BACKGROUND: Alemtuzumab (ALEM) is a humanised monoclonal antibody that depletes circulating lymphocytes by selectively targeting CD52, which is expressed in high levels on T- and B-lymphocytes. This depletion is followed by lymphocyte repopulation and a cytokine expression shift towards a lesser inflammatory profile, both of which may contribute to prolonged efficacy. National recommendations for enrolling and treating multiple sclerosis (MS) patients with ALEM have been established. However, there are no recommendations in place for the treatment of MS reactivation after the ALEM treatment. OBJECTIVES: To evaluate the effectiveness and safety of the use of ALEM and to analyse subsequent disease-modifying treatments (DMTs). A multidimensional prediction model was developed to make a patient-specific prognosis regarding the response to ALEM. DESIGN: A multicentre, prospective, non-controlled, non-interventional, observational cohort study. METHODS: Relapsing multiple sclerosis patients (RMSp) who received ⩾1 dose of ALEM were enrolled. In each treatment year, the following baseline and prospective data were collected: age, MS history, number, type and duration of previous disease-modifying treatment (PDMT), relapse rate (REL), expanded disability status scale (EDSS), magnetic resonance imaging and serious adverse events (AE). In cases of reactivation of MS, all data about the subsequent DMT were collected. RESULTS: A total of 142 RMSp from 10 MS Slovak Centres fulfilled the inclusion criteria. The average age was 35 years (standard error 8.56). The overall average EDSS was 3.87 (1.46) when ALEM was started. The average duration of PDMT was 6.0 (4.04) years, and the median number of PDMTs was 3 (0-5), while the patients were mostly treated with 2 or 3 DMTs (>65.00%). Post-ALEM treatment was needed in 39 cases (27.46%). The most frequent post-ALEM treatment indicated was ocrelizumab, followed by natalizumab (NAT), siponimod and cladribine. The ocrelizumab and NAT treatment bring little benefit to patients. Siponimod showed less EDSS increase in contrast to ocrelizumab and NAT. Another repopulation therapy, cladribine, may also be an effective option. Statistically significant predictors for the expected EDSS are age (p-value <0.0001), number of ALEM cycles (0.0066), high number of PDMT (0.0459) and the occurrence of relapses (<0.0001). There was no statistically significant effect on the patient's gender (0.6038), duration of disease-modifying treatment before alemtuzumab (0.4466), or the occurrence of AE (0.6668). CONCLUSION: The study confirms the positive effect of ALEM on clinical and radiological outcomes. We need more data from long-term sequencing studies.

• Keywords
• alemtuzumab, long-term efficacy, long-term safety, multiple sclerosis, post-alemtuzumab treatment, real-world data,
• Publication type
• Journal Article MeSH

BACKGROUND: Alemtuzumab is an effective therapy for relapsing multiple sclerosis. Autoimmune thyroid events are a common adverse event. OBJECTIVE: Describe endocrine and multiple sclerosis outcomes over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients in the phase 3 CARE-MS I, II, and extension studies who experienced adverse thyroid events. METHODS: Endocrine and multiple sclerosis outcomes were evaluated over 6 years. Thyroid event cases, excluding those pre-existing or occurring after Year 6, were adjudicated retrospectively by expert endocrinologists independently of the sponsor and investigators. RESULTS: Thyroid events were reported for 378/811 (46.6%) alemtuzumab-treated patients. Following adjudication, endocrinologists reached consensus on 286 cases (75.7%). Of these, 39.5% were adjudicated to Graves' disease, 2.5% Hashimoto's disease switching to hyperthyroidism, 15.4% Hashimoto's disease, 4.9% Graves' disease switching to hypothyroidism, 10.1% transient thyroiditis, and 27.6% with uncertain diagnosis; inclusion of anti-thyroid antibody status reduced the number of uncertain diagnoses. Multiple sclerosis outcomes of those with and without thyroid events were similar. CONCLUSION: Adjudicated thyroid events occurring over 6 years for alemtuzumab-treated relapsing multiple sclerosis patients were primarily autoimmune. Thyroid events were considered manageable and did not affect disease course. Thyroid autoimmunity is a common but manageable adverse event in alemtuzumab-treated relapsing multiple sclerosis patients.ClinicalTrials.gov Registration Numbers: CARE-MS I (NCT00530348); CARE-MS II (NCT00548405); CARE-MS Extension (NCT00930553).

