,11–13], coupled with its indication in the EU [2], afford physicians the opportunity to start alemtuzumab treatment in patients with active MS early in the disease course to prevent potentially avoidable CNS damage and provide the patient with the best opportunity for favorable treatment outcomes. This may be particularly important for patients with active MS with poor prognostic signs, for example, patients presenting with motor, cerebellar, or sphincter involvement at onset or those experiencing frequent relapses with poor recovery during the early years of their disease [55,56]. The benefits of early intervention with other DMTs have been widely reported; for example, in the pivotal 2-year SC IFNb-1a study (PRISMS) and its 2-year extension (PRISMS-4), patients who started treatment early had improved clinical outcomes compared with patients whose treatment was delayed [57,58]. These observations have been confirmed in long-term follow-up studies [59–61]. Early intervention is thought to address the inflammatory component of the disease, thereby reducing development of further CNS pathology [53,62]. Aggressive therapy early on in the disease course may provoke an immunological reset and may, therefore, favorably affect long-term disease progression [53]. However, the concept of early treatment of active disease with an immunomodulatory drug such as alemtuzumab, believed to rebalance the immune system, is not yet fully established and would represent a significant change in mindset for some physicians. In some European specialist MS centers, patients with highly active or rapidly evolving severe RRMS are already considered for first-line treatment with fingolimod or natalizumab (both considered typically second-line therapies in the EU), and, as noted above, alemtuzumab was used as a first-line therapy in 15% of all alemtuzumab-treated patients in our experience (Table 4). These observations perhaps indicate that MS treatment may be moving into a new era, away from the escalation paradigm and toward more robust early treatment of active disease. 3.5 Switching to Alemtuzumab from Prior DiseaseModifying Therapies The efficacy of alemtuzumab in patients with active disease who had relapsed on prior DMTs is of particular clinical relevance; in such cases, switching therapies should be considered urgently to bring MS activity under control. As discussed briefly above (Sect. 2.1, Table 2), the CARE-MS II study demonstrated superior efficacy with alemtuzumab vs. SC IFNb-1a in patients with active disease who had relapsed on prior DMTs [12]. The opportunity to switch therapies may be particularly important for certain patient subgroups. For example, patients receiving natalizumab therapy for over 2 years and/or who are positive for antiJohn Cunningham virus (anti-JCV) antibodies, as well as those having previously received other immunosuppressive medications, are at increased risk of developing PML and may require an alternative DMT [63]. Here, too, alemtuzumab may provide a treatment alternative option. However, transitioning from one particular DMT to another can be complex, and a washout period may be required in certain circumstances. Treatment cessation guidelines and recommended washout periods are sometimes provided within the respective label of each DMT (Table 5), although there are currently no recommendations for transitioning to alemtuzumab from these individual DMTs. However, in the CARE-MS II extension, patients who switched from SC IFNb-1a to alemtuzumab were not required to undergo a washout period. Therefore, it is often unclear for which treatment transitions a washout period is required, how long it should be, or what long-term safety surveillance procedures should be implemented [53]. Nevertheless, as with other immunomodulatory therapies, concomitant treatment, including initiation of alemtuzumab within the washout period of the previous DMT, 40 T. Berger et al. is not advisable, owing to the potential risk of carry-over PML from previous treatment and additive effects on the immune system [2]. Consequently, it is important to consider the half-life as well as the mechanism of action (MoA) of the previous DMT when transitioning to alemtuzumab [53]. Despite the absence of specific guidance for switching to alemtuzumab from the DMTs listed in Table 5, there are some considerations that may help guide switching in clinical practice. The proposed MoA of fingolimod (preventing lymphocyte egress from peripheral lymphoid organs) results in low levels of circulating lymphocytes [69]. Therefore, it may be advisable to wait until lymphocyte counts begin to recover before initiating treatment with a DMT, such as alemtuzumab, particularly given that the proposed MoA of alemtuzumab in MS requires effective targeting of circulating T and B cells, leading to their depletion and subsequent repopulation [4,5,64]. Indeed, a recent report demonstrated clinical and MRI disease activity in alemtuzumab-treated patients who had switched from fingolimod but for whom a potentially insufficient washout period following fingolimod cessation had been used, resulting in lymphocyte counts below normal levels at the time of alemtuzumab treatment. The authors hypothesized that the sequestration of lymphocytes in lymph nodes, owing to the mechanism of action of fingolimod, coupled with an inadequate washout period (median 6 weeks, range 4–10 weeks) may have reduced the effectiveness of alemtuzumab [70]. By contrast, the proposed MoA of dimethyl fumarate (DMF) (activation of the nuclear factor erythroid 2-related factor 2) would generally not predict any issues with rapid transition to another therapy, although DMF has also been shown to have a lymphopenic effect in certain patient populations. Thus, as for fingolimod, a washout period might be advisable when transitioning to alemtuzumab [64,71]. Unfortunately, for both fingolimod and DMF, the time period over which lymphocytes return to normal is variable and can take many weeks, during which time the patient is at risk of relapse [64]. Teriflunomide is also associated with a reduction (*15%, mean within normal limits) in lymphocytes and neutrophil counts within the first 3 months following treatment; mean lymphocyte and neutrophil counts then remain within the normal range for white blood cell counts (3.8–10.7 910 9 /L) during treatment [72]. Patients receiving teriflunomide have the opportunity to undergo an accelerated elimination procedure, which can reduce plasma levels by [96% in 11 days [66,73], potentially allowing the initiation of alemtuzumab relatively quickly after stopping teriflunomide. By contrast, natalizumab does not reduce circulating lymphocyte counts, rather it blocks their entry to the CNS resulting in only mild lymphocytosis [64,74], and there may be limited benefit in delaying initiating treatment with another DMT following natalizumab discontinuation [64]. In fact, it has been suggested that starting a new treatment immediately after stopping natalizumab (i.e., no a washout period) may be preferable because the risk of developing PML, even in anti-JCV antibody-positive patients, is lower than the risk of a severe relapse [75,76]. In CARE-MS II, patients previously treated with natalizumab (3%) underwent a 6-month washout period before starting alemtuzumab [12]. In real-world clinical settings, and, in Table 5 General guidance for therapy cessation for common DMTs Interferons, glatiramer acetate No specific guidance for cessation of therapy a No washout period recommended based upon the mechanism of action [64] Teriflunomide An AEP is available if rapid removal of teriflunomide from the circulation is desired [65] AEP will reduce plasma concentrations to 0.02 mg/L in 11 days. Complete elimination requires 8 months to 2 years in the absence of AEP [65,66] Dimethyl fumarate No specific guidance for cessation of therapy or requirement for washout [67] Fingolimod A 6-week treatment-free period is required to clear fingolimod from circulation [39] Natalizumab A washout period might be appropriate as the pharmacodynamic effects of natalizumab last for approximately 12 weeks following the last dose [40] Daclizumab Washout period of 4 weeks is recommended b [68] Rituximab/ocrelizumab c Washout period of 6 months is recommended b [68] AEP accelerated elimination procedure, DMTs disease-modifying therapies, EU European Union, FACS fluorescence-activated cell sorting, IFN interferon, MS multiple sclerosis, SC subcutaneous a In CARE-MS II [12], no washout period was required for patients switching from SC IFNb-1a to alemtuzumab b Washout guidance is based on cited sources along with the expert opinion of the authors c Ocrelizumab is not yet approved for the treatment of MS in the EU In all cases, the immune competence (including FACS analysis for B cells in the case of rituximab/ocrelizumab) should be confirmed before initiating alemtuzumab Recommendations for Alemtuzumab Use in Clinical Practice 41 5. 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