Introduction
Multiple sclerosis (MS) is a chronic autoimmune demyelinating disorder of the central nervous system. The clinical course of MS is variable, usually beginning with recurrent and reversible episodes of neurologic disability termed relapses; this phase of the disease is termed relapsing–remitting MS (RRMS). Relapses can occur months or even years apart [
1]. After a number of years, the majority of RRMS patients enter a second disease phase [called secondary progressive MS (SPMS)], which is characterized by continuous, irreversible neurologic decline. Transition to this phase of MS is ominous, as therapies are not yet available to treat the cognitive and physical decline that occurs. Prevention of this transition to SPMS is, therefore, a major therapeutic goal of MS treatment.
Alemtuzumab (LEMTRADA
®; Sanofi Genzyme, Cambridge, MA, USA) is a humanized anti-CD52 (cluster of differentiation 52) monoclonal antibody approved in more than 65 countries for the treatment of RRMS. Alemtuzumab treatment results in the selective depletion and repopulation of circulating CD52-expressing T and B lymphocytes. Following depletion, a distinct pattern of T- and B-cell repopulation begins within weeks, including a relative increase of regulatory T cells and a decrease in proinflammatory cytokines [
2,
3]. These pharmacological effects potentially lead to a rebalancing of the immune system and may underlie its durable clinical effects in the absence of continuous treatment. Alemtuzumab is administered as 2 annual courses of 12 mg/day intravenously, with the first course given over 5 consecutive days at treatment initiation, and the second course 12 months later over 3 consecutive days.
The efficacy and safety of alemtuzumab have been evaluated in treatment-naive RRMS patients [phase 2 CAMMS223 study (ClinicalTrials.gov identifier: NCT00050778) and phase 3 CARE-MS I (NCT00530348)] and in RRMS patients who had an inadequate response (≥ 1 relapse after ≥ 6 months of treatment) to prior therapy [CARE-MS II study (ClinicalTrials.gov identifier: NCT00548405)]. Alemtuzumab significantly reduced the rate of clinical disease worsening over 36 months in the phase 2 CAMMS223 study [
4]. In the phase 3 CARE-MS trials, alemtuzumab demonstrated significantly greater improvements in disease activity over 2 years versus subcutaneous interferon beta-1a (SC IFNB-1a) administered three times per week [
5,
6]. In both CARE-MS I and II studies, alemtuzumab significantly reduced the frequency of relapses over 2 years compared with SC IFNB-1a, significantly improved MRI outcomes, including gadolinium-enhancing lesions and new or enlarging T2 hyperintense lesions, and significantly reduced the rate of brain volume loss [
5,
6]. Patients treated with alemtuzumab in CARE-MS II also showed a significantly reduced rate of 6-month confirmed disability worsening (CDW) versus SC IFNB-1a, with patients from the CARE-MS I study showing a nonsignificant 30% reduction in CDW. In addition, in CARE-MS II, patients treated with alemtuzumab were more than twice as likely as patients treated with SC IFNB-1a to experience 6-month confirmed disability improvement (hazard ratio 2.57,
p = 0.0002) [
6].
Patients who completed the CAMMS223 and CARE-MS trials could enter an open-label extension study to allow evaluation of long-term alemtuzumab efficacy and safety. Alemtuzumab demonstrated durable efficacy on clinical and MRI outcomes over 10 years in patients who were originally enrolled in CAMMS223 [
7] as well as durable efficacy over 6 years (2 years of core study plus 4 years of extension) in the absence of continuous treatment in patients who were originally enrolled in the CARE-MS studies [
7]. Annualized relapse rate remained low, most patients were free of CDW, and some patients also continued to achieve improvements in disability over 6 years [
7]. These results were achieved with a high retention rate over the 6-year period (82% of patients who enrolled in the CARE-MS studies remained on study through Year 6), and with the majority (56%) of patients who entered the CARE-MS extension study receiving no additional treatment for their MS (no alemtuzumab retreatment nor use of another disease-modifying treatment).
All disease-modifying therapies for MS have side effects. The most common adverse events (AEs) associated with alemtuzumab treatment are mild to moderate infusion-associated reactions, infections (mostly nonserious), and autoimmune AEs [
7‐
11]. Through 6 years of follow-up, AEs involving the thyroid gland were the most frequently reported autoimmune AEs, observed in 42% of patients treated with alemtuzumab (which included both hyperthyroidism and hypothyroidism) [
11]. Other autoimmune AEs observed in patients treated with alemtuzumab were low platelet counts [(immune thrombocytopenia (ITP)] and nephropathies.
