Alemtuzumab for multiple sclerosis.
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ABSTRACT:
SUBMITTER: Riera R
PROVIDER: S-EPMC6486037 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Alemtuzumab is a humanized monoclonal antibody that is administered daily for 5 days, and then no further therapy is required for 12 months. It causes rapid and prolonged lymphocyte depletion; the consequent homeostatic reconstitution leads to a radically reformed lymphocyte pool with a relative increase in regulatory T cells and expansion of autoreactive T cells. Although previously licensed for the treatment of B-cell chronic lymphocytic leukemia, it is now been considered for licensing in the treatment of multiple sclerosis (MS). From a disappointing experience with alemtuzumab in progressive MS, Alastair Compston and I argued that immunotherapies should be given early in the course of the disease. In a unique program of drug development in MS, alemtuzumab has been compared in 1 phase 2 trial and 2 phase 3 trials with the active comparator interferon beta-1a. In all trials, alemtuzumab was more effective in suppressing relapses than interferon beta-1a. In one phase 2 and one phase 3 trial, alemtuzumab also reduced the risk of accumulating disability compared with interferon beta-1a. Indeed, alemtuzumab treatment led to an improvement in disability and a reduction in cerebral atrophy. The safety issues are infusion-associated reactions largely controlled by methylprednisolone, antihistamines, and antipyretics; mild-to-moderate infections (with 3 opportunistic infections from the open-label experience: 1 case each of spirochaetal gingivitis, pyogenic granuloma, and Listeria meningitis); and autoimmunity. Usually autoimmunity is directed against the thyroid gland, but causes (1 %) immune thrombocytopenia, and in a few cases antiglomerular basement membrane syndrome. Alemtuzumab is an effective therapy for early relapsing-remitting MS, offering disability improvement at least to 5 years after treatment. Its use requires careful monitoring so that potentially serious side effects can be treated early and effectively.
| S-EPMC3557360 | biostudies-literature
Project description:ObjectiveTo determine the immunocompetency of patients with multiple sclerosis treated with the lymphodepleting humanized monoclonal antibody alemtuzumab.MethodsIn this pilot case-control study, we assessed immunocompetence in 24 patients after alemtuzumab treatment by measuring antibody responses to 3 vaccines (diphtheria, tetanus, and poliomyelitis vaccine, Haemophilus influenzae type b and meningococcal group C conjugate vaccine, and pneumococcal polysaccharide vaccine). In 20 patients, antibodies to common viruses (mumps, rubella, varicella-zoster, and Epstein-Barr virus) were measured before alemtuzumab treatment, then at 1 and 9-11 months after treatment. Results were compared with well-defined historical controls.ResultsSerum antibodies against common viruses remained detectable after treatment, and vaccine responses were normal to T-cell-dependent recall antigens (tetanus, diphtheria, and polio), a T-cell-dependent novel antigen (meningococcus C), and T-cell-independent antigens (pneumococcal). There was no evidence for a diminished response to vaccinations in 5 patients studied within 6 months of alemtuzumab treatment.ConclusionIn this small historically controlled pilot study, we demonstrated i) retained humoral immunologic memory (in the form of antibodies against common viruses and response to recall antigens), and ii) the retained ability to mount a humoral immune response against a novel antigen after treatment with alemtuzumab.Classification of evidenceThis pilot study provides Class III evidence that patients with relapsing-remitting multiple sclerosis appear immunocompetent after treatment with alemtuzumab.
| S-EPMC3885219 | biostudies-literature
Project description: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 ?-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.
| S-EPMC4519957 | biostudies-literature
Project description:ObjectiveTo characterize changes in myeloid and lymphoid innate immune cells in patients with relapsing-remitting multiple sclerosis (MS) during a 6-month follow-up after alemtuzumab treatment.MethodsCirculating innate immune cells including myeloid cells and innate lymphoid cells (ILCs) were analyzed before and 6 and 12 months after onset of alemtuzumab treatment. Furthermore, a potential effect on granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-23 production by myeloid cells and natural killer (NK) cell cytolytic activity was determined.ResultsIn comparison to CD4+ T lymphocytes, myeloid and lymphoid innate cell subsets of patients with MS expressed significantly lower amounts of CD52 on their cell surface. Six months after CD52 depletion, numbers of circulating plasmacytoid dendritic cells (DCs) and conventional DCs were reduced compared to baseline. GM-CSF and IL-23 production in DCs remained unchanged. Within the ILC compartment, the subset of CD56bright NK cells specifically expanded under alemtuzumab treatment, but their cytolytic activity did not change.ConclusionsOur findings demonstrate that 6 months after alemtuzumab treatment, specific DC subsets are reduced, while CD56bright NK cells expanded in patients with MS. Thus, alemtuzumab specifically restricts the DC compartment and expands the CD56bright NK cell subset with potential immunoregulatory properties in MS. We suggest that remodeling of the innate immune compartment may promote long-term efficacy of alemtuzumab and preserve immunocompetence in patients with MS.
