563522 TAN0010.1177/1756285614563522Therapeutic Advances in Neurological DisordersE Havrdova, D Horakova
`
`research-article2014
`
`Review
`
`Ther Adv Neurol Disord
`
`2015, Vol. 8(1) 31 –45
`
`DOI: 10.1177/
`1756285614563522
`
`© The Author(s), 2014.
`Reprints and permissions:
`http://www.sagepub.co.uk/
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`
`Alemtuzumab in the treatment of multiple
`sclerosis: key clinical trial results and
`considerations for use
`
`Eva Havrdova, Dana Horakova and Ivana Kovarova
`
`Abstract: Alemtuzumab is a humanized monoclonal antibody therapy that has recently been
`approved in over 30 countries for patients with active relapsing-remitting multiple sclerosis.
`It acts by targeting CD52, an antigen primarily expressed on T and B lymphocytes, resulting in
`their depletion and subsequent repopulation. The alemtuzumab clinical development program
`used an active comparator, subcutaneous interferon beta-1a, to show that alemtuzumab is a
`highly efficacious disease-modifying therapy, with benefits on relapses, disability outcomes,
`and freedom from clinical disease and magnetic resonance imaging activity. The safety profile
`was consistent across studies and no new safety signals have emerged during follow-up in
`the extension study. Infusion-associated reactions are common with alemtuzumab, but rarely
`serious. Infection incidence was elevated with alemtuzumab in clinical studies; most infections
`were mild or moderate in severity. Autoimmune adverse events occurred in approximately
`a third of patients, manifesting mainly as thyroid disorders, and less frequently as immune
`thrombocytopenia or nephropathy. A comprehensive monitoring program lasting at least 4
`years after the last alemtuzumab dose allows early detection and effective management of
`autoimmune adverse events. Further experience with alemtuzumab in the clinic will provide
`needed long-term data.
`
`Keywords: alemtuzumab, disease-modifying therapy, efficacy, mechanism of action, multiple
`sclerosis, safety
`
`Introduction
`Alemtuzumab is a humanized monoclonal anti-
`body therapy for relapsing-remitting multiple scle-
`rosis (RRMS). It was granted licensing approval
`by the European Medicines Agency (EMA) in
`September 2013. This was followed soon after-
`wards by approval from regulatory authorities in
`several other countries. The indication varies
`across jurisdictions, being approved for the treat-
`ment of active RRMS defined by clinical or imag-
`ing features, for the treatment of active RRMS
`with inadequate response to interferon beta
`(IFNB) or other disease-modifying therapies
`(DMTs), or the treatment of relapsing forms of
`multiple sclerosis (MS). Approval by the US Food
`and Drug Administration (FDA) was initially
`denied owing to concerns about the design of the
`pivotal studies. Because patients were not blinded
`to treatment assignment, the FDA determined
`that the data were insufficient to demonstrate that
`the benefits of the treatment outweighed the risks
`
`[Coles and Compston, 2014]. Effective patient
`blinding was not possible due to the high inci-
`dence of infusion-associated reactions (IARs)
`associated with the drug, but all efficacy assess-
`ments were performed by blinded neurologists.
`The application was resubmitted for consideration
`with additional data analyses. In November 2014,
`alemtuzumab was approved by the FDA for
`relapsing forms of MS, generally reserved for
`patients who have had an inadequate response to
`2 or more drugs indicated for the treatment of MS
`[Genzyme Corporation, 2014]. It will be available
`through a restricted distribution program.
`
`Correspondence to:
`Eva Havrdova, MD, PhD
`Department of Neurology
`and Center for Clinical
`Neuroscience, First
`Medical Faculty, Charles
`University in Prague,
`Katerinska 30, Prague,
`120 00, Czech Republic
`Eva.havrdova@lf1.cuni.cz
`Dana Horakova, MD, PhD
`Ivana Kovarova, MD
`Department of Neurology
`and Center for Clinical
`Neuroscience, First
`Medical Faculty, Charles
`University in Prague,
`Prague, Czech Republic
`
`Multiple sclerosis
`The pathogenesis of MS is not fully understood,
`but is associated with activation of autoreactive
`lymphocytes, which infiltrate the central nervous
`system (CNS) and mediate demyelination.