• Keywords
• Alemtuzumab, Graves’ disease, Hashimoto's disease, disease-modifying therapy, multiple sclerosis, thyroid,
• Publication type
• Journal Article MeSH

A critical issue in the management of relapsing MS (RMS) is the discontinuation of disease-modifying treatments (DMT) due to lack of efficacy, intolerability or impending risks. With new therapeutic agents introduced into the treatment of RMS, immediate- and long-term consequences of sequential drug use, as well as the effect of the sequence in which the drugs are given, are unclear but may affect efficacy, adverse events, and long-term immunocompetence. In the absence of clinical studies specifically addressing these concerns, observations from clinical practice are of particular value in guiding current management algorithms. Prompted by a study published by Ferraro et al. in this journal, we set out to provide an overview of the published real-world evidence on the effectiveness and safety of switching from fingolimod to another DMT in patients with active RMS. Seventeen publications reporting relevant information were identified. The literature suggests that immune cell depletion induced by alemtuzumab or ocrelizumab is associated with an increased risk of relapse and worsening disability in patients switching from fingolimod compared to patients switching from other therapeutic agents. However, the evidence reported for natalizumab and cladribine is inconclusive. While shortening of the washout period may limit early disease reactivation after fingolimod discontinuation, there is no strong evidence that the duration of the washout period or the absolute lymphocyte count at baseline are predictors of attenuated long-term efficacy. Further real-world studies are required to better understand outcomes among patients who are under-represented in controlled trials.

• Keywords
• Adverse events, Disease-modifying treatment, Effectiveness, Fingolimod, Multiple sclerosis, Switch,
• MeSH
• Fingolimod Hydrochloride adverse effects   MeSH
• Immunosuppressive Agents adverse effects   MeSH
• Humans MeSH
• Natalizumab therapeutic use   MeSH
• Recurrence MeSH
• Multiple Sclerosis, Relapsing-Remitting * drug therapy   MeSH
• Multiple Sclerosis * chemically induced   drug therapy   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Fingolimod Hydrochloride MeSH
• Immunosuppressive Agents MeSH
• Natalizumab MeSH

Monoclonal antibodies have become a mainstay in the treatment of patients with relapsing multiple sclerosis (RMS) and provide some benefit to patients with primary progressive MS. They are highly precise by specifically targeting molecules displayed on cells involved in distinct immune mechanisms of MS pathophysiology. They not only differ in the target antigen they recognize but also by the mode of action that generates their therapeutic effect. Natalizumab, an [Formula: see text]4[Formula: see text]1 integrin antagonist, works via binding to cell surface receptors, blocking the interaction with their ligands and, in that way, preventing the migration of leukocytes across the blood-brain barrier. On the other hand, the anti-CD52 monoclonal antibody alemtuzumab and the anti-CD20 monoclonal antibodies rituximab, ocrelizumab, ofatumumab, and ublituximab work via eliminating selected pathogenic cell populations. However, potential adverse effects may be serious and can necessitate treatment discontinuation. Most importantly, those are the risk for (opportunistic) infections, but also secondary autoimmune diseases or malignancies. Monoclonal antibodies also carry the risk of infusion/injection-related reactions, primarily in early phases of treatment. By careful patient selection and monitoring during therapy, the occurrence of these potentially serious adverse effects can be minimized. Monoclonal antibodies are characterized by a relatively long pharmacologic half-life and pharmacodynamic effects, which provides advantages such as permitting infrequent dosing, but also creates disadvantages regarding vaccination and family planning. This review presents an overview of currently available monoclonal antibodies for the treatment of RMS, including their mechanism of action, efficacy and safety profile. Furthermore, we provide practical recommendations for risk management, vaccination, and family planning.

• Keywords
• Alemtuzumab, Disease-modifying therapy, Monoclonal antibodies, Multiple sclerosis, Natalizumab, Ocrelizumab, Ofatumumab, Rituximab, Ublituximab,
• MeSH
• Humans MeSH
• Antibodies, Monoclonal therapeutic use   MeSH
• Natalizumab therapeutic use   MeSH
• Antineoplastic Agents, Immunological * therapeutic use   MeSH
• Risk Management MeSH
• Multiple Sclerosis * therapy   MeSH
• Pregnancy MeSH
• Vaccination MeSH
• Check Tag
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Antibodies, Monoclonal MeSH
• Natalizumab MeSH
• Antineoplastic Agents, Immunological * MeSH