| S-EPMC5063395 | biostudies-literature
Project description:Alemtuzumab (previously known as Campath(®)) is a humanized monoclonal antibody directed against the CD52 antigen on mature lymphocytes that results in lymphopenia and subsequent modification of the immune repertoire. Here we explore evidence for its efficacy and safety in relapsing-remitting multiple sclerosis. One Phase II and two Phase III trials of alemtuzumab versus active comparator (interferon beta-1a) have been reported. Two of these rater-blinded randomized studies assessed clinical and radiological outcomes in treatment-naïve patients; one explored patients who had relapsed despite first-line therapy. Compared to interferon beta-1a, alemtuzumab reduced the relapse rate by 49%-74% (P < 0.0001), and in two studies it reduced the risk of sustained disability accumulation by 42%-71% (P < 0.01). In one study (Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis; CARE-MS1), there was no significant difference compared to interferon, perhaps reflecting the surprisingly low frequency of disability events in the comparator group. After alemtuzumab, the Expanded Disability Status Scale score improved by 0.14-1.2 points, culminating in a net advantage with alemtuzumab of 0.41-0.77 points over interferon in the CAMMS223 and CARE-MS2 trials (both P < 0.001). Radiological markers of new lesion formation and brain atrophy following alemtuzumab were significantly improved when compared to interferon in all studies. Adverse events were more common following alemtuzumab than interferon beta-1a (7.2-8.66 versus 4.9-5.7 events per person-year). While infusion reactions are the most common, autoimmunity is the most concerning; within Phase III studies, thyroid disorders (17%-18% versus 5%-6%) and immune thrombocytopenic purpura (1% versus 0%) were reported in patients taking alemtuzumab and interferon beta-1a, respectively. All patients responded to conventional therapy. One patient taking alemtuzumab in the Phase II study suffered a fatal intracranial hemorrhage following immune thrombocytopenic purpura, heralding assiduous monitoring of all patients thereafter. Alemtuzumab has been submitted for licensing in relapsing-remitting multiple sclerosis in the United States and Europe.
| S-EPMC3593763 | biostudies-literature
Project description:Alemtuzumab is a humanized monoclonal antibody directed against CD52 to deplete circulating T and B lymphocytes; lymphocyte depletion is followed by a distinctive pattern of T- and B-cell repopulation, changing the balance of the immune system. This review reports the efficacy and safety findings of the phase 2 CAMMS223 trial and the phase 3 CARE-MS I and II trials investigating alemtuzumab for the treatment of active relapsing-remitting MS. Alemtuzumab, administered intravenously, was shown to improve relapse rate versus subcutaneous interferon beta-1a in patients who were treatment-naive (CAMMS223 and CARE-MS I) or had relapsed on prior therapy (CARE-MS II), and to reduce sustained accumulation of disability (CAMMS223 and CARE-MS II). Important adverse events were infusion-associated reactions, serious infections and autoimmune events. A safety monitoring program allowed for early detection and management of autoimmune events. Recommendations for the monitoring of adverse events are made. Alemtuzumab's mechanism of action, pharmacodynamics and opportunities for future research are discussed.
| S-EPMC4361497 | biostudies-literature
Project description:Alemtuzumab (Lemtrada™) is a humanized monoclonal antibody approved in more than 50 countries. Within the European Union, alemtuzumab is indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS) with active disease defined by clinical or imaging features; in the USA, the indication states that alemtuzumab should generally be reserved for the treatment of patients with relapsing forms of multiple sclerosis who have had an inadequate response to two or more disease-modifying therapies (DMTs). In clinical trials, alemtuzumab demonstrated efficacy in treatment-naïve patients with active RRMS and those relapsing on prior DMTs, with a consistent and manageable safety and tolerability profile. The European Union indication provides physicians with significant flexibility regarding treatment decisions, affording the opportunity for individualized treatment. Thus, alemtuzumab may be an appropriate treatment choice across a broad range of patients with RRMS, including, for example, treatment-naïve patients with active disease, patients with highly active disease, or for patients relapsing on prior DMTs. There are several practicalities to consider when using alemtuzumab, including the unique dosing regimen, administered via intravenous infusion on 5 consecutive days at baseline and on 3 consecutive days 12 months later, and as-needed retreatment (3 consecutive days at least 12 months after the last course) in cases of disease recurrence. Additionally, routine monthly monitoring is required for up to 48 months after the last infusion to promptly identify potentially serious autoimmune adverse events. Given these considerations, it is beneficial to gain insight into how alemtuzumab is being used in the real-world clinical setting. Here, we report recommendations from European multiple sclerosis experts regarding best practices for alemtuzumab treatment, including management of adverse events and compliance with ongoing safety monitoring requirements.