`Demyelination leaves axons susceptible to injury
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`Therapeutic Advances in Neurological Disorders 8(1)
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`from the inflammatory environment [Compston
`and Coles, 2008; Keough and Yong, 2013].
`Ultimately, axonal transection or neural death
`results in irreversible functional deficits.
`
`Various lymphocyte populations have been impli-
`cated
`in demyelination. Interleukin (IL)-17–
`producing T cells have been observed in active
`MS lesions in the CNS. Under experimental con-
`ditions, they have been associated with breaking
`down the blood–brain barrier, killing neurons,
`interfering with neural stem cell proliferation and
`enhancing oligodendrocyte apoptosis [Kebir et al.
`2007; Paintlia et  al. 2011; Yamout et  al. 2013].
`Regulatory T cells function to suppress autoreac-
`tive T-cell proliferation in healthy individuals
`through cytokine production and contact with
`effector T cells or antigen-presenting cells [Zozulya
`and Wiendl, 2008]. In patients with MS, this sup-
`pressive function is impaired [Viglietta et al. 2004;
`Fletcher et  al. 2009]. B lymphocytes also play a
`role in MS pathology. Clonally expanded B lym-
`phocytes have been observed in MS lesions and
`normal-appearing white matter [Baranzini et  al.
`1999]. The precise function of B cells in MS patho-
`genesis is unknown but likely involves antigen
`presentation, cytokine production and/or immu-
`noglobulin synthesis [Krumbholz et al. 2012].
`
`Alemtuzumab pharmacodynamics and
`mechanism of action
`Alemtuzumab targets CD52, an antigen of
`unknown function that is expressed on lympho-
`cytes, monocytes, some dendritic cell populations
`and, to a lesser degree, on natural killer (NK)
`cells and other leukocytes (Figure 1) [Rao et al.
`2012]. Alemtuzumab primarily depletes circulat-
`ing T and B lymphocytes via antibody-dependent
`cytolysis and complement-dependent cytolysis.
`Antibody-dependent cytolysis predominates in
`the mouse model and is mediated by neutrophils
`and NK cells [Hu et al. 2009]. Human lympho-
`cytes are also susceptible to complement-depend-
`ent cytolysis after alemtuzumab exposure, at least
`in vitro [Rao et al. 2012].
`
`Depletion is followed by lymphocyte repopulation,
`which begins within weeks. B-lymphocyte counts
`typically return to baseline by 6 months post-treat-
`ment, whereas in clinical trials, mean T-cell counts
`approached normal (but not baseline) levels by 12
`months post-treatment [Kovarova et  al. 2012;
`Kasper et  al. 2013]. CD4+ T-cell repopulation is
`particularly delayed. In a long-term follow-up of 37
`
`patients who had received alemtuzumab treatment
`in the 1990s for MS, median recovery time to nor-
`mal levels was 8.4 months for B cells, 20 months for
`CD8+ T cells and 12 years for CD4+ T cells [Hill-
`Cawthorne et  al. 2012]. It should be noted that
`many of these patients received a single treatment
`course of 100 mg over 5 infusion days, which is
`higher than the approved dose (60 mg over 5 days
`for the initial course, and 36 mg over 3 days for sub-
`sequent courses). T-lymphocyte repopulation is
`accomplished through proliferation of mature lym-
`phocytes that escaped depletion (i.e. ‘homeostatic’
`proliferation) as well as new production from pre-
`cursors in the thymus [Cox et al. 2005; Jones et al.
`2013].
`
`Despite profound depletion of circulating lym-
`phocytes, animal studies have shown that lym-
`phocyte numbers in primary and secondary
`lymphoid organs are maintained [Hu et al. 2009].
`Other aspects of the immune system are also
`unaffected by alemtuzumab, including innate
`immune cells, some T-cell subsets (tissue-resident
`effector memory T cells), plasma cells and serum
`immunoglobulin levels [Coles et al. 1999b; Clark
`et al. 2012; Turner et al. 2013].
