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The International Journal of... Mar 2019Sporadic inclusion body myositis is the most common inflammatory myopathy over the age of 50. The aetiopathogenesis of the disease remains unclear and to the day there... (Review)
Review
BACKGROUND
Sporadic inclusion body myositis is the most common inflammatory myopathy over the age of 50. The aetiopathogenesis of the disease remains unclear and to the day there is no effective treatment.
OBJECTIVES
The aim of the present review is to present the latest data on the new insights and developments in the treatment of sporadic inclusion body myositis, focusing on Bimagrumab and Alemtuzumab.
METHODS
For the purpose of the review we searched multiple internet databases in order to find the most recent studies and clinical trials on the safety, tolerability and efficacy of Bimagrumab and Alemtuzumab in sporadic inclusion body myositis.
RESULTS
We found four trials on Bimagrumab, with one of them being an extension phase III study, and one small series trial on Alemtuzumab. The first clincopathological trial on Bimagrumab showed promising evidence, which were partially confirmed by the double-blinded controlled multicentre trial, however the primary endpoint of improving 6-m walking distance or improving the muscle strength has not been reached. The evidence from the Alemtuzumab trial was also promising, but the risk of bias of the study was relatively high, because it was open labelled, the number of patient was low and the yearly disease progression was much higher than in other recent studies.
CONCLUSIONS
Although both Bimagrumab and Alemtuzumab were well tolerated and showed promising results, the Bimagrumab trial did not reach the primary endpoint, and the Alemtuzumab trial has a relatively high risk of bias and the results need to be interpreted with caution.
Topics: Alemtuzumab; Antibodies, Blocking; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Humans; Immunologic Factors; Myositis, Inclusion Body
PubMed: 30238817
DOI: 10.1080/00207454.2018.1527329 -
Frontiers in Immunology 2022Induction therapy is used in about 80% of lung transplant centers and is increasing globally. Currently, there are no standards or guidelines for the use of induction...
BACKGROUND
Induction therapy is used in about 80% of lung transplant centers and is increasing globally. Currently, there are no standards or guidelines for the use of induction therapy. At our institution, we have two induction strategies, basiliximab, and alemtuzumab. The goal of this manuscript is to share our experience and practice since this is an area of controversy.
METHODS
We retrospectively reviewed 807 lung transplants performed at our institution between 2011 and 2020. Indications for the use of the basiliximab protocol were as follows: patients over the age of 70 years, history of cancer, hepatitis C virus or human immunodeficiency virus infection history, and cytomegalovirus or Epstein-Barr virus (donor positive/ recipient negative). In the absence of these clinical factors, the alemtuzumab protocol was used.
RESULTS
453 patients underwent alemtuzumab induction and 354 patients underwent basiliximab. There were significant differences in delayed chest closure (24.7% alemtuzumab vs 31.4% basiliximab, p = 0.037), grade 3 primary graft dysfunction observed within 72 hours (19.9% alemtuzumab vs 29.9% basiliximab, p = 0.002), postoperative hepatic dysfunction (8.8% alemtuzumab vs 14.7% basiliximab, p = 0.009), acute cellular rejection in first year (39.1% alemtuzumab vs 53.4% basiliximab, p < 0.001). The overall survival rate of the patients with alemtuzumab induction was significantly higher than those of the patients with basiliximab induction (5 years survival rate: 64.1% alemtuzumab vs 52.3%, basiliximab, p < 0.001). Multivariate Cox regression analysis confirmed lower 5-year survival for basiliximab induction (HR = 1.41, p = 0.02), recipient cytomegalovirus positive (HR = 1.49, p = 0.01), postoperative hepatic dysfunction (HR = 2.20, p < 0.001), and acute kidney injury requiring renal replacement therapy (HR = 2.27, p < 0.001).
CONCLUSIONS
In this single center retrospective review, there was a significant difference in survival rates between induction strategies. This outcome may be attributable to differences in recipient characteristics between the groups. However, the Alemtuzumab group experienced less episodes of acute cellular rejection within the first year.
