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Clinical and Experimental Immunology Dec 2018Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is approved for treatment of relapsing multiple sclerosis (MS). In the Phase II/III trials, patients received 12... (Randomized Controlled Trial)
Randomized Controlled Trial
Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is approved for treatment of relapsing multiple sclerosis (MS). In the Phase II/III trials, patients received 12 or 24 mg/day of alemtuzumab in two treatment courses (5 days for course 1 and 3 days for course 2), 12 months apart. Serum concentrations of alemtuzumab peaked on the last day of dosing in each course and mostly fell below the limit of quantitation by day 30. Alemtuzumab rapidly depleted circulating T and B lymphocytes, with the lowest observed values occurring within days. Lymphocytes repopulated over time, with B cell recovery usually complete within 6 months. T lymphocytes recovered more slowly and generally did not return to baseline by 12 months post-treatment. Approximately 40 and 80% of patients had total lymphocyte counts, reaching the lower limit of normal by 6 and 12 months after each course, respectively. The clearance of alemtuzumab is dependent on circulating lymphocyte count. A majority of treated patients tested positive for anti-alemtuzumab antibodies, including inhibitory antibodies, during the 2-year studies, and a higher proportion of patients tested positive in course 2 than in course 1. The presence of anti-alemtuzumab antibody appeared to be associated with slower clearance of alemtuzumab from the circulation but had no impact on the pharmacodynamics. No effects of age, race or gender on the pharmacokinetics or pharmacodynamics were observed. Together, the pharmacokinetics, pharmacodynamics and immunogenicity results support the continued development and use of alemtuzumab for the treatment of MS, and probably explain its sustained effects beyond the dosing interval.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alemtuzumab; Antibodies, Anti-Idiotypic; B-Lymphocytes; CD52 Antigen; Child; Female; Humans; Lymphocyte Count; Lymphocyte Depletion; Male; Middle Aged; Multiple Sclerosis; T-Lymphocytes; Young Adult
PubMed: 30144037
DOI: 10.1111/cei.13208 -
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 -
Multiple Sclerosis (Houndmills,... Apr 2022Does preexisting or treatment-emergent autoimmunity increase the risk of subsequent autoimmune disease in individuals with relapsing-remitting multiple sclerosis (MS)... (Review)
Review
Does preexisting or treatment-emergent autoimmunity increase the risk of subsequent autoimmune disease in individuals with relapsing-remitting multiple sclerosis (MS) after alemtuzumab? In the extended phase 2/3 trials, 34/96 (35.4%) patients with and 395/1120 (35.3%) without preexisting autoimmunity developed non-MS autoimmunity. Thyroid autoimmunity after alemtuzumab courses 1 or 2 did not increase subsequent non-thyroid autoimmune adverse events. Therefore, autoimmune disease before or after alemtuzumab treatment does not predict autoimmunity after further courses, so should not preclude adequate alemtuzumab dosing to control MS. Finally, post-marketing safety data contribute toward a full record of the alemtuzumab benefit/risk profile for the MS field.
Topics: Alemtuzumab; Autoimmunity; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Humans; Marketing; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting
PubMed: 34882037
DOI: 10.1177/13524585211061335 -
Multiple Sclerosis and Related Disorders Jul 2021Highly active MS may warrant higher efficacy treatments for disease control. However, these often confer more risk and have not been compared in head-to-head clinical...
BACKGROUND
Highly active MS may warrant higher efficacy treatments for disease control. However, these often confer more risk and have not been compared in head-to-head clinical trials, making relative efficacy and safety difficult to interpret. Alemtuzumab and cladribine are two high-efficacy treatments given as discrete courses separated by one year, followed by a durable response that potentially does not require ongoing treatment. Before the approval of oral cladribine, our centre had been treating patients with a bioequivalent intravenous (IV) regimen since 2010. The objective of this study is to report the safety and efficacy data of alemtuzumab and cladribine in a real-world, single centre setting.
