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The Journal of Clinical Endocrinology... Jan 2024Atypical Graves disease (GD) is a common complication in multiple sclerosis (MS) patients treated with alemtuzumab. We present epidemiological, clinical, and biochemical...
OBJECTIVE
Atypical Graves disease (GD) is a common complication in multiple sclerosis (MS) patients treated with alemtuzumab. We present epidemiological, clinical, and biochemical characteristics of alemtuzumab-induced GD.
METHODS
Retrospective follow-up study of MS patients treated with alemtuzumab from 2014 to 2020, including clinical course of GD, pregnancy outcome, and thyroid eye disease (TED).
RESULTS
We enrolled 183 of 203 patients (90%, 68% women) treated with alemtuzumab at 4 hospitals in Norway. Seventy-five (41%) developed thyroid dysfunction, of whom 58 (77%) had GD. Median time from the first dose of alemtuzumab to GD diagnosis was 25 months (range, 0-64). Twenty-four of 58 GD patients (41%) had alternating phases of hyper- and hypothyroidism. Thyrotropin receptor antibodies became undetectable in 23 of 58 (40%) and they could discontinue antithyroid drug treatment after a median of 22 (range, 2-58) months. Conversely, 26 (44%) had active disease during a median follow-up of 39 months (range, 11-72). Two patients (3%) received definitive treatment with radioiodine, 6 (10%) with thyroidectomy. Nine developed TED (16%), 7 had mild and 2 moderate to severe disease. Four patients completed pregnancy, all without maternal or fetal complications. Patients who developed GD had a lower frequency of new MS relapses and MRI lesions than those without.
CONCLUSION
GD is a very common complication of alemtuzumab treatment and is characterized by alternating hyper- and hypothyroidism. Both remission rates and the prevalence of TED were lower than those reported for conventional GD. Pregnancies were uncomplicated and GD was associated with a lower risk of subsequent MS activity.
Topics: Humans; Female; Pregnancy; Male; Alemtuzumab; Retrospective Studies; Iodine Radioisotopes; Prevalence; Follow-Up Studies; Graves Disease; Multiple Sclerosis; Hypothyroidism; Graves Ophthalmopathy; Risk Factors
PubMed: 37708353
DOI: 10.1210/clinem/dgad540 -
Blood Advances Jul 2023Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is...
Overall survival after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using alemtuzumab, fludarabine, and melphalan is associated with high rates of mixed chimerism (MC) and secondary graft failure (GF). We hypothesized that peritransplantation alemtuzumab levels or specific patterns of inflammation would predict these risks. We assessed samples from the Bone Marrow Transplant Clinical Trials Network 1204 (NCT01998633) to study the impact of alemtuzumab levels and cytokine patterns on MC and impending or established secondary GF (defined as donor chimerism <5% after initial engraftment and/or requirement of cellular intervention). Thirty-three patients with hemophagocytic lymphohistiocytosis (n = 25) and other IEIs (n = 8) who underwent HCTs with T-cell-replete grafts were included. Patients with day 0 alemtuzumab levels ≤0.32 μg/mL had a markedly lower incidence of MC, 14.3%, vs 90.9% in patients with levels >0.32 μg/mL (P = .008). Impending or established secondary GF was only observed in patients with day 0 alemtuzumab levels >0.32 μg/mL (P = .08). Unexpectedly, patients with impending or established secondary GF had lower CXCL9 levels. The cumulative incidence of impending or established secondary GF in patients with a day 14+ CXCL9 level ≤2394 pg/mL (day 14+ median) was 73.6% vs 0% in patients with a level >2394 pg/mL (P = .002). CXCL9 levels inversely correlated with alemtuzumab levels. These data suggest a model in which higher levels of alemtuzumab at day 0 deplete donor T cells, inhibit the graft-versus-marrow reaction (thereby suppressing CXCL9 levels), and adversely affect sustained engraftment in the nonmyeloablative HCT setting. This trial was registered at www.clinicaltrials.gov as #NCT01998633.
Topics: Humans; Alemtuzumab; Antibodies, Monoclonal, Humanized; Melphalan; Hematopoietic Stem Cell Transplantation; Tissue Donors; Chemokine CXCL9
PubMed: 37042921
DOI: 10.1182/bloodadvances.2022009478 -
Multiple Sclerosis and Related Disorders Jun 2021The SARS-CoV-2 pandemic impact on people with Multiple Sclerosis (pwMS) continues to worry. The disease modifying therapies in pwMS can add a more severe risk of...
BACKGROUND
The SARS-CoV-2 pandemic impact on people with Multiple Sclerosis (pwMS) continues to worry. The disease modifying therapies in pwMS can add a more severe risk of infection when compared to the general population. Alemtuzumab is an anti-CD52 monoclonal antibody and it is one of the most immunosuppressive drugs used in Multiple Sclerosis (MS).