`
`The therapeutic effect of alemtuzumab is likely
`not solely a consequence of lymphocyte deple-
`tion, but also of repopulation features. Patients
`with and without breakthrough disease activity
`after alemtuzumab treatment did not differ in the
`kinetics of lymphocyte repopulation, suggesting
`that the nature of the repopulating lymphocytes is
`as important as lymphocyte numbers [Kousin-
`Ezewu et al. 2014]. During repopulation, the rela-
`tive proportions of regulatory T cells and
`memory-phenotype T cells are increased, and the
`proportion of naive T cells is decreased [Cox et al.
`2005; Zhang et al. 2013]. These effects are most
`marked at month 1 and the cells generally return
`to baseline proportions by month 12. Similarly,
`the relative proportions of B-cell subsets are also
`shifted after alemtuzumab treatment [Hartung
`et al. 2012; Kasper et al. 2013]. The proportion of
`B cells with a mature naive phenotype was
`reduced after treatment, whereas the immature
`cell fraction increased. By month 6, these propor-
`tions approached their baseline levels. The serum
`cytokine profile is also altered for at least 6 months
`post-treatment, with marked decreases in IL-17
`and cytokines that promote IL-17 production,
`including IL-21 and IL-23 [Zhang et  al. 2013].
`There are also decreases in the proinflammatory
`cytokines IFN-γ, IL-12 and IL-27.
`
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`Figure 1. Alemtuzumab proposed mechanism of action.
`NK, natural killer.
`
`Development of alemtuzumab for MS
`Alemtuzumab was initially developed as a treat-
`ment for B-cell chronic lymphocytic leukemia
`(B-CLL), and was approved for that use by the
`FDA and EMA in 2001. The dose used in the set-
`ting of B-CLL (30 mg/day 3 times weekly for 12
`weeks) is considerably higher than that used for
`MS [Genzyme Corporation, 2007; Genzyme
`Europe, 2007].
`
`The initial trial of alemtuzumab in MS focused
`on patients (n = 28) with secondary progressive
`disease [Coles et  al. 1999b]. Despite effective
`suppression of inflammation, more than half the
`patients had a sustained increase in disability
`measured by the Expanded Disability Status
`Scale (EDSS) and/or had further brain volume
`loss during the 18-month follow-up period. These
`observations led to the hypothesis that, although
`axonal degeneration in patients with secondary
`progression occurs largely in the absence of
`inflammation, it is conditioned by the amount of
`prior inflammation-driven disease activity. The
`focus therefore shifted to treating patients earlier
`in their disease course. Patients with relapsing-
`remitting disease were targeted in the phase II
`and III studies.
`
`Efficacy
`
`Phase II
`CAMMS223 [ClinicalTrials.gov identifier: NCT
`00050778] was a randomized, rater-blinded, active-
`controlled, head-to-head trial of alemtuzumab versus
`subcutaneous (SC) IFNB-1a [CAMMS Trial
`Investigators et al. 2008]. Patients had early, active
`MS, defined as fulfilling the 2001 McDonald criteria
`[McDonald et al. 2001], ⩾2 relapses in the prior 2
`years and ⩾1 gadolinium (Gd)-enhancing lesion,
`baseline EDSS score ⩽3.0, MS symptom onset
`within 3 years, and no prior immunotherapy for MS
`other than steroids. Alemtuzumab was administered
`by intravenous infusion on 5 consecutive days at
`baseline and on 3 consecutive days 12 months later
`(Figure 2). A third course at month 24 was available
`at the treating physician’s discretion if the CD4+
`T-cell count was ⩾100 × 106 cells/l. All patients
`received prophylaxis for IARs consisting of methyl-
`prednisolone 1 g/day on the first 3 days of infusion of
`each course; antihistamines and antipyretics were
`also permitted. Almost 3 years after the study start,
`alemtuzumab dosing was suspended after three
`reports of immune thrombocytopenia (ITP), includ-
`ing the fatal index case, but safety and efficacy assess-
`ments continued. Coprimary efficacy outcomes
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`Figure 2. CAMMS223 phase II study design. Alemtuzumab was infused intravenously (IV) on 5 consecutive
`days at baseline and on 3 consecutive days at year 1. The third treatment course at year 2 was given at the
`discretion of the investigator if CD4+ T-cell counts were ⩾100 × 106 cells/l. In the extension study, patients
`originally randomized to SC IFNB-1a were not eligible for alemtuzumab treatment, but could take other
`disease-modifying therapies. Patients originally randomized to alemtuzumab could receive alemtuzumab
`retreatment at any point during the extension after the dosing suspension was lifted and ⩾12 months after the
`previous treatment course. Only the 12-mg dose was used for retreatment.