BACKGROUND: In the 2-year CARE-MS I and II trials, alemtuzumab 12 mg administered on 5 consecutive days at core study baseline and on 3 consecutive days 12 months later significantly improved outcomes versus subcutaneous interferon beta-1a (SC IFNB-1a) in relapsing-remitting multiple sclerosis patients. Here, we present the final 6-year CARE-MS extension trial results (CAMMS03409), and compare outcomes over 6 years in patients randomized to both treatment groups at core study baseline. METHODS: Over a 4-year extension, alemtuzumab patients (alemtuzumab-only) received as-needed additional alemtuzumab (⩾12 months apart) for disease activity after course 2. SC IFNB-1a patients who entered the extension discontinued SC IFNB-1a and received 2 alemtuzumab 12 mg courses (IFN-alemtuzumab), followed by additional, as-needed, alemtuzumab. RESULTS: Through year 6, 63% of CARE-MS I and 50% of CARE-MS II alemtuzumab-only patients received neither additional alemtuzumab nor other disease-modifying therapy, with lasting suppression of disease activity, improved disability, and slowing of brain volume loss (BVL). In CARE-MS I patients (treatment-naive; less disability; shorter disease duration), disease activity and BVL were significantly reduced in IFN-alemtuzumab patients, similar to alemtuzumab-only patients at year 6. Among CARE-MS II patients (inadequate response to prior treatment; more disability; longer disease duration), alemtuzumab significantly improved clinical and magnetic resonance imaging outcomes, including BVL, in IFN-alemtuzumab patients; however, disability outcomes were less favorable versus alemtuzumab-only patients. Safety profiles, including infections and autoimmunities, following alemtuzumab were similar between treatment groups. CONCLUSION: This study demonstrates the high efficacy of alemtuzumab over 6 years, with a similar safety profile between treatment groups. CLINICALTRIALSGOV IDENTIFIERS: NCT00530348; NCT00548405; NCT00930553.

• Keywords
• CD52, MRI, alemtuzumab, brain volume, disability, disease activity, efficacy, extension, multiple sclerosis, relapse, safety,
• Publication type
• Journal Article MeSH

BACKGROUND: Few data exist concerning conversion to secondary progressive MS in patients treated with disease-modifying therapies. OBJECTIVE: Determine the proportion of alemtuzumab-treated patients converting from relapsing-remitting to secondary progressive MS during the CARE-MS core and extension studies. METHODS: Patients (N = 811) were analyzed post hoc for secondary progressive MS conversion. Optimal conversion definition: Expanded Disability Status Scale (EDSS) score ≥4, pyramidal functional system score ≥2, and confirmed progression over ≥3 months including confirmation within the functional system leading to progression, independent of relapse. RESULTS: Over 6.2 years median follow-up, 20 alemtuzumab-treated patients converted (Kaplan-Meier estimate, 2.7%; 95% confidence interval, 1.8%-4.2%). Sensitivity analysis accounting for dropouts showed similar results (3%), as did analyses using alternative definitions with different EDSS thresholds and/or confirmation periods, and analysis of core study subcutaneous interferon beta-1a-treated patients who received alemtuzumab in the extension. Patients converting to secondary progressive MS were older, and had higher EDSS scores and greater brain lesion volumes at baseline, but did not need additional alemtuzumab or other therapies. CONCLUSIONS: The 6-year conversion rate to secondary progressive MS was low for alemtuzumab-treated patients, supporting further study of the role alemtuzumab may play in reducing risk of secondary progression.ClinicalTrials.gov identifiers: NCT00530348, NCT00548405, NCT00930553.

• Keywords
• Relapsing-remitting multiple sclerosis, alemtuzumab, disease progression, secondary progressive multiple sclerosis,
• Publication type
• Journal Article MeSH