Topics: Aged; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Basiliximab; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Lung Transplantation; Retrospective Studies
PubMed: 35720296
DOI: 10.3389/fimmu.2022.864545 -
Zhurnal Nevrologii I Psikhiatrii Imeni... 2020Multiple sclerosis is a central nervous system disease with autoimmune and neurodegenerative mechanisms of development. This disease can lead to severe disability and... (Review)
Review
Multiple sclerosis is a central nervous system disease with autoimmune and neurodegenerative mechanisms of development. This disease can lead to severe disability and neurological defects. Although its etiology and pathogenesis remain unclear, research data show that multiple sclerosis is a multifactorial disease, the development of which depends on environmental factors, as well as a genetic predisposition. The impact of these factors lead to the death of neural cells, accompanied by demyelination of nerves and neuronal dysfunction. Therapy of multiple sclerosis is based on the use of anti-inflammatory and immunomodulating substances, however, there are certain disadvantages associated with the constant use of these drugs and a possible change in dosage over time. This review discusses the pathogenesis of multiple sclerosis and the role of various subpopulations of immune cells in the development of diseases, as well as existing approaches to therapy. It is noted that immunoreconstitution therapy has advantages over immunomodulation and immunosuppression maintenance therapy for some patients. Thus, short courses of therapy provide more adequate treatment for patients and lower risks of adverse events associated with chronic immunosuppression. The review also discusses the data of clinical studies on the immunoreconstitution therapy drugs, such as alemtuzumab, ocrelizumab and cladribine. It is noted that nowadays the exact mechanisms underlying this type of therapy remain unclear. In this regard, further studies are needed to explain the therapeutic effects. It is assumed that patients with a high risk of multiple sclerosis progression are the optimal group of patients for the early use of selective immunoreconstitution therapy. Thus, immunoreconstitution therapy may be the treatment of choice for many patients with highle active multiple sclerosis.
Topics: Alemtuzumab; Cladribine; Disease Progression; Humans; Multiple Sclerosis
PubMed: 32307419
DOI: 10.17116/jnevro2020120021103 -
Therapeutic Drug Monitoring Aug 2017Multiple sclerosis is a heterogenous disease. Although several EMA-approved disease-modifying treatments including biopharmaceuticals are available, their efficacy is... (Review)
Review
Multiple sclerosis is a heterogenous disease. Although several EMA-approved disease-modifying treatments including biopharmaceuticals are available, their efficacy is limited, and a certain percentage of patients are always nonresponsive. Drug efficacy monitoring is an important tool to identify these nonresponsive patients early on. Currently, detection of antidrug antibodies and quantification of biological activity are used as methods of efficacy monitoring for interferon beta and natalizumab therapies. For natalizumab and alemtuzumab treatments, drug level quantification could be an essential component of the overall disease management. Thus, utilization and development of strategies to determine treatment response are vital aspects of multiple sclerosis management given the tremendous clinical and economic promise of this tool.
Topics: Alemtuzumab; Animals; Antibodies, Monoclonal, Humanized; Biological Factors; Drug Monitoring; Humans; Immunosuppressive Agents; Interferon-beta; Multiple Sclerosis; Treatment Outcome
PubMed: 28328761
DOI: 10.1097/FTD.0000000000000393 -
Neurology Feb 2024It is not possible to fully establish the safety of a disease-modifying drug (DMD) for multiple sclerosis (MS) from randomized controlled trials as only very common...
BACKGROUND AND OBJECTIVES
It is not possible to fully establish the safety of a disease-modifying drug (DMD) for multiple sclerosis (MS) from randomized controlled trials as only very common adverse events occurring over the short-term can be captured, and the quality of reporting has been variable. We examined the relationship between the DMDs for MS and potential adverse events in a multiregion population-based study.
METHODS
We identified people with MS using linked administrative health data from 4 Canadian provinces. MS cases were followed from the most recent of first MS or related demyelinating disease event on January 1, 1996, until the earliest of emigration, death, or December 31, 2017. DMD exposure primarily comprised β-interferon, glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, teriflunomide, and alemtuzumab. We examined associations between DMD exposure and infection-related hospitalizations and physician visits using recurrent events proportional means models and between DMD exposure and 15 broad categories of incident adverse events using stratified multivariate Cox proportional hazard models.