`CARE-MS, Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; IFNB, interferon beta; MS, multiple
`sclerosis; SC, subcutaneous.
`
`were the time to sustained accumulation of disability
`(SAD) (⩾1.5-point increase in EDSS score in
`patients with baseline score of 0 and ⩾1-point
`increase for patients with baseline score of ⩾1.0)
`confirmed over 6 months, and relapse rate.
`
`Primary efficacy endpoints were met and have
`been reviewed elsewhere [Menge et al. 2014]. Post
`hoc analyses showed that at year 3, 73% of patients
`treated with alemtuzumab 12 mg were free of
`clinical disease activity, defined as an absence of
`6-month SAD and relapse, compared with 43%
`in the SC IFNB-1a group (HR, 0.33; p < 0.0001)
`[Coles et  al. 2011]. More alemtuzumab-treated
`patients also experienced a sustained reduction
`in disability, defined as a ⩾1-point decrease in
`EDSS score sustained over a 6-month period in
`patients with baseline EDSS score ⩾2.0 (45%
`versus 27% at year 3; p = 0.01) [Coles et al. 2011].
`Median brain volume change from baseline to
`year 3 was −1.8% with SC IFNB-1a versus −0.9%
`with alemtuzumab 12 mg (p = 0.16).
`
`Phase III
`The Comparison of Alemtuzumab and Rebif®
`Efficacy in Multiple Sclerosis (CARE-MS) stud-
`ies [ClinicalTrials.gov identifier: NCT00530348,
`NCT00548405] were 2-year, phase III, rand-
`omized, active-controlled, head-to-head trials
`(Figure 3) [Cohen et al. 2012; Coles et al. 2012b].
`
`Although both CARE-MS studies enrolled
`patients with RRMS fulfilling the 2005 McDonald
`criteria [Polman et  al. 2005] and active disease
`(defined as ⩾2 relapses in the prior 2 years and
`⩾1 relapse in the prior year), their main point of
`differentiation was the treatment history of the
`target populations. In CARE-MS I, eligible
`patients had never received DMT, had a baseline
`EDSS score ⩽3.0 and MS symptom onset within
`5 years. In contrast, CARE-MS II patients were
`required to have relapsed on prior IFNB or glati-
`ramer acetate treatment after receiving that ther-
`apy for ⩾6 months (prior treatment with other
`therapies, including natalizumab, was also per-
`mitted). Additionally, they had to have baseline
`EDSS score ⩽5.0 and MS symptom onset within
`10 years. In both studies, patients were rand-
`omized 2:1 to two annual treatment courses of
`alemtuzumab 12 mg/day or SC IFNB-1a 44 µg
`three times weekly, with corticosteroid premedi-
`cation on the first 3 days of each treatment course
`for IAR prophylaxis. In CARE-MS II, there was
`an additional alemtuzumab 24-mg treatment
`arm; however, randomization into this arm was
`discontinued early to increase enrollment in the
`12-mg arm and it was deemed exploratory for sta-
`tistical purposes.
`
`The coprimary efficacy outcomes were relapse
`rate and time to 6-month SAD. Patient character-
`istics and primary efficacy results have been
`
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`Figure 3. CARE-MS phase III study design. CARE-MS studies were 2-year, phase III, randomized, active-
`controlled, head-to-head trials. Both studies enrolled patients with active relapsing-remitting multiple
`sclerosis (defined as ⩾2 relapses in the prior 2 years and ⩾1 relapse in the prior year). In the extension study,
`patients originally randomized to subcutaneous interferon beta-1a (SC IFNB-1a) received two annual courses of
`alemtuzumab 12 mg. Patients originally randomized to alemtuzumab could receive alemtuzumab retreatment if
`they fulfilled magnetic resonance imaging (MRI) or relapse criteria (⩾1 protocol-defined relapse in the previous
`year or ⩾2 unique MRI lesions on brain or spinal cord). Retreatment could occur at any point during the
`extension ⩾12 months after the previous treatment course. Only the 12-mg dose was used for retreatment.