INTRODUCTION: In clinical trials of alemtuzumab, autoimmune thyroid adverse events (AEs) were frequent. Here, we assess the impact of thyroid AEs on health-related quality of life (HRQL) in alemtuzumab-treated patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: In phase 3 CARE-MS I (NCT00530348) and II (NCT00548405) trials, patients with RRMS were administered alemtuzumab 12 mg/day on 5 consecutive days at baseline and on 3 consecutive days 12 months later. Patients could participate in an extension study (NCT00930553) through year 6. HRQL was assessed at baseline and annually using the Functional Assessment of Multiple Sclerosis (FAMS), EuroQoL-5 Dimension Visual Analog Scale (EQ-5D VAS), and 36-Item Short-Form Survey (SF-36) questionnaires. Outcomes were analyzed in patients with or without thyroid AEs (nonserious or serious). A subset of patients with thyroid AEs was analyzed to assess HRQL before and during the onset of thyroid AEs. RESULTS: A total of 811 CARE-MS patients were treated with alemtuzumab. Of these, 342 (42%) patients experienced thyroid AEs over 6 years; serious thyroid AEs occurred in 44 (5%) patients. At year 6, HRQL outcomes generally remained slightly improved or similar to core study baseline in alemtuzumab-treated patients with or without thyroid AEs: FAMS (least-squares mean change from baseline without thyroid AEs, 0.7; with nonserious thyroid AEs, 5.1; with serious thyroid AEs, - 5.3), EQ-5D VAS (2.0; 3.0; - 6.8), SF-36 mental component summary (MCS [0.6; 1.6; - 2.8]), SF-36 physical component summary (PCS [0.8; 1.0; 1.1]). Over 6 years, 63-82% of patients in each group had improved/stable SF-36 MCS and PCS scores. Among patients with thyroid AE onset in year 3 (peak incidence), there were minimal differences between HRQL outcomes before onset (year 2) and after onset (year 3). CONCLUSION: Autoimmune thyroid AEs (serious and nonserious) had minimal impact on HRQL in alemtuzumab-treated patients. These data may aid therapeutic decisions in patients with relapsing MS.

This study looked at alemtuzumab, an approved treatment for multiple sclerosis (MS). People who receive alemtuzumab may develop thyroid problems. The researchers wanted to know whether people who developed thyroid problems with alemtuzumab had a worse quality of life compared with those who did not. The researchers measured quality of life using a questionnaire. The questionnaire looked at people’s physical, social, and psychological well-being over 6 years. A total of 811 people with MS treated with alemtuzumab took part in this study. Of these, 469 people (58%) did not develop thyroid problems and 342 people (42%) developed thyroid problems. The thyroid problems were serious in 44 people. The researchers observed that thyroid problems during alemtuzumab treatment did not make quality of life worse in most people. Some people with serious thyroid problems had worsened quality of life; this was mostly among people who required certain treatments for their thyroid problems. Quality of life did not change much in people while the thyroid problems were ongoing. This study shows that thyroid problems after alemtuzumab treatment for MS have little negative impact on quality of life for most people. These findings may help healthcare providers make decisions about MS treatment.

• Keywords
• Alemtuzumab, Health-related quality of life, Relapsing-remitting multiple sclerosis, Thyroid adverse events,
• Publication type
• Journal Article MeSH

BACKGROUND: Reduced MS disease activity with alemtuzumab versus subcutaneous interferon beta-1a (SC IFNB-1a) in core phase 2/3 studies was accompanied by increased incidence of infections that were mainly nonserious and responsive to treatment. Alemtuzumab efficacy was durable over 6 years. OBJECTIVE: To evaluate infections over 6 years in alemtuzumab-treated patients. METHODS: Three randomized trials (CAMMS223, Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I, and CARE-MS II) compared two courses of alemtuzumab 12 mg with SC IFNB-1a 44 μg in patients with active relapsing-remitting MS. An extension study (CAMMS03409) provided further evaluation and as-needed alemtuzumab retreatment. RESULTS: Infections occurred more frequently with alemtuzumab 12 mg than SC IFNB-1a during Years 1 (58.7% vs 41.3%) and 2 (52.6% vs 37.7%), but declined for alemtuzumab-treated patients in Years 3 (46.6%), 4 (42.8%), 5 (40.9%), and 6 (38.1%). Serious infections were uncommon (1.0%-1.9% per year). Infections were predominantly (>95%) mild to moderate and included upper respiratory tract infections, urinary tract infections, and mucocutaneous herpetic infections. Prophylactic acyclovir reduced herpetic infections. Lymphocyte counts after alemtuzumab therapy did not predict infection risk. CONCLUSION: Infections with alemtuzumab were mostly mild to moderate and decreased over time, consistent with preservation of components of protective immunity.

• Keywords
• Alemtuzumab, disease-modifying therapy, infection, relapsing-remitting multiple sclerosis, safety,
• MeSH
• Alemtuzumab adverse effects   therapeutic use   MeSH
• Time Factors MeSH
• Adult MeSH
• Antibodies, Monoclonal, Humanized adverse effects   MeSH
• Infections MeSH
• Interferon beta-1a administration & dosage   MeSH
• Humans MeSH
• Disease Susceptibility MeSH
• Recurrence MeSH
• Risk Factors MeSH
• Multiple Sclerosis drug therapy   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Alemtuzumab MeSH
• Antibodies, Monoclonal, Humanized MeSH
• Interferon beta-1a MeSH