METHODS
We retrospectively reviewed all patients treated with alemtuzumab or cladribine at the Ottawa Hospital MS Clinic with 2 or more years of follow-up. Information on baseline demographic variables, previous treatment, and prior disease activity was collected. Outcomes investigated were "no evidence of disease activity" (NEDA) and its constituents: new clinical relapse, new MRI activity, and Expanded Disability Status Scale (EDSS) progression; as well as any adverse events or treatment discontinuation. We performed univariate and multiple logistic regression to determine differences in 2-year NEDA and time-to-event analyses with Cox regression models to determine factors associated with each outcome through the study period.
RESULTS
Forty-six patients were treated with alemtuzumab and 65 with cladribine of whom 51 (78%) received the intravenous regimen, followed for a total of 420.1 person-years. The cladribine group was older (p=.0002), with higher baseline EDSS (p=.0015), and more likely secondary progressive (p<.0001). Alemtuzumab had a higher rate of 2-year NEDA than cladribine (OR 4.78, 95%CI: 1.57-14.50, p=.006), but beyond 2 years the difference was not statistically significant (HR 0.50, 95%CI: 0.25-1. 30, p=.061). More prior treatments were associated with lower likelihood of retaining NEDA (HR 1.26, 95%CI: 1.03-1.54, p=.027). Alemtuzumab had more infusion reactions (80% vs. 17%, p<.0001), shingles (22% vs. 2%, p=.005), and secondary autoimmunity (52% vs. 3%, p<.0001) than cladribine, but there was no difference in grade 3 or higher adverse events (21.7% vs. 18.5%, p=1.0).
CONCLUSION
In our cohort alemtuzumab and cladribine achieved similar rates of NEDA in long-term follow-up, with overall less adverse events with cladribine. Patient registries would allow more robust comparisons, detection of adverse events, and assessment of a durable response.
Topics: Alemtuzumab; Cladribine; Humans; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Neoplasm Recurrence, Local; Retrospective Studies
PubMed: 33901969
DOI: 10.1016/j.msard.2021.102945 -
American Journal of Transplantation :... Dec 2020Kidney transplant outcomes are limited by toxicities associated with calcineurin inhibitors and steroids. This trial was conducted to determine whether a costimulation...
Kidney transplant outcomes are limited by toxicities associated with calcineurin inhibitors and steroids. This trial was conducted to determine whether a costimulation blockade (CoB)-based regimen could achieve acceptable long-term outcomes and graft survival could be maintained solely with CoB. Forty patients underwent alemtuzumab induction followed by belatacept and sirolimus maintenance therapy. Patients were offered weaning to belatacept monotherapy after 1 year and followed for 5 years. Five-year patient and graft survival rates were 100% and 95%, respectively. Graft function remained stable with a mean estimated glomerular filtration rates of 67 ± 21 and 71 ± 19 at 36 and 60 months, respectively. There was no clinical rejection in the first year; subclinical rejection was detected by protocol biopsy in 4 patients. Twelve patients were successfully weaned to belatacept monotherapy. Cytomegalovirus and Epstein-Barr virus reactivations were well controlled, but 9 patients experienced transient BK viremia during the first year. Alemtuzumab produced profound lymphopenia followed by gradual T cell and more rapid B cell reconstitution to a repertoire deviated toward naïve cells with increased regulatory T cells. This regimen effectively prevents allograft rejection without using steroids or calcineurin inhibitors, enriches for naïve cells susceptible to control with CoB, and permits control of rejection with belatacept monotherapy in selected patients.
Topics: Abatacept; Alemtuzumab; Epstein-Barr Virus Infections; Follow-Up Studies; Graft Rejection; Graft Survival; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Kidney Transplantation; Sirolimus
PubMed: 32515087
DOI: 10.1111/ajt.16121 -
Therapeutic Drug Monitoring Feb 2023Alemtuzumab is a humanized monoclonal antibody that targets the CD52 glycoprotein expressed on most lymphocytes, subsequently inducing complement-mediated and...