CASE DESCRIPTION
We present a case of Covid-19 infection that occurred in a 24-year-old woman with MS and treated with alemtuzumab. The infection occurred 4 months after administration of the first course of alemtuzumab and had a benign course with subsequent development of antibodies. Furthermore, we present a brief review of the literature on similar published cases.
DISCUSSION
We reviewed 17 articles concerning COVID-19 infection in MS patients in treatment with Alemtuzumab. In our case and all screened cases no severe course of disease was noted and no fatality was observed. Systematic compilation of this observation comforts clinicians about the course of Covid-19 infection despite alemtuzumab immunosuppressive treatment CONCLUSIONS: The risk of serious COVID-19 disease in MS patients treated with alemtuzumab is unknown. Physicians need to monitor carefully pwMS treated with alemtuzumab and to consider COVID-19 infection related relapse in the MS patients. Further research is recommended to evaluate the beneficial-risk profile of alemtuzumab in pandemic era.
Topics: Adult; Alemtuzumab; COVID-19; Female; Humans; Multiple Sclerosis; Pandemics; SARS-CoV-2; Young Adult
PubMed: 33812222
DOI: 10.1016/j.msard.2021.102908 -
Frontiers in Immunology 2022Development of disease-modifying therapies including monoclonal antibody (mAb)-based therapeutics for the treatment of multiple sclerosis (MS) has been extremely... (Review)
Review
Development of disease-modifying therapies including monoclonal antibody (mAb)-based therapeutics for the treatment of multiple sclerosis (MS) has been extremely successful over the past decades. Most of the mAb-based therapies approved for MS deplete immune cell subsets and act through activation of cellular Fc-gamma receptors expressed by cytotoxic lymphocytes and phagocytes, resulting in antibody-dependent cellular cytotoxicity or by initiation of complement-mediated cytotoxicity. The therapeutic goal is to eliminate pathogenic immune cell components and to potentially foster the reconstitution of a new and healthy immune system. Ab-mediated immune cell depletion therapies include the CD52-targeting mAb alemtuzumab, CD20-specific therapeutics, and new Ab-based treatments which are currently being developed and tested in clinical trials. Here, we review recent developments in effector mechanisms and clinical applications of Ab-based cell depletion therapies, compare their immunological and clinical effects with the prototypic immune reconstitution treatment strategy, autologous hematopoietic stem cell transplantation, and discuss their potential to restore immunological tolerance and to achieve durable remission in people with MS.
Topics: Alemtuzumab; Antibodies, Monoclonal; Antigens, CD20; Humans; Immunotherapy; Multiple Sclerosis
PubMed: 36172350
DOI: 10.3389/fimmu.2022.953649 -
International Journal of Molecular... Jul 2015Alemtuzumab is a humanized monoclonal antibody against CD52 (cluster of differentiation 52) and is approved for the therapy of relapsing-remitting multiple sclerosis.... (Review)
Review
Alemtuzumab is a humanized monoclonal antibody against CD52 (cluster of differentiation 52) and is approved for the therapy of relapsing-remitting multiple sclerosis. The application of alemtuzumab leads to a rapid, but long-lasting depletion predominantly of CD52-bearing B and T cells with reprogramming effects on immune cell composition resulting in the restoration of tolerogenic networks. Alemtuzumab has proven high efficacy in clinical phase II and III trials, where interferon β-1a was used as active comparator. However, alemtuzumab is associated with frequent and considerable risks. Most importantly secondary autoimmune disease affects 30%-40% of patients, predominantly impairing thyroid function. Extensive monitoring and early intervention allow for an appropriate risk management. However, new and reliable biomarkers for individual risk stratification and treatment response to improve patient selection and therapy guidance are a significant unmet need. Only a deeper understanding of the underlying mechanisms of action (MOA) will reveal such markers, maximizing the best potential risk-benefit ratio for the individual patient. This review provides and analyses the current knowledge on the MOA of alemtuzumab. Most recent data on efficacy and safety of alemtuzumab are presented and future research opportunities are discussed.
Topics: Alemtuzumab; Animals; Antibodies, Monoclonal, Humanized; Clinical Trials as Topic; Humans; Multiple Sclerosis
PubMed: 26204829
DOI: 10.3390/ijms160716414 -
Cold Spring Harbor Perspectives in... Oct 2018Alemtuzumab, the first monoclonal antibody to be used as a therapy and the first to be humanized, was introduced into the treatment of multiple sclerosis in 1991 after... (Review)
Review
Alemtuzumab, the first monoclonal antibody to be used as a therapy and the first to be humanized, was introduced into the treatment of multiple sclerosis in 1991 after its successful use in hematology, oncology, and transplantation medicine. One phase 2 and two phase 3 trials of this lymphocyte-depleting agent have established alemtuzumab's superior efficacy to interferon β-1a over the short term (2-3 years) with greater relapse rate reduction, reduced accumulation of disability, and more frequent sustained improvement in disability. Longer-term extension studies show durable effects on slowing cerebral atrophy over 6 years and maintained low relapse rates over 10 years, despite roughly half of patients not needing further dosing. Homeostatic proliferation of residual T cells after alemtuzumab-induced lymphopenia is probably responsible for its most common side effects: secondary autoimmunity 1 or 2 years after the last infusion of alemtuzumab affecting the thyroid gland (30% of patients), platelets (1%), or renal glomeruli (0.1%). With the prerequisite of patient and physician adherence to a prolonged safety-monitoring protocol, alemtuzumab offers durable high efficacy from infrequent dosing.