RESULTS
We identified 35,894 people with MS. While virtually all DMDs were associated with a 42%-61% lower risk of infection-related hospitalizations, there was a modest increase in infection-related physician visits by 10%-33% for select DMDs. For incident adverse events, most elevated risks involved a second-generation DMD, with alemtuzumab's hazard of thyroid disorders being 19.42 (95% CI 9.29-36.51), hypertension 4.96 (95% CI 1.78-13.84), and cardiovascular disease 3.72 (95% CI 2.12-6.53). Natalizumab's highest risk was for cardiovascular disease (adjusted hazard ratio [aHR] 1.61; 95% CI 1.24-2.10). For the oral DMDs, fingolimod was associated with higher hazards of cerebrovascular (aHR 2.04; 95% CI 1.27-3.30) and ischemic heart diseases (aHR 1.64; 95% CI 1.10-2.44) and hypertension (aHR 1.73; 95% CI 1.30-2.31); teriflunomide with higher hazards of thyroid disorders (aHR 2.30; 95% CI 1.11-4.74), chronic liver disease (aHR 1.94; 95% CI 1.19-3.18), hypertension (aHR 1.76; 95% CI 1.32-2.37), and hyperlipidemia (aHR 1.61; 95% CI 1.07-2.44); and from complementary analyses (in 1 province), dimethyl fumarate with acute liver injury (aHR 6.55; 95% CI 1.96-21.87).
DISCUSSION
Our study provides an extensive safety profile of several different DMDs used to treat MS in the real-world setting. Our findings not only complement those observed in short-term clinical trials but also provide new insights that help inform the risk-benefit profile of the DMDs used to treat MS in clinical practice. The results of this study highlight the continued need for long-term, independent safety studies of the DMDs used to treat MS.
CLASSIFICATION OF EVIDENCE
This study provides Class III evidence that for patients with MS, while DMD exposure reduces the risk of infection-related hospitalizations, there are increased risks of infection-related physician visits and incident adverse events for select DMDs.
Topics: Humans; Multiple Sclerosis; Natalizumab; Alemtuzumab; Canada; Cardiovascular Diseases; Dimethyl Fumarate; Fingolimod Hydrochloride; Hypertension
PubMed: 38181306
DOI: 10.1212/WNL.0000000000208006 -
Cells Jun 2020Alemtuzumab is a monoclonal antibody that binds to CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes... (Review)
Review
Alemtuzumab is a monoclonal antibody that binds to CD52, a protein present on the surface of mature lymphocytes, but not on the stem cells from which these lymphocytes are derived. It is currently used as an immune reconstitution therapy in patients with relapsing-remitting multiple sclerosis. Alemtuzumab treatment is an intermittent infusion that induces long-term remission of Multiple Sclerosis also in the treatment-free period. After the robust T and B cell depletion induced by alemtuzumab, the immune system undergoes radical changes during its reconstitution. In this review, we will discuss the current knowledge on the reconstitution of the lymphocyte repertoire after alemtuzumab treatment and how it could affect the development of side effects, which led to its temporary suspension by the European Medical Agency.
Topics: Alemtuzumab; Animals; Clinical Trials as Topic; Disease Models, Animal; Humans; Immune Reconstitution; Multiple Sclerosis; Translational Research, Biomedical
PubMed: 32503344
DOI: 10.3390/cells9061396 -
Pharmacotherapy Jan 2022Alemtuzumab is a monoclonal antibody that targets the cell surface antigen CD52 on lymphocytes. Although it is used for the treatment of hematologic malignancies, such... (Clinical Trial)
Clinical Trial
STUDY OBJECTIVE
Alemtuzumab is a monoclonal antibody that targets the cell surface antigen CD52 on lymphocytes. Although it is used for the treatment of hematologic malignancies, such as chronic lymphocytic leukemia, and incorporated into many hematopoietic stem cell transplant (HSCT) conditioning regimens, few studies have evaluated the pharmacology of alemtuzumab in adult patients with sickle cell disease (SCD). We therefore examined the pharmacokinetics (PK) and pharmacodynamics (PD) of alemtuzumab in adults with SCD who received a matched related donor HSCT to determine if the clearance of alemtuzumab affects transplant outcomes.