`CARE-MS, Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; IV, intravenous.
`
`reviewed elsewhere [Menge et al. 2014]. Although
`the SAD endpoint was met in CARE-MS II, a sta-
`tistically significant difference between alemtu-
`zumab and SC IFNB-1a was not detectable in
`CARE-MS I. The inability to detect a treatment
`difference stemmed from the unexpectedly low
`rate of SAD in the SC IFNB-1a group. Power cal-
`culations for the study were based on CAMMS223
`data; 20% of patients were expected to attain
`6-month SAD with SC IFNB-1a rather than the
`observed 11%. In both studies, alemtuzumab 12
`mg was superior to SC IFNB-1a in reducing
`relapses and increasing the proportion of patients
`who were free of clinical disease (absence of
`relapses and SAD), and the proportion free of
`magnetic resonance
`imaging (MRI) activity
`(Gd-enhancing and new/enlarging T2 lesions) and
`clinical disease (Figure 4).
`
`the phase III program were 26−31% over 4 years
`of follow-up [Coles et al. 2014; Hartung et  al.
`2014]. In several long-term investigator-led stud-
`ies (‘the Cambridge cohort’; n = 87), this figure
`rose to 48% over up to 12 years of follow-up
`[Tuohy et al. 2014].
`
`In a 5-year follow-up of the CAMMS223 exten-
`sion, the risk of SAD from baseline to year 5 was
`reduced by 69% (p = 0.0005) in the alemtuzumab
`12-mg group relative to the SC IFNB-1a group
`[Coles et al. 2012a]. The EDSS score improved or
`remained stable in 74% of alemtuzumab 12-mg
`patients from baseline to year 5 compared with
`54% of SC IFNB-1a patients (p = 0.014), and
`relapses were reduced by 66% (p < 0.0001). From
`year 3 to year 5, there was a 56% relative reduc-
`tion in relapse rate, but this failed to reach signifi-
`cance (p = 0.09).
`
`Long-term efficacy
`All patients completing the phase II and III
`trials were eligible to continue in an ongoing exten-
`sion study [ClinicalTrials.gov identifier: NCT
`00930553] in which they could receive as-needed
`alemtuzumab retreatment. Retreatment rates in
`
`The phase III extension study currently has pre-
`liminary data up to 4 years after alemtuzumab
`initiation [Coles et al. 2014; Hartung et al. 2014].
`In this study, 349 patients enrolled from the
`CARE-MS I alemtuzumab group and 393
`patients enrolled
`from
`the CARE-MS
`II
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`Figure 4. Efficacy of alemtuzumab in core phase III clinical trials compared with patients who received
`subcutaneous interferon beta-1a (SC IFNB-1a).
`ARR, annualized relapse rate; CARE-MS, Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis; MRI,
`magnetic resonance imaging.
`
`alemtuzumab 12-mg group. The annualized
`relapse rate (ARR) over 4 years was 0.16 in treat-
`ment-naive patients and 0.24 in patients who had
`relapsed on prior therapy; ARRs in years 3 and 4
`were similar to that of the core studies. The exten-
`sion study is ongoing and planned to continue for
`at least 5 years of total follow-up.
`
`Safety
`Long-term safety data for alemtuzumab are not
`yet available. However, safety data up to 4 years
`(CARE-MS extension), 7 years (CAMMS223
`extension) or up to 12 years (Cambridge cohort)
`have thus far been consistent with what was
`observed in the core clinical trials. Whether any
`new safety signals emerge beyond this point
`remains to be seen.
`
`In the core phase II and III studies, adverse events
`(AEs) were reported in 96−100% of patients
`treated with alemtuzumab 12 mg [CAMMS Trial
`Investigators et al. 2008; Cohen et al. 2012; Coles
`et al. 2012b]. The rate of AEs (number per patient
`per year) ranged from 7.2 to 8.7 across studies.