BACKGROUND: Autoimmune disorders including nephropathies have been reported more frequently in alemtuzumab-treated multiple sclerosis (MS) patients than in the general population. OBJECTIVE: Describe instances of autoimmune nephropathy in alemtuzumab-treated MS patients. METHODS: Cases were identified from safety monitoring within the alemtuzumab relapsing-remitting multiple sclerosis (RRMS) clinical development program (CDP) or post-marketing, or following off-label use. RESULTS: As of 16 June 2017, 16 autoimmune nephropathies have occurred following alemtuzumab treatment for MS. The incidence of autoimmune nephropathies was 0.34% within the CDP (5/1485 patients). The five CDP cases (one of anti-glomerular basement membrane (anti-GBM) disease, two of membranous glomerulonephropathy, and two of serum anti-GBM antibody without typical anti-GBM disease) were identified early, responded to conventional therapy (where needed), and had favorable outcomes. Three of 11 cases outside the CDP occurred following off-label alemtuzumab use prior to approval for RRMS and were all anti-GBM disease. Diagnosis was delayed in one of these three cases and another did not receive appropriate treatment; all three cases resulted in end-stage renal failure. All anti-GBM disease cases with documented urinalysis demonstrated prior microscopic hematuria. CONCLUSION: Close monitoring of alemtuzumab-treated MS patients facilitates diagnosis and treatment early in the nephropathy course when preservation of renal function is more likely.

• Keywords
• Alemtuzumab, anti-glomerular basement membrane disease, disease-modifying therapy, membranous glomerulonephropathy, multiple sclerosis, nephropathy,
• MeSH
• Alemtuzumab adverse effects   MeSH
• Adult MeSH
• Glomerulonephritis chemically induced   diagnosis   epidemiology   immunology   MeSH
• Immunologic Factors adverse effects   MeSH
• Incidence MeSH
• Hemorrhage chemically induced   diagnosis   epidemiology   immunology   MeSH
• Humans MeSH
• Glomerulonephritis, Membranous chemically induced   diagnosis   epidemiology   immunology   MeSH
• Follow-Up Studies MeSH
• Lung Diseases chemically induced   diagnosis   epidemiology   immunology   MeSH
• Multiple Sclerosis, Relapsing-Remitting drug therapy   epidemiology   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Alemtuzumab MeSH
• Immunologic Factors MeSH

The introduction of high-efficacy therapies for relapsing-remitting multiple sclerosis has driven re-evaluation of treatment goals and benefit:risk considerations in treatment choice. In the alemtuzumab Phase II and III clinical trials, patients treated with alemtuzumab 12 mg versus subcutaneous interferon beta-1a demonstrated significantly reduced annualized relapse rates and improved magnetic resonance imaging outcomes, and were significantly more likely to achieve no evidence of disease activity and reduction in brain volume loss. In two of the studies, alemtuzumab-treated patients had a significantly reduced risk of 6-month confirmed disease worsening, compared with subcutaneous interferon beta-1a. Benefits were maintained throughout 5 years, with a majority of patients receiving no alemtuzumab retreatment or other disease-modifying therapy. Trial results support alemtuzumab's manageable, consistent safety profile in relapsing-remitting multiple sclerosis. Infusion-associated reactions, the most frequent adverse events (AEs), can be minimized by corticosteroid pretreatment, monitoring, and symptomatic management. Other AEs include infections and autoimmune events. Oral anti-herpes prophylaxis should be initiated on the first day of each alemtuzumab treatment course and continued according to local guidelines. Overall cancer risk was lower in the alemtuzumab clinical trials than in a reference population; however, continuing surveillance will determine if alemtuzumab may be associated with certain malignancies such as thyroid papillary carcinoma and melanoma, which are currently identified as potential risks. The post-approval risk management strategy includes a safety monitoring program. Autoimmune AEs (thyroid events, immune thrombocytopenia, nephropathies) can be detected in a timely manner with the monitoring program, which includes physician and patient education about the signs and symptoms, monthly renal and hematologic monitoring, and quarterly thyroid function monitoring for 48 months after the last alemtuzumab course. Education, vigilance by physicians and patients, and monthly laboratory monitoring are recommended to maintain alemtuzumab's positive benefit:risk profile.

• Keywords
• MRI outcomes, NEDA, alemtuzumab, annualized relapse rate, autoimmune event, infusion-associated reaction, multiple sclerosis, no evidence of disease activity, risk mitigation,
• Publication type
• Journal Article MeSH
• Review MeSH