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Multiple Sclerosis (Houndmills,... May 2020
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Cardiotoxicity; Humans; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting
PubMed: 32298205
DOI: 10.1177/1352458520913277 -
Neurological Sciences : Official... Sep 2022
Topics: Alemtuzumab; Humans; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Myelodysplastic Syndromes
PubMed: 35543831
DOI: 10.1007/s10072-022-06124-6 -
Multiple Sclerosis (Houndmills,... Jan 2020Alemtuzumab is a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS), and immune thrombocytopenia (ITP) has been identified as a risk. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Alemtuzumab is a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS), and immune thrombocytopenia (ITP) has been identified as a risk.
OBJECTIVE
To examine ITP incidence, treatment, and outcomes during the clinical development of alemtuzumab for RRMS and discuss postmarketing experience outside clinical trials.
METHODS
CAMMS223 and Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I and II investigated two annual courses of alemtuzumab 12 mg (or 24 mg in CAMMS223/CARE-MS II) versus subcutaneous interferon beta-1a three times per week. Patients completing core studies could enroll in an extension. Monthly monitoring for ITP continued until 48 months after the last alemtuzumab infusion.
RESULTS
Of 1485 alemtuzumab-treated MS patients in the clinical development program, 33 (2.2%) developed ITP (alemtuzumab 12 mg, 24 [2.0%]; alemtuzumab 24 mg, 9 [3.3%]) over median 6.1 years of follow-up after the first infusion; most had a sustained response to first-line ITP therapy with corticosteroids, platelets, and/or intravenous immunoglobulin. All cases occurred within 48 months of the last alemtuzumab infusion. Postmarketing surveillance data suggest that the ITP incidence is not higher in clinical practice than in clinical trials.
CONCLUSION
Alemtuzumab-associated ITP occurs in approximately 2% of patients and is responsive to therapy. Careful monitoring is key for detection and favorable outcomes.
Topics: Adult; Alemtuzumab; Female; Follow-Up Studies; Humans; Immunologic Factors; Incidence; Interferon beta-1a; Male; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Purpura, Thrombocytopenic, Idiopathic
PubMed: 30785358
DOI: 10.1177/1352458518816612 -
Le Infezioni in Medicina Jun 2020Few cases of complicated infections with Listeria monocytogenes (LM) have been reported to date in patients with multiple sclerosis (MS) treated with alemtuzumab.... (Review)
Review
Few cases of complicated infections with Listeria monocytogenes (LM) have been reported to date in patients with multiple sclerosis (MS) treated with alemtuzumab. Primary prevention strategies may be suggested in such patients to avoid infections. However, these may be ineffective because patients may already be carriers of LM. We report herein a case of bloodstream infection due to LM in a 25-year-old woman with MS treated with alemtuzumab. We searched the UMC/WHO Vigibase system for all reported cases of LM in patients treated with alemtuzumab and found 29 cases overall up to 21 July 2019. We also performed a literature review of MS cases with LM on alemtuzumab, in order to evaluate epidemiology, clinical characteristics, and outcome of this complication. Since the published cases (N=8) were mainly reported in recent years but more cases were found in the UMC/WHO Vigibase system (although not necessarily in patients with MS), we hypothesize that this complication is more frequent than currently believed and may become even more important in the future. Therefore, it is worth reaching a consensus on appropriate algorithms to stratify individuals by risk so as to implement targeted prevention strategies (whether primary or secondary).
Topics: Adult; Alemtuzumab; Female; Humans; Listeriosis; Multiple Sclerosis
PubMed: 32487792
DOI: No ID Found -
European Journal of Neurology Jan 2022Real-world data on alemtuzumab are limited and do not provide evidence of its effectiveness after various disease-modifying therapies (DMTs). Our aim was to provide...
BACKGROUND AND PURPOSE
Real-world data on alemtuzumab are limited and do not provide evidence of its effectiveness after various disease-modifying therapies (DMTs). Our aim was to provide real-world data on the impact of clinical variables and previous DMTs on clinical response to alemtuzumab.
METHODS
Sixteen Italian multiple sclerosis centers retrospectively included patients who started alemtuzumab from January 2015 to December 2018, and recorded demographics, previous therapies, washout duration, relapses, Expanded Disability Status Scale (EDSS) score, and magnetic resonance imaging data. Negative binomial regression models were used to assess the effect of factors on annualized relapse (ARR) after alemtuzumab initiation.
