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American Journal of Transplantation :... Aug 2014This editorial puts into perspective the findings of the first randomized, controlled trial examining alemtuzumab induction for lung transplantation, and highlights the...
This editorial puts into perspective the findings of the first randomized, controlled trial examining alemtuzumab induction for lung transplantation, and highlights the challenges encountered with alemtuzumab induction in other solid organs. See article by Jaksch et al on page 1839.
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Female; Humans; Lung Transplantation; Male
PubMed: 25039475
DOI: 10.1111/ajt.12825 -
Expert Opinion on Drug Safety Jul 2018Alemtuzumab is a monoclonal anti CD-52 antibody recently approved for use in relapsing-remitting multiple sclerosis(MS). Given that the targeted antigen is primarily... (Review)
Review
INTRODUCTION
Alemtuzumab is a monoclonal anti CD-52 antibody recently approved for use in relapsing-remitting multiple sclerosis(MS). Given that the targeted antigen is primarily expressed on B and T lymphocytes, the administration of this biological drug is associated with rapid but protracted peripheral lymphopenia.
AREAS COVERED
The impact on infective risk of this immune impairment is still to be fully understood. In this review, we attempt to summarize all the available literature concerning opportunistic infections occurring in patients with MS receiving alemtuzumab. Infective adverse events were observed in more than 70% of patients in phase 2/3 RCTs, mainly of mild-to-moderate severity. Nevertheless, several post-marketing reports documented cases of serious, rare, and unexpected infections.
EXPERT OPINION
Predictive risk factors and prognostic features of opportunistic infections in this setting still need to be exactly assessed. At present, the only recommended preventive measures consist in anti-herpetic prophylaxis, Listeria-free diet, Tuberculosis prophylaxis and annual Papillomavirus screening. Given the non-negligible risk of unpredicted infective events, we advise physicians to take into account patients' history of infectious diseases and vaccine status and to consider supplementary prophylactic strategies, including screening for Toxoplasma gondii and viral hepatitis serostatus as well as pre-emptive approaches to avert CMV reactivation and Pneumocystosis.
Topics: Alemtuzumab; Humans; Multiple Sclerosis, Relapsing-Remitting; Opportunistic Infections; Product Surveillance, Postmarketing; Prognosis; Randomized Controlled Trials as Topic; Risk Factors; Severity of Illness Index
PubMed: 29848085
DOI: 10.1080/14740338.2018.1483330 -
Lancet (London, England) Apr 2019
Topics: Alemtuzumab; Aortic Dissection; Antibodies, Monoclonal, Humanized; Humans; Multiple Sclerosis; Myocardial Infarction; Safety-Based Drug Withdrawals; Stroke
PubMed: 31034363
DOI: 10.1016/S0140-6736(19)30935-3 -
Neurology May 2018To evaluate acute acalculous cholecystitis (AAC) as a potential safety risk for patients treated with alemtuzumab. (Review)
Review
OBJECTIVE
To evaluate acute acalculous cholecystitis (AAC) as a potential safety risk for patients treated with alemtuzumab.
METHODS
The Food and Drug Administration Adverse Event Reporting System and the medical literature were searched for cases of AAC in conjunction with alemtuzumab for all clinical indications.
RESULTS
Eight spontaneously reported cases meeting the case definition of AAC in close temporal association with alemtuzumab use were identified. Based on established criteria within the Food and Drug Administration Division of Pharmacovigilance for causality assessment, 4 cases were assessed as probable while 4 were possible. All cases occurred in patients with relapsing-remitting multiple sclerosis. Seven of the 8 cases presented with AAC during or shortly after alemtuzumab treatment, thereby suggesting an acute cytokine release syndrome as a putative pathogenic mechanism. The cases identified in this review differ from the typical AAC cases described in the medical literature based on female preponderance, lack of concurrent critical illnesses, inconsistent presence of other risk factors, and resolution with conservative treatment in the majority of cases.
CONCLUSIONS
AAC represents a new and potentially life-threatening adverse event associated with alemtuzumab use in relapsing-remitting multiple sclerosis. In cases seen to date, early and conservative treatment resulted in good clinical outcome, although the natural history of AAC in this population without critical illness is not well defined. Awareness of this safety risk by general and specialty neurologists is important for prompt recognition and optimal management.
Topics: Acalculous Cholecystitis; Alemtuzumab; Cholecystitis, Acute; Humans; Immunologic Factors; Multiple Sclerosis, Relapsing-Remitting; Risk
PubMed: 29602912
DOI: 10.1212/WNL.0000000000005422 -
Journal of Neurology Feb 2022Alemtuzumab is an effective disease-modifying therapy (DMT) for highly active multiple sclerosis (MS). However, safety concerns limit its use in clinical practice.