BACKGROUND
Alemtuzumab is a humanized monoclonal antibody that targets the CD52 glycoprotein expressed on most lymphocytes, subsequently inducing complement-mediated and antibody-mediated cytotoxicity. Owing to its ability to induce profound immune depletion, alemtuzumab is frequently used in patients before allogeneic hematopoietic stem cell transplantation to prevent graft rejection and acute graft-versus-host disease. In this clinical context, a stable immunoassay with high sensitivity and specificity to determine alemtuzumab levels is essential for performing pharmacokinetic and pharmacodynamic analyses; however, the available methods have several limitations. Here, we report the successful development and validation of an efficient and highly sensitive enzyme-linked immunosorbent assay technique based on commercially available reagents to quantify alemtuzumab in human serum or plasma.
METHODS
This enzyme-linked immunosorbent assay technique was developed and validated in accordance with the European Medicines Agency guidelines on bioanalytical method validation.
RESULTS
The assay sensitivity (lower limit of quantification) is 0.5 ng·mL -1 , and the dynamic range is 0.78-25 ng·mL -1 . To accommodate quantification of peak concentration and concentrations below the lympholytic level (<0.1 mcg·mL -1 ), patients' serum samples were prediluted 20-400 times according to the expected alemtuzumab concentration. The overall within-run accuracy was between 96% and 105%, whereas overall within-run precision (coefficient of variation) was between 3% and 9%. The between-run assessment provided an overall accuracy between 86% and 95% and an overall coefficient of variation between 5% and 14%.
CONCLUSIONS
The developed assay provides accurate insight into alemtuzumab exposure and its effects on the clinical response to treatment, which is key to optimizing treatment strategies.
Topics: Humans; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Graft vs Host Disease; Enzyme-Linked Immunosorbent Assay
PubMed: 36150715
DOI: 10.1097/FTD.0000000000001037 -
Immunotherapy Feb 2022We report on the presentation and outcome of a 28-year-old female who developed red cell aplasia following alemtuzumab therapy for relapsing remitting multiple...
We report on the presentation and outcome of a 28-year-old female who developed red cell aplasia following alemtuzumab therapy for relapsing remitting multiple sclerosis. The patient also developed synchronous immune thrombocytopenia and immune neutropenia, but not aplastic anemia. This patient received high dose steroids, intravenous immunoglobulin (iv.Ig), rituximab, red cell transfusions, vincristine, G-CSF, cyclosporin and mycophenolate to treat the combination of cytopenias over a period of 6 months with subsequent improvement in bone marrow function. While alemtuzumab has several recognized autoimmune complications, little is known about the potential hematological side effects. The combination of red cell aplasia, immune thrombocytic purpura and autoimmune neutropenia has not previously been described in the literature following alemtuzumab immunotherapy and highlights the importance of monthly blood monitoring post alemtuzumab administration.
Topics: Adrenal Cortex Hormones; Adult; Alemtuzumab; Antineoplastic Agents, Immunological; Cyclosporine; Female; Granulocyte Colony-Stimulating Factor; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Multiple Sclerosis, Relapsing-Remitting; Mycophenolic Acid; Neutropenia; Purpura, Thrombocytopenic, Idiopathic; Red-Cell Aplasia, Pure; Rituximab; Treatment Outcome; Vincristine
PubMed: 34743591
DOI: 10.2217/imt-2021-0163 -
British Journal of Clinical Pharmacology Jan 2022Alemtuzumab is a lymphodepleting monoclonal antibody utilized in conditioning regimens for allogeneic haematopoietic cell transplantation (HCT). A recently proposed...
UNLABELLED
Alemtuzumab is a lymphodepleting monoclonal antibody utilized in conditioning regimens for allogeneic haematopoietic cell transplantation (HCT). A recently proposed therapeutic range of 0.15-0.6 μg/mL on the day of transplantation is associated with better HCT outcomes. The purpose of this study was to characterize alemtuzumab population pharmacokinetic/pharmacodynamic (PK/PD) and to propose individualized subcutaneous dosing schemes to achieve this optimal level for paediatric patients.