Following a fatality associated with ITP in the phase 2 CAMMS223 trial, a safety monitoring program was implemented to facilitate the early detection and management of autoimmune events. The program includes physician and patient education about the possible signs and symptoms of autoimmune events, as well as monthly monitoring for renal and hematologic events and quarterly monitoring of thyroid function [throughout treatment and for 48 months after the last alemtuzumab course (second or subsequent course)].
The cause of autoimmunity in alemtuzumab-treated patients is not well understood, but may be related to the pattern of T- and B-cell depletion and repopulation following alemtuzumab treatment. The repopulation of T cells may occur through two pathways: (1) thymopoiesis and (2) homeostatic proliferation of cells that have escaped depletion. Autoimmune disease may be more likely when homeostatic proliferation predominates over thymic reconstitution [
12]. Another hypothesis is that the depletion followed by the rapid repopulation of B cells may be a factor in the development of autoimmunity with alemtuzumab, particularly in individuals with a genetic predisposition for autoimmunity [
13]. However, evidence to support these hypotheses is lacking, and additional studies are needed to elucidate the cause of autoimmunity in alemtuzumab-treated patients.
Although the safety monitoring program was designed and implemented to facilitate the timely detection of autoimmune events related to alemtuzumab, and despite some recommendations for the management of thyroid-related events [
14], there remains a paucity of published practical recommendations on how to monitor and manage these events if detected in clinical practice. In particular, there continues to be uncertainty regarding when, and which, patients with renal and hematologic events may require referral to another specialist.
Based on the published literature and the authors’ own real-world experiences, this article offers practical real-world recommendations for the monitoring, management, and referral of MS patients with possible autoimmune AEs (thyroid events, ITP, and nephropathies) associated with alemtuzumab treatment.
Discussion
Alemtuzumab treatment can provide significant benefits for patients with RRMS, having been shown to significantly reduce relapses, CDW, and brain volume loss compared with SC IFNB-1a. The proportion of patients showing disability improvement was also more favorable in patients receiving alemtuzumab compared with SC IFNB-1a. These benefits were sustained for at least 6 years in the absence of continuous treatment and, notably, most patients did not receive additional alemtuzumab treatment or another disease-modifying therapy during the follow-up period.
Although the progression of MS is not entirely predictable, the consequences associated with not managing MS can be significant and can include more frequent relapses, progression of disability, and conversion to SPMS [
35,
36]. Initiating treatment with alemtuzumab improves clinical outcomes and reduces the rate of conversion of RRMS to SPMS with a manageable safety profile [
5,
6,
8‐
10,
37‐
40]. Alemtuzumab has also been shown to significantly improve physical, mental, and emotional quality of life, and the 6-year phase 3 CARE-MS extension efficacy and safety data are consistent with the 10-year phase 2 data [
41,
42].
Treatment with alemtuzumab is accompanied by an increased risk for autoimmunity that most frequently involves the thyroid gland. These autoimmune events are predictable and identifiable, and are manageable with early detection and intervention. Since the implementation of the autoimmunity monitoring program, no deaths related to autoimmunity in alemtuzumab-treated patients have occurred. Furthermore, the half-life of alemtuzumab is approximately 2 weeks and serum concentrations are generally undetectable within approximately 30 days following each treatment course [
43]. As most autoimmune events occur in the timeframe of months to years after infusion, these events are occurring in the absence of alemtuzumab, although they may potentially be related to the distinct pattern of T- and B-cell depletion and repopulation that occurs following alemtuzumab treatment. Additional studies are needed to definitively elucidate the cause of autoimmunity in alemtuzumab-treated patients.
Autoimmune events can have serious consequences, and patients receiving treatment with alemtuzumab will require close monitoring to mitigate risk. Should autoimmunity develop, early and appropriate intervention can lead to favorable outcomes. The recommendations detailed here will help provide healthcare professionals with a thorough understanding of the presentation of autoimmune events in alemtuzumab-treated patients to identify them in a timely manner and to initiate appropriate treatment.
Compliance with ethical standards