`With the 12-mg dose, serious AEs were reported
`in 18–22% of patients across studies; the rate was
`0.1–0.16 events per patient per year. During the
`core studies, two deaths occurred in CAMMS223
`(cardiovascular disease and
`ITP), one
`in
`CARE-MS I (automobile accident) and two in
`
`CARE-MS II (automobile accident and aspira-
`tion pneumonia following brainstem relapse).
`
`Infusion-associated reactions
`IARs were the most common AEs in all three
`studies and those associated with alemtuzumab
`are thought to be mainly attributable to cytokine-
`release syndrome [Genzyme Therapeutics, 2013].
`Cytokine release occurs as a result of target cell
`lysis and recruitment of
`inflammatory cells
`[Breslin, 2007; Maggi et al. 2011]. In the alemtu-
`zumab studies, IARs were defined as any AE that
`occurred during the infusion or within 24 hours
`after infusion, regardless of causality. The inci-
`dence of IARs was ⩾90% across studies [CAMMS
`Trial Investigators et al. 2008; Cohen et al. 2012;
`Coles et al. 2012b]. Serious IARs were reported
`in up to 1−3% of patients in each alemtuzumab
`treatment group. Most common IARs and their
`incidence with alemtuzumab 12 mg were as fol-
`lows: headache (43−56%); rash (39−89%);
`pyrexia (16−36%); nausea (14−20%); urticaria
`(11−26%); pruritus (10−28%); flushing (8−11%);
`insomnia (10−19%); fatigue (7−24%); chills
`(7−18%); chest discomfort (6−14%); and dysp-
`nea (6−13%). There were no cases of anaphylaxis
`and no IARs resulted in death in the core studies.
`The IARs were most frequent during the first
`treatment course (85%), and decreased during
`course 2 (69%) and course 3 (63%) [Mayer et al.
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`2014]. Few patients (2−6.6% per infusion day)
`required infusion interruption or infusion rate
`adjustment.
`
`Infections
`As would be expected with any lymphocyte-
`depleting agent, infections were more common
`with alemtuzumab 12 mg than with SC IFNB-1a
`in clinical trials (CAMMS223: 66% versus 47%;
`CARE-MS I: 67% versus 45%; CARE-MS II:
`77% versus 66%). However, most were mild or
`moderate in severity [CAMMS Trial Investi-
`gators et al. 2008; Cohen et al. 2012; Coles et al.
`2012b]. Serious infections were rare, but slightly
`elevated with alemtuzumab versus SC IFNB-1a
`(CAMMS223: 2.8% versus 1.9%; CARE-MS I:
`2% versus 1%; CARE-MS II: 4% versus 1%). The
`most common infections were those of the res-
`piratory tract and urinary tract. Herpetic infec-
`tions, including mucocutaneous herpes simplex
`and herpes zoster, were increased with alemtu-
`zumab in the CARE-MS studies, but declined
`after the introduction of acyclovir prophylaxis as a
`study protocol amendment [Cohen et  al. 2012;
`Coles et al. 2012b; Wray et al. 2013a, 2013b].
`
`Follow-up for up to 7 years in CAMMS223
`showed that infection incidence did not increase
`with each course of alemtuzumab [Coles et al.
`2012a]. For all alemtuzumab-treated patients,
`infections peaked in year 1, at 47%, and declined
`thereafter. By year 7, infection incidence was 10%
`among patients in the 12-mg arm. Most infec-
`tions (96%) were mild or moderate over the fol-
`low-up period and upper respiratory tract
`infections were most common.
`
`Alemtuzumab has not been associated with any
`cases of progressive multifocal leukoencephalopa-
`thy in studies of patients with MS. There have
`been several case reports of progressive multifocal
`leukoencephalopathy in patients treated with
`alemtuzumab for transplant rejection or for CLL
`[Waggoner et  al. 2009; Isidoro et  al. 2014]. In
`these cases, however, patients had been heavily
`treated with immunosuppressive therapies before
`receiving alemtuzumab.