METHODS
Alemtuzumab concentration and absolute lymphocyte count (ALC) profiles were obtained from 29 paediatric and young adult patients (median age 6.4 y; range 0.28-21.4 y) with nonmalignant disorders undergoing HCT. PK/PD analyses were performed using nonlinear mixed effects modelling. Monte Carlo simulation was conducted to evaluate different improved dosing approaches.
RESULTS
A one-compartment model with sequential zero- and first-order absorption adequately described subcutaneously administered alemtuzumab PK. Model fit was significantly improved by including allometrically scaled body weight on clearance (0.080 L/h/70 kg) and volume of distribution (17.4 L/70 kg). ALC reduction following subcutaneous alemtuzumab was swift. An inhibitory E model best characterized the relationship between alemtuzumab concentration and ALC. E and EC were estimated as 1.18 × 10 /μL and 0.045 μg/mL, respectively. The currently used per kg dosing was found to cause uneven alemtuzumab exposure across different age and weight cohorts. Simulations indicated optimal target achieving dose as allometry-based dose of 18 mg × (weight/70) or body surface area-based dose of 10 mg/m , divided over 3 days, with a potential individualized top-up dose; both of which yielded similar results.
CONCLUSION
An allometry- or body surface area-based starting dosing regimen in combination with individualized Bayesian PK estimation using concentration feedback is proposed for alemtuzumab precision dosing in children undergoing allogeneic HCT.
Topics: Alemtuzumab; Bayes Theorem; Child; Computer Simulation; Hematopoietic Stem Cell Transplantation; Humans; Transplantation Conditioning; Young Adult
PubMed: 34182590
DOI: 10.1111/bcp.14955 -
Expert Review of Hematology Oct 2019: About 60% of aplastic anemia (AA) patients are in need of further treatment after frontline standard immunosuppressive therapy (IST). This along with the prolonged... (Review)
Review
: About 60% of aplastic anemia (AA) patients are in need of further treatment after frontline standard immunosuppressive therapy (IST). This along with the prolonged survival of AA subjects who do not respond to or relapse after this treatment makes management of these patients a rising and very challenging issue. : Literature research, carried out from the most commonly used databases, included the following keywords: aplastic anemia, immunosuppressive treatment, antithymocyte globuline, ciclosporine A, refractory aplastic anemia, relapsing aplastic anemia, hematopoietic stem cell transplantation including haploidentical and cord blood transplantations thrombopoietin mimetics, supportive treatment, chelation and infections. Studies on the treatment of aplastic anemia with different levels of evidence were included. Top level of evidence studies (metanalyses and randomized prospective controlled trials) were a minority because severe AA, particularly in the subset of patients who fail upfront IST, is an extremely rare disease. Guidelines from National Societies and review articles were also included. : The most commonly used treatments after failure of upfront immunosuppression are hematopoietic stem cell transplantation, a second course of immunosuppression and thrombopoietin mimetics alone or in combination with immunosuppression. Other potential options are alemtuzumab, androgens, oral cyclosporine A in monotherapy. Not many comparative studies exist to clearly establish the superiority of one over another strategy. Therefore, the choice of the best treatment for these patients should rely on major driving factors like patient's age and comorbidities, availability of a matched unrelated donor, donor's characteristics and drug-availability.
Topics: Alemtuzumab; Androgens; Anemia, Aplastic; Antilymphocyte Serum; Clinical Trials as Topic; Cord Blood Stem Cell Transplantation; Cyclophosphamide; Cyclosporine; Disease Management; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Peptides; Practice Guidelines as Topic; Recurrence; Remission Induction; Survival Analysis; Unrelated Donors
PubMed: 31311355
DOI: 10.1080/17474086.2019.1645003 -
Vox Sanguinis Apr 2023
Topics: Humans; Anemia, Hemolytic, Autoimmune; Alemtuzumab
PubMed: 36683306
DOI: 10.1111/vox.13405