DESIGN
PK and PD analysis of patient data from a single-center clinical trial.
SETTING
Clinical research center.
PATIENTS
Twenty-two adult patients with SCD who received one of two nonmyeloablative allogeneic HSCT regimens: alemtuzumab and total body irradiation (Alem-TBI) or pentostatin, cyclophosphamide, alemtuzumab, and total body irradiation (Pento-Cy-Alem-TBI).
MEASUREMENTS AND MAIN RESULTS
Alemtuzumab serum concentrations, absolute lymphocyte counts, T-cell (CD3), and myeloid (CD14/15) chimerism were collected at distinct time points and analyzed. A semi-mechanistic PK population model was built to understand inter-individual differences in pharmacology. Alemtuzumab was detectable up to 28 days post-HSCT. The mean alemtuzumab level 7 days after transplant for patients on Alem-TBI was 818 ng/ml, significantly lower than the mean level of 1502 ng/ml for patients on Pento-Cy-Alem-TBI (p < 0.001), but this difference decreased as time progressed. The clearance of alemtuzumab was linear, and the half-life was longer in the Pento-Cy-Alem-TBI group (average half-life = 61.1 h) compared to the Alem-TBI group (average half-life = 44.1 h) (p < 0.001). The CD3 chimerism at 2 and 4 months after transplant positively correlated with alemtuzumab levels collected on day 14 after transplant (R = 0.40 and p = 0.004 at 2 months, R = 0.36 and p = 0.005 at 4 months), but this significance was lost by 6 months after HSCT. No correlation was seen between alemtuzumab levels and CD14/15 chimerism.
CONCLUSION
Between 2 and 4 months after transplant, higher alemtuzumab levels measured 14 days after transplant correlated with patients having better engraftment, suggesting more lymphodepletion may be needed to reduce graft failure in these two non-myeloablative matched related donor HSCT regimens.
Topics: Adult; Alemtuzumab; Anemia, Sickle Cell; Chimerism; Drug Elimination Routes; Hematopoietic Stem Cell Transplantation; Humans; Lymphocyte Count; T-Lymphocytes
PubMed: 34669981
DOI: 10.1002/phar.2641 -
Pediatric Transplantation Mar 2018Alemtuzumab is a humanized mAb targeted to CD52. Alemtuzumab is highly immunosuppressive with the ability to deplete T and B cells (in addition to other immune cell... (Review)
Review
Alemtuzumab is a humanized mAb targeted to CD52. Alemtuzumab is highly immunosuppressive with the ability to deplete T and B cells (in addition to other immune cell lines). A growing understanding of the PKs, dosing, and timing of administration of alemtuzumab has allowed for the study of its use as a conditioning agent for allogeneic HCT. The highly immunosuppressive properties of the drug are particularly appealing in the setting of non-malignant HCT, where GVHD provides no clinical benefit and relapse of malignancy is not applicable. In addition, the degree of immune suppression achieved with alemtuzumab has allowed for a reduction in the intensity of myeloablative cytotoxic agents included in some HCT conditioning regimens, allowing for fewer acute and late toxicities. This review paper will provide a comprehensive summary of the mechanism of action, PKs, dosing, and timing of alemtuzumab, a brief description of its use in various allogeneic HCT protocols for non-malignant conditions and a summary of the data regarding its use for GVHD therapy. The goal of this review was to provide an understanding as to how alemtuzumab might be safely incorporated into HCT conditioning regimens for children with non-malignant disease, allowing for expanded access to curative HCT therapy.
Topics: Alemtuzumab; Child; Drug Administration Schedule; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Transplantation Conditioning
PubMed: 29352515
DOI: 10.1111/petr.13142 -
Multiple Sclerosis and Related Disorders Jun 2023Alemtuzumab, a humanized anti-CD52 monoclonal antibody, has been approved as a treatment in persons with active relapsing-remitting multiple sclerosis (RRMS). Real-world... (Observational Study)
Observational Study
BACKGROUND
Alemtuzumab, a humanized anti-CD52 monoclonal antibody, has been approved as a treatment in persons with active relapsing-remitting multiple sclerosis (RRMS). Real-world data in middle east is very limited. We aimed to evaluate the effectiveness and safety of alemtuzumab in a real-world clinical setting.