`
`Malignancy
`Of 1486 alemtuzumab-treated patients in the clini-
`cal development program, 29 have been diagnosed
`with a malignancy, six of which were thyroid carci-
`nomas [Miller et  al. 2014]. The apparently high
`
`rate of thyroid cancer is related to increased sur-
`veillance of thyroid function; at least four cases
`were detected as incidental findings during treat-
`ment for Graves’ disease. A case report of thyroid
`carcinoma after alemtuzumab in a patient with
`otherwise normal thyroid function has also been
`published [Ibitoye and Wilkins, 2014]. Other malig-
`nancies occurring in >1 alemtuzumab-treated
`patient included basal cell carcinoma (n = 6), breast
`(n = 5) and malignant melanoma (n = 4).
`
`Autoimmune AEs
`Autoimmune AEs represent the most important
`risk associated with alemtuzumab treatment.
`Autoimmune sequelae are thought to arise from
`the way in which lymphocyte repopulation pro-
`ceeds [Jones et al. 2013]. T lymphocytes repopu-
`late via two mechanisms: the ‘homeostatic’
`proliferation of mature lymphocytes that escaped
`depletion by alemtuzumab; and generation of
`new T cells in the thymus. Homeostatic prolifera-
`tion predominates in patients who go on to
`develop autoimmune AEs; in contrast, patients
`without autoimmune AEs tend to generate rela-
`tively more new T lymphocytes in the thymus.
`The relative contribution of these repopulation
`mechanisms has implications for the clonal diver-
`sity of the resulting T-cell pool and autoimmunity
`is associated with reduced lymphocyte diversity.
`
`With alemtuzumab, autoimmune AEs most com-
`monly affect the thyroid, but rare cases of ITP
`and antiglomerular basement membrane disease
`have also been described; these events spurred the
`need for active monitoring after alemtuzumab
`treatment. A case of type 1 diabetes after alemtu-
`zumab treatment has recently been described in
`the literature [Malmeström et al. 2014], but it is
`unknown whether this is an isolated case or repre-
`sents another form of autoimmune AE that should
`be monitored. Because autoimmune AEs may
`develop years after the last dose of alemtuzumab,
`the potential for as-yet unrecognized AEs remains.
`
`Thyroid. In the 5-year follow-up of CAMMS223,
`thyroid autoimmune AEs occurred in 39% of
`patients treated with alemtuzumab 12 mg and
`29% of those who received the 24-mg dose [Dan-
`iels et  al. 2014]. In total, 102 episodes were
`reported in 73 alemtuzumab patients. Graves’
`hyperthyroidism (65.8%), hypothyroidism (20.5%)
`and subacute thyroiditis (12.3%) were most com-
`mon. Onset ranged from 6 to 61 months after
`the first treatment course [Coles et al. 2012a].
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`Incidence peaked at year 3 and declined in subse-
`quent years [Daniels et al. 2014]. Thyroid disor-
`ders responded to conventional therapy with
`antithyroid drugs, radioactive iodine, thyroid hor-
`mone or surgery. Most patients (85%) who devel-
`oped thyroid disorders were negative for thyroid
`peroxidase antibodies at baseline. At the time of
`thyroid dysfunction, antithyroid-stimulating hor-
`mone receptor antibodies were present in 70% of
`episodes.
`
`The CARE-MS studies have shown similar thy-
`roid outcomes as observed in the phase II study.
`In pooled data from 4-year follow-up, the inci-
`dence of thyroid AEs was highest in year 3
`(20.9%) and declined in year 4 (12.4%) [Twyman
`et  al. 2014], consistent with
`the 5-year
`CAMMS223 results [Coles et al. 2012a] and
`12-year results from the Cambridge cohort
`[Tuohy et  al. 2014]. Overall, thyroid AEs were
`reported in 36% of patients and serious thyroid
`AEs in 3.8% of patients over 4 years of follow-up
`in the CARE-MS studies [Twyman et al. 2014].
`Hyperthyroidism, hypothyroidism, goiter and
`thyroiditis were most common.
`
`ITP. Alemtuzumab is associated with a unique
`form of ITP characterized by delayed onset,
`responsiveness to conventional ITP therapies, and
`prolonged remission [Cuker et al. 2011]. The index
`case of ITP occurred during CAMMS223, when a
`patient presented with intracranial hemorrhage
`and died. This prompted the implementation of a
`risk-management plan that comprised patient and
`physician education, monthly complete blood
`count (CBC) and monthly symptom surveys offset
`from the CBC by 2 weeks [Cuker et  al. 2014].