| S-EPMC5225231 | biostudies-literature
Project description:ObjectiveTo test the hypothesis that accelerated peripheral blood mononuclear cell recovery after alemtuzumab treatment of multiple sclerosis is associated with recurrent disease activity and to investigate the claim that CD4 counts greater than 388.5 × 10(6) cells/mL at 12 months can be used to identify patients who may benefit from further treatment.MethodsA total of 108 patients were followed for a median of 99 months post alemtuzumab. Patients were classified as active or nonactive after each cycle of treatment based on clinical relapse, increasing disability, or new T2/enhancing MRI lesions. These outcomes were correlated with CD4, CD8, CD19, CD56+ NK, and monocyte counts.ResultsOf 108 patients, 56 (52%) relapsed at some point during follow-up. Mean annualized relapse rate after alemtuzumab was 0.17 vs 1.67 prior to treatment (equating to a 90% reduction). Of 108 patients, 28 (26%) met the criteria for sustained accumulation of disability. Median time to the lower limit of normal for CD19, CD8, and CD4 was 3, 19.5, and 32 months, respectively. There was no significant difference in the recovery of any cell population between patients with and without disease activity or accumulation of disability after treatment.ConclusionThis study does not support the use of cell counts as biomarkers for identifying patients at greater risk of active disease following treatment with alemtuzumab.
| S-EPMC4113466 | biostudies-literature
Project description:BackgroundAlemtuzumab is a monoclonal antibody directed against CD52 that depletes T and B lymphocytes.ObjectiveTo evaluate the treatment effect of alemtuzumab on low-contrast vision in relapsing-remitting multiple sclerosis (RRMS) patients.MethodsThis was a pre-defined exploratory analysis within a randomized, rater-blinded trial (CAMMS223) that was run at 49 academic medical centers in the US and in Europe. Patients with untreated, early, RRMS (McDonald, n = 334) were randomized 1:1:1 to subcutaneous interferon beta-1a (IFNB-1a), or alemtuzumab 12 mg or 24 mg. Visual contrast sensitivity was measured for each eye at baseline and quarterly, with Pelli-Robson charts.ResultsThe eyes of patients in the pooled alemtuzumab group (versus IFNB-1a) had a greater than 2-fold higher rate of both 3-month and 6-month sustained visual improvement, of at least 0.3 log units (2 triplets, 6 letters) (At 3 months the hazard ratio (HR) = 2.26; CI = 1.19 to 4.31; P = 0.013; and at 6 months the HR = 2.44; CI =1.16 to 5.15; P = 0.019), and they had a lower risk of 3- and 6-month sustained worsening of at least 0.15 log units (1 triplet, 3 letters) (At 3 months the HR = 0.58; CI = 0.38 to 0.89; P = 0.012; and at 6 months HR = 0.55; CI=0.35 to 0.87; P = 0.010). Over the 36-month study period, the eyes of patients in the pooled alemtuzumab group improved in mean contrast sensitivity to a greater extent than those in the IFNB-1a group (0.080 log units versus 0.038 log units; P = 0.0102).ConclusionsAlemtuzumab was associated with a greater chance of improved contrast sensitivity in patients with RRMS and may delay the worsening of visual function. Contrast sensitivity testing was sensitive to treatment effects, even within an active comparator study design. These results support the validity of low-contrast vision testing as a clinical outcome in MS trials.
| S-EPMC3807733 | biostudies-literature
Project description:IntroductionAlemtuzumab is a highly effective pulsed immune reconstitution therapy for multiple sclerosis (MS).AimTo evaluate serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) in patients with relapsing-remitting MS who have been treated with Alemtuzumab over the course of 2 years.MethodsThis prospective study involved MS patients treated with Alemtuzumab at a referral MS center. Both sNfL and sGFAP were analyzed at baseline and then again at 6, 12, and 24 months post-treatment using the single molecule array (SiMoA) technique. We also recruited matched healthy controls (HCs) for comparison.ResultsThe study included 46 patients (with a median age of 34.2 [Interquartile range (IQR), 28.7-42.3] years, 27 of which were women [58%]) and 76 HCs. No differences in demographic characteristics were observed between patients and HC. The median disease duration was 6.22 (IQR, 1.56-10.13) years. The median annualized relapse rate before treatment was 2 (IQR, 1-3). At baseline, sNfL and sGFAP levels were higher in MS patients (median of 18.8 [IQR, 10.7-52.7] pg/ml and 158.9 [IQR, 126.9-255.5] pg/ml, respectively) when compared to HC (6.11 [IQR, 2.03-8.54] pg/ml and 91.0 [72.6-109] pg/ml, respectively) (p<0.001 for both comparisons). The data indicates that 80% of patients had high (≥10 pg/ml) sNfL values at baseline. We observed a significant decrease in sNfL levels at 6 (65%, p = 0.02), 12 (70.8%, p<0.001), and 24 (78.1%, p<0.001) months. sNfL reached similar levels to HC only after 24 months of Alemtuzumab treatment. During the follow-up period, no changes were identified in the sGFAP values.ConclusionAlemtuzumab leads to the normalization of sNfL values in MS patients after 2 years of treatment, with no apparent effect on sGFAP values.
| S-EPMC11366608 | biostudies-literature