RESULTS
We studied 322 patients (mean age 36.8 years, median EDSS score 3, median follow-up 1.94 years). Previous treatments were: fingolimod (106), natalizumab (80), first-line oral agents (56), first-line injectables (interferon/glatiramer acetate; 30), and other drugs (15). Thirty-five patients were treatment-naïve. The pre-alemtuzumab ARR was 0.99 and decreased to 0.13 during alemtuzumab treatment (p < 0.001). The number of previous-year relapses was associated with alemtuzumab ARR (adjusted risk ratio [RR] 1.38, p = 0.009). Progression-free survival was 94.5% after 1 year, and 89.2% after 2 years of alemtuzumab treatment. EDSS score improvement occurred in 13.5% after 1 year, and 20.6% after 2 years. Re-baselining patients after 6 months of alemtuzumab treatment, led to no evidence of disease activity status in 71.6% after 1 year and 58.9% after 2 years.
CONCLUSIONS
Alemtuzumab decreases ARR independent of previous therapy, including patients with disease activity during natalizumab treatment. Overall, 90% of patients showed no disease progression, and 20% an improvement after 2 years of alemtuzumab.
Topics: Adult; Alemtuzumab; Fingolimod Hydrochloride; Glatiramer Acetate; Humans; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Retrospective Studies
PubMed: 34558755
DOI: 10.1111/ene.15121 -
Multiple Sclerosis and Related Disorders Apr 2021Alemtuzumab significantly improved clinical and MRI outcomes vs. subcutaneous interferon beta-1a (SC IFNB-1a) in the CARE-MS trials (NCT00530348, NCT00548405), with...
BACKGROUND
Alemtuzumab significantly improved clinical and MRI outcomes vs. subcutaneous interferon beta-1a (SC IFNB-1a) in the CARE-MS trials (NCT00530348, NCT00548405), with sustained efficacy in 2 consecutive extensions (NCT00930553, NCT02255656 [TOPAZ]).
METHODS
Post hoc analysis of 8-year alemtuzumab efficacy and safety in pooled CARE-MS patients (N=811) stratified by baseline age (≥18 to ≤25, >25 to ≤35, >35 to ≤45, >45 to ≤55 years).
RESULTS
Compared with SC IFNB-1a over 2 years across age cohorts, alemtuzumab lowered annualized relapse rates (ARR; 0.22-0.24 vs. 0.38-0.51), improved or stabilized disability (freedom from 6-month confirmed disability worsening [CDW]: 85%-92% vs. 62%-88%; achievement of 6-month confirmed disability improvement [CDI]: 20%-31% vs. 13%-25%), increased proportions free of MRI disease activity (70%-86% vs. 42%-63% per year), and slowed brain volume loss (BVL; -0.45% to -0.87% vs. -0.50% to -1.39%). Through Year 2, the treatment effect with alemtuzumab did not significantly differ among age groups for ARR (p-interaction=0.6325), 6-month CDW-free (p-interaction=0.4959), 6-month CDI (p-interaction=0.9268), MRI disease activity-free (p-interaction=0.6512), and BVL (p-interaction=0.4970). Alemtuzumab remained effective on outcomes through Year 8 across age groups. Age-related increases in malignancies (≤45 years: 0.9%-2.2% vs. >45 years: 8.1%) and deaths (0%-1.7% vs. 7.0%) were observed. Serious infections also increased from the youngest (5.1%) to oldest (12.8%) age cohorts.
CONCLUSIONS
Alemtuzumab had greater efficacy than SC IFNB-1a over 2 years across comparable age groups, with no significant differences between alemtuzumab-treated age groups. Efficacy on relapse, disability, and MRI outcomes continued through Year 8 across age groups. Age-related increases in serious infections, malignancies, and deaths were observed.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Child; Humans; Interferon beta-1a; Middle Aged; Multiple Sclerosis, Relapsing-Remitting; Treatment Outcome
PubMed: 33476880
DOI: 10.1016/j.msard.2020.102717 -
Nature Communications Apr 2022T-cell large granular lymphocyte leukemia (T-LGLL) is a lymphoproliferative disease and bone marrow failure syndrome which responds to immunosuppressive therapies. We...
T-cell large granular lymphocyte leukemia (T-LGLL) is a lymphoproliferative disease and bone marrow failure syndrome which responds to immunosuppressive therapies. We show single-cell TCR coupled with RNA sequencing of CD3 T cells from 13 patients, sampled before and after alemtuzumab treatments. Effector memory T cells and loss of T cell receptor (TCR) repertoire diversity are prevalent in T-LGLL. Shared TCRA and TCRB clonotypes are absent. Deregulation of cell survival and apoptosis gene programs, and marked downregulation of apoptosis genes in CD8 clones, are prominent features of T-LGLL cells. Apoptosis genes are upregulated after alemtuzumab treatment, especially in responders than non-responders; baseline expression levels of apoptosis genes are predictive of hematologic response. Alemtuzumab does not attenuate TCR clonality, and TCR diversity is further skewed after treatment. Inferences made from analysis of single cell data inform understanding of the pathophysiologic mechanisms of clonal expansion and persistence in T-LGLL.