`During clinical trials, ITP was defined in the study
`protocols as normal hemoglobin, white blood cell
`count, and peripheral smear except for a decrease
`in platelets without clumping; absence of spleno-
`megaly; and either a confirmed platelet count
`between 50 and 100 × 109/l on ⩾2 consecutive
`occasions over a period of at least 1 month, or a
`confirmed platelet count <50 × 109/l without
`clumping documented on two or more consecutive
`occasions over any period of time [Cuker et  al.
`2014]. The incidence of protocol-defined alemtu-
`zumab-induced ITP was 2.0% (n = 30/1486)
`across the clinical development program, including
`the ongoing extension study [Cuker et al. 2014]. A
`further 21 patients did not meet the protocol defi-
`nition but had platelet counts below normal limits.
`ITP onset occurred a mean of 16 months (range:
`1−34) after the last dose of alemtuzumab. Most
`
`patients responded to first-line therapy with corti-
`costeroids, intravenous immunoglobulin or plate-
`let transfusion. Other therapies were rituximab
`(n = 4) and splenectomy (n = 1), and several events
`(n = 2) resolved spontaneously.
`
`Nephropathy. Nephropathy has been described in
`clinical studies of alemtuzumab in RRMS. In
`pilot studies, two patients developed antiglomer-
`ular basement membrane (anti-GBM) disease
`that ultimately required renal transplant [Meyer
`et al. 2012]. In phase II and III trials, four cases of
`glomerulonephritis occurred
`among 1486
`patients
`treated with alemtuzumab (0.3%),
`including 1 case of anti-GBM disease, 1 case of
`glomerulonephritis with positive anti-GBM anti-
`body, and 2 cases of membranous glomerulone-
`phritis [Cohen et  al. 2012; Coles et  al. 2012b;
`Wynn et  al. 2013]. Onset ranged from 4 to 39
`months after the last dose of alemtuzumab. Each
`case responded to medical treatment.
`
`Pregnancy and fertility
`Alemtuzumab is in the pregnancy category C,
`with no controlled studies on its effect on preg-
`nant women or the developing fetus [Genzyme
`Corporation, 2007]. Immunoglobulin G mole-
`cules can cross the placental barrier and poten-
`tially affect the fetus. Women of childbearing
`potential are advised to use contraception during
`a course of alemtuzumab and for 4 months after-
`wards. Although contraception was required dur-
`ing clinical studies, 139 pregnancies in 104
`patients occurred after exposure to alemtuzumab
`as of October 2013 [McCombe et  al. 2014].
`These pregnancies resulted in 67 live births, 14
`elective abortions, 24 spontaneous abortions, one
`stillbirth, and 33 ongoing or with unknown out-
`come. Serious AEs occurred in 11 fetuses/infants,
`including two fetuses with abnormal development
`(cystic hygroma and hypoplastic heart; anembry-
`onic gestation) and one intrauterine death due to
`nuchal cord.
`
`CD52 is expressed in the male reproductive sys-
`tem, including the epididymis and seminal vesi-
`cle, sperm and seminal fluid, posing a theoretical
`risk of alemtuzumab for male fertility [Hale et al.
`1993]. However, developing sperm are negative
`for CD52 expression, and although mature sperm
`express CD52, an abundance of CD52 antigen in
`seminal plasma effectively competes with sperm
`for alemtuzumab binding, making an adverse
`impact on male fertility unlikely. A limited data
`
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`E Havrdova, D Horakova et al.
`
`set (n = 13) showed that at baseline, and 1, 3 and
`6 months post alemtuzumab treatment, there was
`no evidence of defects in sperm motility or mor-
`phology, and no patient had a consistently
`depressed sperm count [Margolin et al. 2013].
`
`Managing safety risks associated with
`alemtuzumab
`Every MS drug has a unique side effect profile
`that requires active management. Although alem-
`tuzumab treatment is associated with safety risks,
`those risks are manageable in most patients. To
`enable early detection and treatment of autoim-
`mune AEs, patients undergo a program of
`monthly testing for 4 years after the last alemtu-
`zumab dos