METHODS
This observational, registry based study assessed persons with multiple sclerosis (PwMS) who were treated with alemtuzumab and completed at least follow up one year after second course. Baseline clinical and radiological characteristics within one year prior to alemtuzumab initiation were collected. The relapse rate, disability measures, radiological activity and adverse events at last follow-up visits were assessed.
RESULTS
Data of seventy-three persons with multiple sclerosis (MS) was analyzed, of which 53 (72.6%) were females. Mean age and mean disease duration were 34.25 ± 7.62 and 9.23 ± 6.20 years respectively. Alemtuzumab was started in 32 (43.8%) naïve patients due to highly active disease and in 25 (34.2%) (PwMS) who were on prior therapies and in 16 (22%) patients due to adverse events on prior medications. Mean follow-up period was 4 ± 1.67 years. In the last follow-up visits, most of our cohort was relapse free (79.5% vs. 17.8%; p < 0.001) compared to baseline before alemtuzumab treatment while mean EDSS score was reduced (2.21 ± 2.15 vs. 2.41 ± 1.85; p < 0.059). The proportion of PwMS who had MRI activity (new T2/ Gd-enhancing) lesions were significantly reduced compared to baseline (15.1% vs. 82.2%; p < 0.001). NEDA-3 was achieved in 57.5% of (PwMS). NEDA-3 was significantly better in naïve patients (78% versus. 41.5%; p < 0.002) and in patients with disease duration < 5 years, (82.6% v 43.2%; p < 0.002). Several adverse events such as infusion reactions (75.3%), autoimmune thyroiditis (16.4%) and glomerulonephritis (2.7%) were reported.
CONCLUSION
The effectiveness and safety profile of alemtuzumab in this cohort were consistent with data of clinical trials. Early initiation of Alemtuzumab is associated with favorable outcome.
Topics: Female; Humans; Male; Alemtuzumab; Multiple Sclerosis; Kuwait; Multiple Sclerosis, Relapsing-Remitting; Magnetic Resonance Imaging
PubMed: 37054581
DOI: 10.1016/j.msard.2023.104712 -
Journal of Neurology Nov 2018Alemtuzumab is a humanized anti-CD52 monoclonal antibody approved in more than 65 countries for the treatment of relapsing-remitting multiple sclerosis (RRMS). Compared... (Review)
Review
Alemtuzumab is a humanized anti-CD52 monoclonal antibody approved in more than 65 countries for the treatment of relapsing-remitting multiple sclerosis (RRMS). Compared with subcutaneous interferon-beta-1a, alemtuzumab significantly reduced clinical disease activity and the rate of brain volume loss, and improved disability outcomes in patients with active RRMS who were either treatment naive (CARE-MS I study) or who had an inadequate response (≥ 1 relapse after ≥ 6 months of treatment) to prior therapy (CARE-MS II study). Adverse events (AEs) associated with alemtuzumab include infusion-associated reactions, infections, and autoimmunity. The most commonly reported autoimmune AEs observed with alemtuzumab involve the thyroid gland, followed by immune thrombocytopenia and nephropathies. A monitoring program was designed and implemented to facilitate the early detection of autoimmune events to ensure timely and adequate management. The aim of this article is to provide physicians (including neurologists, general practitioners, endocrinologists, hematologists, and nephrologists who may be less familiar with the symptoms and treatment of autoimmune events), with practical real-world recommendations for the monitoring and management of autoimmunity associated with alemtuzumab treatment.
Topics: Alemtuzumab; Autoimmunity; Disease Management; Humans; Immunologic Factors; Monitoring, Immunologic; Multiple Sclerosis, Relapsing-Remitting; Practice Guidelines as Topic
PubMed: 29525836
DOI: 10.1007/s00415-018-8822-y