Topics: Alemtuzumab; Clone Cells; Humans; Leukemia, Large Granular Lymphocytic; Receptors, Antigen, T-Cell; Sequence Analysis, RNA
PubMed: 35411048
DOI: 10.1038/s41467-022-29175-x -
Journal of Neuroimmunology Dec 2021We aimed to determine whether Alemtuzumab-induced immune reconstitution affects immunoglobulin and complement levels in the serum of Relapsing-Remitting Multiple...
We aimed to determine whether Alemtuzumab-induced immune reconstitution affects immunoglobulin and complement levels in the serum of Relapsing-Remitting Multiple Sclerosis (RRMS) patients. IgG4-levels were increased 24-months after treatment initiation compared to baseline levels in twenty-nine patients. Alemtuzumab-treated patients with the highest IgG4-levels were more prone to thyroid-related autoimmune manifestations and specific autoimmune adverse events such as Crohn's disease, Graves' disease, and hemolytic anemia. Compared to baseline, total IgG-levels showed a trend towards reduced levels following two-courses of Alemtuzumab, but no significant change of C3 and/or C4-levels was observed. In conclusion, monitoring of IgG4-levels can serve as a marker for secondary autoimmunity risk in multiple sclerosis patients treated with Alemtuzumab.
Topics: Adult; Alemtuzumab; Autoantibodies; Autoimmune Diseases of the Nervous System; Biomarkers; Complement System Proteins; Female; Graves Disease; Humans; Immune Reconstitution; Immunoglobulin G; Infections; Lymphocyte Count; Male; Multiple Sclerosis, Relapsing-Remitting; Retrospective Studies; Young Adult
PubMed: 34742035
DOI: 10.1016/j.jneuroim.2021.577759 -
The Neurologist Jul 2023Cerebral vasculitides are often devastating conditions that require immediate diagnosis and treatment. (Review)
Review
INTRODUCTION
Cerebral vasculitides are often devastating conditions that require immediate diagnosis and treatment.
CASE REPORT
We report a pathologically proven clinical case of primary central nervous system vasculitis in a 50-year-old man with a diagnosis of relapsing-remitting multiple sclerosis after alemtuzumab therapy, which required additional immunosuppression to control this life-threatening condition.
CONCLUSION
In patients presenting subacute neurological deterioration after alemtuzumab therapy, primary central nervous system vasculitis should be considered as a differential diagnosis among other autoimmune conditions.
Topics: Male; Humans; Middle Aged; Alemtuzumab; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Diagnosis, Differential; Immunosuppression Therapy
PubMed: 36728655
DOI: 10.1097/NRL.0000000000000480 -
Journal of Molecular Graphics &... Sep 2021Specific antibody-antigen recognition is crucial for the immune response. Knowledge of molecular interaction details in the recognition process is fundamental for the...
Specific antibody-antigen recognition is crucial for the immune response. Knowledge of molecular interaction details in the recognition process is fundamental for the rational design of antibodies with improved properties. We used state-of-the-art computer simulation tools to deepen the molecular-level understanding of the interactions between the monoclonal antibody Alemtuzumab and its antigen, the CD52 membrane receptor, of great biotechnological importance. Thus, we seek such responses by modeling the interaction of native and known mutants single-chain fragment variable (scFv) of Alemtuzumab with CD52 inserted in a membrane model to mimic the physiological conditions of antibody-antigen binding. Extensive molecular dynamics simulations of the interaction between Alemtuzumab's scFvs and CD52 promoted greater understanding of the structural and energetic bases, which can be translated into the biological action and affinity of this antibody. The quantification of the scFv-CD52 complexes binding free energy (ΔG) by Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) correlated with the experimental binding energies described before. Thus, the mutants D53K, K54D, and K56D resulted in less attractive ΔG, therefore lower scFv-CD52 affinity than the native scFv. On the other hand, K56D and K54D/K56D showed lower binding to CD52. These Results revealed that the model system mimicking an environment close to the physiological with the presence of the CD52 in a membrane model proved essential for this system's study. The present study allowed to unveil the molecular mechanisms involved in antigen-antibody interaction and the effects of mutations. Thus, these mechanisms may be explored in the Alemtuzumab variants' rational design with enhanced properties.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Antigens, CD; Antigens, Neoplasm; CD52 Antigen; Glycoproteins; Molecular Dynamics Simulation; Single-Chain Antibodies
PubMed: 34089985
DOI: 10.1016/j.jmgm.2021.107949