BACKGROUND
Alemtuzumab is an effective disease-modifying therapy (DMT) for highly active multiple sclerosis (MS). However, safety concerns limit its use in clinical practice.
OBJECTIVES
To evaluate the safety of alemtuzumab in a nationwide cohort of Finnish MS patients.
METHODS
In this retrospective case series study, we analyzed the data of all but two MS patients who had received alemtuzumab in Finland until 2019. Data were systematically collected from patient files.
RESULTS
Altogether 121 patients were identified, most of whom had received previous DMTs (82.6%). Median follow-up time after treatment initiation was 30.3 months and exceeded 24 months in 78 patients. Infusion-associated reactions (IARs) were observed in 84.3%, 57.3%, and 57.1% of patients during alemtuzumab courses 1-3, respectively. Serious adverse events (SAEs) were observed in 32.2% of patients, serious IARs in 12.4% of patients, and SAEs other than IARs in 23.1% of patients. Autoimmune adverse events were observed in 30.6% of patients. One patient died of hemophagocytic lymphohistiocytosis, and one patient died of pneumonia. A previously unreported case of thrombotic thrombocytopenic purpura was documented.
CONCLUSIONS
SAEs were more frequent in the present cohort than in previous studies. Even though alemtuzumab is a highly effective therapy for MS, vigorous monitoring with a long enough follow-up time is advised.
Topics: Alemtuzumab; Finland; Humans; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Retrospective Studies
PubMed: 34255182
DOI: 10.1007/s00415-021-10664-w -
Journal of Comparative Effectiveness... Jul 2023To assess the relative efficacy of disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS) including newer therapies (ozanimod, ponesimod,... (Meta-Analysis)
Meta-Analysis
To assess the relative efficacy of disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS) including newer therapies (ozanimod, ponesimod, ublituximab) using network meta-analysis (NMA). Bayesian NMAs for annualised relapse rate (ARR) and time to 3-month and 6-month confirmed disability progression (3mCDP and 6mCDP) were conducted. For each outcome, the three most efficacious treatments versus placebo were monoclonal antibody (mAb) therapies: alemtuzumab, ofatumumab, and ublituximab for ARR; alemtuzumab, ocrelizumab, and ofatumumab for 3mCDP; and alemtuzumab, natalizumab, and either ocrelizumab or ofatumumab (depending on the CDP definition used for included ofatumumab trials) for 6mCDP. The most efficacious DMTs for RMS were mAb therapies. Of the newer therapies, only ublituximab ranked among the three most efficacious treatments (for ARR).
Topics: Humans; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Alemtuzumab; Network Meta-Analysis; Bayes Theorem; Recurrence
PubMed: 37265062
DOI: 10.57264/cer-2023-0016 -
Experimental Neurology Dec 2014The lymphocyte depleting anti-CD52 monoclonal antibody alemtuzumab has been used in Cambridge, UK, as an experimental treatment of multiple sclerosis since 1991. One... (Review)
Review
The lymphocyte depleting anti-CD52 monoclonal antibody alemtuzumab has been used in Cambridge, UK, as an experimental treatment of multiple sclerosis since 1991. One phase-2 trial (CAMMS-223) and two phase-3 studies (CARE-MS1 and CARE-MS2) have confirmed its efficacy in treatment-naive patients, and have established superiority over interferon beta-1a in patients who continue to relapse in spite of first-line therapy (Cohen et al., 2012; Coles et al., 2008; Coles et al., 2012a; Coles et al., 2012b). Despite causing a prolonged T cell lymphopenia, significant infections have not been an issue following treatment; rather alemtuzumab's primary safety concern is secondary autoimmunity, occurring up to five years after treatment and maximally at two years: 30% of patients develops thyroid autoimmunity, and 1% develops idiopathic thrombocytopenic purpura (ITP). In addition, 4 out of 1486 patients (<0.3%) treated on the commercially sponsored studies developed glomerulonephritis. Two of these patients developed anti-glomerular basement membrane disease, a condition which may result in renal failure unless treated aggressively. In September 2013, the European Medicine Agency (EMA) ruled that the benefit-to-risk balance for alemtuzumab was favourable, approving it as a first-line therapy for adults with active relapsing remitting multiple sclerosis (under the trade name Lemtrada). Lemtrada is now also approved as a treatment of multiple sclerosis in Canada, Australia, Switzerland, Israel, Mexico and Brazil. However, in December 2013, Lemtrada failed to gain approval from the U.S. Food and Drug Administration (FDA), with concerns over trial design and safety stated as the main reasons. In this review we describe our local experience and explain the rationale behind its initial use as a treatment of multiple sclerosis and behind the design of the commercially sponsored trials, summarising their key findings. We also sum up our understanding of its mechanism of action.
