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High-Efficacy Therapies for Treatment-Naïve Individuals with Relapsing-Remitting Multiple Sclerosis.CNS Drugs Dec 2022There are > 18 distinct disease-modifying therapy (DMT) options covering 10 mechanisms of action currently approved by the US Food and Drug Administration for the... (Review)
Review
There are > 18 distinct disease-modifying therapy (DMT) options covering 10 mechanisms of action currently approved by the US Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis (RRMS). Given the multitude of available treatment options, and recent international consensus guidelines offering differing recommendations, there is broad heterogeneity in how the DMTs are used in clinical practice. Choosing a DMT for newly diagnosed patients with MS is currently a topic of significant debate in MS care. Historically, an escalation approach to DMT was used for newly diagnosed patients with RRMS. However, the evidence for clinical benefits of early treatment with high-efficacy therapies (HETs) in this population is emerging. In this review, we provide an overview of the DMT options and MS treatment strategies, and discuss the clinical benefits of HETs (including ofatumumab, ocrelizumab, natalizumab, alemtuzumab, and cladribine) in the early stages of MS, along with safety concerns associated with these DMTs. By minimizing the accumulation of neurological damage early in the disease course, early treatment with HETs may enhance long-term clinical outcomes over the lifetime of the patient.
Topics: Humans; Multiple Sclerosis, Relapsing-Remitting; Multiple Sclerosis; Immunologic Factors; Natalizumab; Alemtuzumab
PubMed: 36350491
DOI: 10.1007/s40263-022-00965-7 -
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 -
Multiple Sclerosis and Related Disorders May 2019Natalizumab break exposes multiple sclerosis (MS) patients to a high risk of disease reactivation or rebound, whose prevention and treatment constitute a clinical... (Review)
Review
INTRODUCTION
Natalizumab break exposes multiple sclerosis (MS) patients to a high risk of disease reactivation or rebound, whose prevention and treatment constitute a clinical challenge.
CASE PRESENTATION
We describe a dramatic case of MS rebound, characterized by the development of severe neurological and psychiatric symptoms, following natalizumab break. Alemtuzumab rapidly and completely suppressed brain inflammation as demonstrated by clinical and radiological findings.
CONCLUSIONS
Our case further adds to the available literature evidence on Alemtuzumab as first-choice rescue therapy following Natalizumab discontinuation.
Topics: Alemtuzumab; Antineoplastic Agents, Immunological; Humans; Immunologic Factors; Male; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Young Adult
PubMed: 30851640
DOI: 10.1016/j.msard.2019.03.002 -
BMJ Case Reports Jun 2022Alemtuzumab has been associated with the emergence of secondary autoimmune diseases. We report a case of a patient with relapsing-remitting multiple sclerosis who...
Alemtuzumab has been associated with the emergence of secondary autoimmune diseases. We report a case of a patient with relapsing-remitting multiple sclerosis who developed a refractory immune thrombocytopaenia associated with vasculitis, myelofibrosis and later Guillain-Barré syndrome following alemtuzumab. The medical community should be aware of unusual and unexpected adverse events that may be associated with alemtuzumab, especially when occurring simultaneously in the same patient.
Topics: Alemtuzumab; Antineoplastic Agents, Immunological; Autoimmune Diseases; Humans; Multiple Sclerosis, Relapsing-Remitting
PubMed: 35760506
DOI: 10.1136/bcr-2021-248037 -
Pharmacogenomics Jul 2022
Topics: Alemtuzumab; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation
PubMed: 35763447
DOI: 10.2217/pgs-2022-0071 -
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 -
Vox Sanguinis Apr 2023
Topics: Humans; Anemia, Hemolytic, Autoimmune; Alemtuzumab
PubMed: 36683306
DOI: 10.1111/vox.13405 -
American Journal of Hematology Jun 2023Immune severe aplastic anemia (SAA) is characterized by pancytopenia and immune-mediated bone marrow destruction. SAA may be treated with hematopoietic stem cell...
Immune severe aplastic anemia (SAA) is characterized by pancytopenia and immune-mediated bone marrow destruction. SAA may be treated with hematopoietic stem cell transplantation (HSCT) or immunosuppressive therapy (IST). However, 30% of patients treated with IST relapse. We previously reported a clinical trial of alemtuzumab in which more than half of 25 relapsed SAA patients (56%) responded hematologically. Here, we present long-term results of a total of 42 patients. Participants with SAA who had previously completed antithymocyte globulin (ATG)-based IST, but had relapsed, were enrolled on this study. Alemtuzumab was administered intravenously (IV) (n = 28) or subcutaneously (SC) (n = 14). The primary endpoint was hematologic response at 6 months. Secondary endpoints included relapse, clonal evolution, and survival. This trial was registered at clinicaltrials.gov (NCT00195624). Patients were enrolled over 9 years, with median follow-up of 6 years. Median age was 32 years, with 57% being female. At 6 months, 18 patients (43%) achieved response; 15 (54%) of those who received IV compared with 3 (21%) who received SC therapy. Six patients (14%) had durable long-term response without need for subsequent AA-directed therapy or HSCT at last follow-up. Nine patients had clonal evolution, with high-risk evolution occurring in 6. Overall survival was 67% at median follow-up of 6 years. Prolonged iatrogenic immunosuppression was observed as long as 2 years after alemtuzumab administration. Alemtuzumab induces responses in relapsed SAA, some of which are durable long-term. However, immunosuppression can persist for years, requiring long-term monitoring.
Topics: Humans; Female; Adult; Male; Immunosuppressive Agents; Cyclosporine; Alemtuzumab; Anemia, Aplastic; Treatment Outcome; Antilymphocyte Serum; Recurrence
PubMed: 37021397
DOI: 10.1002/ajh.26924 -
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 -
Neurology Jul 2014
Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Humans; Multiple Sclerosis
PubMed: 24920853
DOI: 10.1212/WNL.0000000000000554