Topics: Alemtuzumab; Humans; Multiple Sclerosis, Relapsing-Remitting; Secondary Prevention
PubMed: 29500306
DOI: 10.1101/cshperspect.a032029 -
Problemy Endokrinologii Jun 2023Multiple sclerosis (MS) is a severe chronic autoimmune demyelinating disease of the central nervous system, mediated by Th1/Th17 lymphocytes as well as B lymphocytes,...
Multiple sclerosis (MS) is a severe chronic autoimmune demyelinating disease of the central nervous system, mediated by Th1/Th17 lymphocytes as well as B lymphocytes, macrophages and other immune cells. Some patients with MS are treated with alemtuzumab, a monoclonal antibody against CD52+ cells, which belongs to the disease-modifying therapies (DMTs). The main effect of alemtuzumab is related to changes in immune recruitment. Alemtuzumab therapy can induce secondary autoimmunity against the background of immune rebalancing. The thyroid gland is generally involved in the autoimmune process. Graves' disease (GD) develops most often, followed by autoimmune thyroiditis.We present a clinical case of a patient with GD developed after alemtuzumab therapy for MS. The patient was referred to a radiologist at the Department of Radionuclide Therapy of Endocrinology Research Centre for radioiodine therapy (RAIT) due to relapse of thyrotoxicosis after anti-thyroid drug therapy for GD. The goal of treatment was achieved in 2 months, thyroid hormone therapy was initiated, against the background of this, there was compensation of thyroid function.
Topics: Humans; Alemtuzumab; Iodine Radioisotopes; Neoplasm Recurrence, Local; Graves Disease; Multiple Sclerosis
PubMed: 37448247
DOI: 10.14341/probl13238 -
Brain : a Journal of Neurology Jun 2022Alemtuzumab is a monoclonal antibody that causes rapid depletion of CD52-expressing immune cells. It has proven to be highly efficacious in active relapsing-remitting...
Alemtuzumab is a monoclonal antibody that causes rapid depletion of CD52-expressing immune cells. It has proven to be highly efficacious in active relapsing-remitting multiple sclerosis; however, the high risk of secondary autoimmune disorders has greatly complicated its use. Thus, deeper insight into the pathophysiology of secondary autoimmunity and potential biomarkers is urgently needed. The most critical time points in the decision-making process for alemtuzumab therapy are before or at Month 12, where the ability to identify secondary autoimmunity risk would be instrumental. Therefore, we investigated components of blood and CSF of up to 106 multiple sclerosis patients before and after alemtuzumab treatment focusing on those critical time points. Consistent with previous reports, deep flow cytometric immune-cell profiling (n = 30) demonstrated major effects on adaptive rather than innate immunity, which favoured regulatory immune cell subsets within the repopulation. The longitudinally studied CSF compartment (n = 18) mainly mirrored the immunological effects observed in the periphery. Alemtuzumab-induced changes including increased numbers of naïve CD4+ T cells and B cells as well as a clonal renewal of CD4+ T- and B-cell repertoires were partly reminiscent of haematopoietic stem cell transplantation; in contrast, thymopoiesis was reduced and clonal renewal of T-cell repertoires after alemtuzumab was incomplete. Stratification for secondary autoimmunity did not show clear immununological cellular or proteomic traits or signatures associated with secondary autoimmunity. However, a restricted T-cell repertoire with hyperexpanded T-cell clones at baseline, which persisted and demonstrated further expansion at Month 12 by homeostatic proliferation, identified patients developing secondary autoimmune disorders (n = 7 without secondary autoimmunity versus n = 5 with secondary autoimmunity). Those processes were followed by an expansion of memory B-cell clones irrespective of persistence, which we detected shortly after the diagnosis of secondary autoimmune disease. In conclusion, our data demonstrate that (i) peripheral immunological alterations following alemtuzumab are mirrored by longitudinal changes in the CSF; (ii) incomplete T-cell repertoire renewal and reduced thymopoiesis contribute to a proautoimmune state after alemtuzumab; (iii) proteomics and surface immunological phenotyping do not identify patients at risk for secondary autoimmune disorders; (iv) homeostatic proliferation with disparate dynamics of clonal T- and B-cell expansions are associated with secondary autoimmunity; and (v) hyperexpanded T-cell clones at baseline and Month 12 may be used as a biomarker for the risk of alemtuzumab-induced autoimmunity.