Topics: Alemtuzumab; Animals; Antibodies, Monoclonal, Humanized; Antigens, CD; Antigens, Neoplasm; CD52 Antigen; Clinical Trials as Topic; Glycoproteins; Humans; Multiple Sclerosis
PubMed: 24792641
DOI: 10.1016/j.expneurol.2014.04.018 -
International Journal of Molecular... Jul 2023T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells. Most patients with T-PLL present with lymphocytosis, anemia,... (Review)
Review
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells. Most patients with T-PLL present with lymphocytosis, anemia, thrombocytopenia, and hepatosplenomegaly. Correct identification of T-PLL is essential because treatment for this disease is distinct from that of other T-cell neoplasms. In 2019, the T-PLL International Study Group (TPLL-ISG) established criteria for the diagnosis, staging, and assessment of response to treatment of T-PLL with the goal of harmonizing research efforts and supporting clinical decision-making. T-PLL pathogenesis is commonly driven by T-cell leukemia 1 () overexpression and loss, genetic alterations that are incorporated into the TPLL-ISG diagnostic criteria. The cooperativity between family members and is seemingly unique to T-PLL across the spectrum of T-cell neoplasms. The role of the T-cell receptor, its downstream kinases, and JAK/STAT signaling are also emerging themes in disease pathogenesis and have obvious therapeutic implications. Despite improved understanding of disease pathogenesis, alemtuzumab remains the frontline therapy in the treatment of naïve patients with indications for treatment given its high response rate. Unfortunately, the responses achieved are rarely durable, and the majority of patients are not candidates for consolidation with hematopoietic stem cell transplantation. Improved understanding of T-PLL pathogenesis has unveiled novel therapeutic vulnerabilities that may change the natural history of this lymphoproliferative neoplasm and will be the focus of this concise review.
Topics: Humans; Leukemia, Prolymphocytic, T-Cell; Alemtuzumab; Hematopoietic Stem Cell Transplantation; Mutation
PubMed: 37569479
DOI: 10.3390/ijms241512106 -
Multiple Sclerosis (Houndmills,... Oct 2020
Topics: Alemtuzumab; Antibodies, Antineutrophil Cytoplasmic; Humans; Multiple Sclerosis; Systemic Vasculitis; Vasculitis
PubMed: 32081067
DOI: 10.1177/1352458520908040 -
Frontiers in Immunology 2023Alemtuzumab is a monoclonal antibody targeting CD52 on the surface of immune cells, approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS)....
Immune reconstitution following alemtuzumab therapy is characterized by exhausted T cells, increased regulatory control of proinflammatory T cells and reduced B cell control.
Alemtuzumab is a monoclonal antibody targeting CD52 on the surface of immune cells, approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS). The purpose of this study was to analyze the repopulation of peripheral lymphocytes following alemtuzumab-induced lymphocyte depletion and investigate associations with disease activity and development of secondary autoimmunity. For this, blood samples were collected two years after initiation of alemtuzumab treatment and lymphocytes were subjected to a comprehensive flow cytometry analysis. Included in the study were 40 patients treated with alemtuzumab and 40 treatment-naïve patients with RRMS. Disease activity and development of secondary autoimmune disease was evaluated after three years of treatment. Our study confirms that alemtuzumab treatment profoundly alters the circulating lymphocyte phenotype and describes a reconstituted immune system characterized by T cell activation/exhaustion, an increased regulatory control of IL-17 producing effector T cells and CD20 T cells, and a reduced control of B cells. There were no obvious associations between immune cell subsets and disease activity or development of secondary autoimmune disease during treatment with alemtuzumab. Our results indicate that the reconstituted immune response is skewed towards a more effective regulatory control of MS-associated proinflammatory T cell responses. Also, the enlarged pool of naïve B cells together with the apparent decrease in control of B cell activity may explain why alemtuzumab-treated patients retain the ability to mount a humoral immune response towards new antigens.
Topics: Humans; T-Lymphocytes; Alemtuzumab; Immune Reconstitution; B-Lymphocytes; Multiple Sclerosis, Relapsing-Remitting
PubMed: 37744364
DOI: 10.3389/fimmu.2023.1249201