Topics: Alemtuzumab; Autoimmune Diseases; Autoimmunity; Humans; Phenotype; Proteomics
PubMed: 35661859
DOI: 10.1093/brain/awac064 -
The Journal of Allergy and Clinical... May 2022Treatment of hypereosinophilic syndrome (HES) often requires the use of immunomodulators with substantial side effect profiles. The emergence of biologics offers an...
BACKGROUND
Treatment of hypereosinophilic syndrome (HES) often requires the use of immunomodulators with substantial side effect profiles. The emergence of biologics offers an alternative treatment modality.
OBJECTIVE
To examine real-world practice data to describe the safety and consequences of various biologics suspected to directly or indirectly affect eosinophilic inflammation for the treatment of HES.
METHODS
Retrospective data from 13 centers were collected via an online Research Electronic Data Capture repository. Inclusion criteria included (1) peripheral eosinophil count of 1,500/mm or greater without a secondary cause; (2) clinical manifestations attributable to the eosinophilia; and (3) having received mepolizumab (anti-IL-5), benralizumab (afucosylated anti-IL-5 receptor α), omalizumab (anti-IgE), alemtuzumab (anti-CD52), dupilumab (anti-IL-4 receptor α), or reslizumab (anti-IL-5) outside a placebo-controlled clinical trial.
RESULTS
Of the 151 courses of biologics prescribed for 121 patients with HES, 59% resulted in improved HES symptoms and 77% enabled tapering of other HES medications. Overall, 105 patients were receiving daily systemic glucocorticoids at the time of a biologic initiation and were able to reduce the glucocorticoid dose by a median reduction of 10 mg of daily prednisone equivalents. Biologics were generally safe and well-tolerated other than infusion reactions with alemtuzumab. Thirteen of 24 patients had clinical improvement after switching biologics and nine patients responded to increasing the dose of mepolizumab after a lack of response to a lower dose.
CONCLUSIONS
Biologics may offer a safer treatment alternative to existing therapies for HES, although the optimal dosing and choice for each subtype of HES remain to be determined. Limitations of this study include its retrospective nature and intersite differences in data collection and availability of each biologic.
Topics: Alemtuzumab; Biological Products; Glucocorticoids; Humans; Hypereosinophilic Syndrome; Interleukin-5; Off-Label Use; Retrospective Studies
PubMed: 35181548
DOI: 10.1016/j.jaip.2022.02.006 -
Frontiers in Immunology 2023Lymphodepletion (LD) or conditioning is an essential step in the application of currently used autologous and allogeneic chimeric antigen receptor T-cell (CAR-T)... (Review)
Review
Lymphodepletion (LD) or conditioning is an essential step in the application of currently used autologous and allogeneic chimeric antigen receptor T-cell (CAR-T) therapies as it maximizes engraftment, efficacy and long-term survival of CAR-T. Its main modes of action are the depletion and modulation of endogenous lymphocytes, conditioning of the microenvironment for improved CAR-T expansion and persistence, and reduction of tumor load. However, most LD regimens provide a broad and fairly unspecific suppression of T-cells as well as other hematopoietic cells, which can also lead to severe side effects, particularly infections. We reviewed 1271 published studies (2011-2023) with regard to current LD strategies for approved anti-CD19 CAR-T products for large B cell lymphoma (LBCL). Fludarabine (Flu) and cyclophosphamide (Cy) (alone or in combination) were the most commonly used agents. A large number of different schemes and combinations have been reported. In the respective schemes, doses of Flu and Cy (range 75-120mg/m2 and 750-1.500mg/m2) and wash out times (range 2-5 days) differed substantially. Furthermore, combinations with other agents such as bendamustine (benda), busulfan or alemtuzumab (for allogeneic CAR-T) were described. This diversity creates a challenge but also an opportunity to investigate the impact of LD on cellular kinetics and clinical outcomes of CAR-T. Only 21 studies explicitly investigated in more detail the influence of LD on safety and efficacy. As Flu and Cy can potentially impact both the activity and toxicity of CAR-T, a more detailed analysis of LD outcomes will be needed before we are able to fully assess its impact on different T-cell subsets within the CAR-T product. The T2EVOLVE consortium propagates a strategic investigation of LD protocols for the development of optimized conditioning regimens.
Topics: Receptors, Chimeric Antigen; Adaptor Proteins, Signal Transducing; Alemtuzumab; Antibodies; Cyclophosphamide; Cell- and Tissue-Based Therapy
PubMed: 38187393
DOI: 10.3389/fimmu.2023.1303935