Background: Alemtuzumab efficacy and safety were established in phase 3 randomized trials. We cha... more Background: Alemtuzumab efficacy and safety were established in phase 3 randomized trials. We characterize vital signs during and after the first alemtuzumab infusion course. Methods: Patients with relapsing-remitting multiple sclerosis commercially prescribed alemtuzumab 12 mg/day on 5 consecutive days (initial course) were enrolled in this prospective, observational study. Preinfusion medications included methylprednisolone, antihistamine, and antipyretics. Primary end point: change from precourse baseline in vital signs during and 2 hours after each alemtuzumab infusion. Secondary end points: infusion duration and serious adverse events (AEs) starting within 24 hours and within 7 days after infusion (AEs collected up to 15 days after treatment). Potentially clinically significant vital sign abnormalities were based on predefined thresholds from literature review. Results: In the 304 patients treated, minimal increases in mean systolic (≤8 mm Hg) and diastolic (≤3 mm Hg) blood pre...
Summary Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is approved for treatment of rela... more Summary 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 treat...
Background: Alemtuzumab is given as two annual courses. Patients with continued disease activity ... more Background: Alemtuzumab is given as two annual courses. Patients with continued disease activity may receive as-needed additional courses. Objective: To evaluate efficacy and safety of additional alemtuzumab courses in the CARE-MS (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis) studies and their extensions. Methods: Subgroups were based on the number of additional alemtuzumab courses received. Exclusion criteria: other disease-modifying therapy (DMT); <12-month follow-up after last alemtuzumab course. Results: In the additional-courses groups, Courses 3 and 4 reduced annualized relapse rate (12 months before: 0.73 and 0.74, respectively; 12 months after: 0.07 and 0.08). For 36 months after Courses 3 and 4, 89% and 92% of patients were free of 6-month confirmed disability worsening, respectively, with 20% and 26% achieving 6-month confirmed disability improvement. Freedom from magnetic resonance imaging (MRI) disease activity increased after Courses 3 and 4 (...
Supplemental material, sj-pdf-1-mso-10.1177_2055217320972137 for Proportion of alemtuzumab-treate... more Supplemental material, sj-pdf-1-mso-10.1177_2055217320972137 for Proportion of alemtuzumab-treated patients converting from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis over 6 years by Dana Horáková, Aaron Boster, Antonio Bertolotto, Mark S Freedman, Isabel Firmino*, Steven J Cavalier, Alan K Jacobs*, Karthinathan Thangavelu*, Nadia Daizadeh, Elizabeth M Poole*, Darren P Baker, David H Margolin*, Tjalf Ziemssen and on behalf of the CARE-MS I, CARE-MS II, and CAMMS03409 Investigators in Multiple Sclerosis Journal—Experimental, Translational and Clinical
ObjectiveTo examine the association between peripheral blood lymphocyte pharmacodynamics and auto... more ObjectiveTo examine the association between peripheral blood lymphocyte pharmacodynamics and autoimmune adverse events (AEs) or return of disease activity in alemtuzumab-treated patients with relapsing-remitting MS.MethodsPatients received 2 alemtuzumab courses (12 mg/d IV; 5 days at baseline, 3 days 12 months later) in the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis studies (NCT00530348 and NCT00548405) and could then receive as-needed alemtuzumab or other disease-modifying therapy in a 4-year extension (NCT00930553). Lymphocytes were phenotyped quarterly over 2 years using fluorescence-activated cell sorting. Pharmacodynamic assessments included counts of total lymphocytes, CD3+ T cells, CD4+/CD8+ T cells (total/naive/memory/regulatory [Treg]), and CD19+ B cells (total/immature/mature/memory) and ratios of CD19+ (total/immature/mature/memory) to Treg (CD4+/CD8+) counts. Assessed autoimmune AEs included immune thrombocytopenia, nephropathies, and thyro...
Two cases of headache during pregnancy were associated with MRI findings suggestive of venous sin... more Two cases of headache during pregnancy were associated with MRI findings suggestive of venous sinus thrombosis. The findings, however, were atypical, and of uncertain clinical significance. Venous sinus thrombosis typically does not occur during the first and second trimesters (less than 10 percent of reported cases). Thus, these two cases are doubly unusual. The correct significance of these equivocal MRI findings of possible venous sinus thrombosis must be understood so that unnecessary and potentially harmful therapies are not employed, and so that appropriate management of what may otherwise be a typical vascular headache syndrome may be undertaken.
Multiple Sclerosis Journal - Experimental, Translational and Clinical, 2020
Background Few data exist concerning conversion to secondary progressive MS in patients treated w... more Background Few data exist concerning conversion to secondary progressive MS in patients treated with disease-modifying therapies. Objective Determine the proportion of alemtuzumab-treated patients converting from relapsing-remitting to secondary progressive MS during the CARE-MS core and extension studies. Methods Patients ( N = 811) were analyzed post hoc for secondary progressive MS conversion. Optimal conversion definition: Expanded Disability Status Scale (EDSS) score ≥4, pyramidal functional system score ≥2, and confirmed progression over ≥3 months including confirmation within the functional system leading to progression, independent of relapse. Results Over 6.2 years median follow-up, 20 alemtuzumab-treated patients converted (Kaplan-Meier estimate, 2.7%; 95% confidence interval, 1.8%–4.2%). Sensitivity analysis accounting for dropouts showed similar results (3%), as did analyses using alternative definitions with different EDSS thresholds and/or confirmation periods, and ana...
Background: Alemtuzumab efficacy and safety were established in phase 3 randomized trials. We cha... more Background: Alemtuzumab efficacy and safety were established in phase 3 randomized trials. We characterize vital signs during and after the first alemtuzumab infusion course. Methods: Patients with relapsing-remitting multiple sclerosis commercially prescribed alemtuzumab 12 mg/day on 5 consecutive days (initial course) were enrolled in this prospective, observational study. Preinfusion medications included methylprednisolone, antihistamine, and antipyretics. Primary end point: change from precourse baseline in vital signs during and 2 hours after each alemtuzumab infusion. Secondary end points: infusion duration and serious adverse events (AEs) starting within 24 hours and within 7 days after infusion (AEs collected up to 15 days after treatment). Potentially clinically significant vital sign abnormalities were based on predefined thresholds from literature review. Results: In the 304 patients treated, minimal increases in mean systolic (≤8 mm Hg) and diastolic (≤3 mm Hg) blood pre...
Summary Alemtuzumab, a humanized anti-CD52 monoclonal antibody, is approved for treatment of rela... more Summary 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 treat...
Background: Alemtuzumab is given as two annual courses. Patients with continued disease activity ... more Background: Alemtuzumab is given as two annual courses. Patients with continued disease activity may receive as-needed additional courses. Objective: To evaluate efficacy and safety of additional alemtuzumab courses in the CARE-MS (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis) studies and their extensions. Methods: Subgroups were based on the number of additional alemtuzumab courses received. Exclusion criteria: other disease-modifying therapy (DMT); <12-month follow-up after last alemtuzumab course. Results: In the additional-courses groups, Courses 3 and 4 reduced annualized relapse rate (12 months before: 0.73 and 0.74, respectively; 12 months after: 0.07 and 0.08). For 36 months after Courses 3 and 4, 89% and 92% of patients were free of 6-month confirmed disability worsening, respectively, with 20% and 26% achieving 6-month confirmed disability improvement. Freedom from magnetic resonance imaging (MRI) disease activity increased after Courses 3 and 4 (...
Supplemental material, sj-pdf-1-mso-10.1177_2055217320972137 for Proportion of alemtuzumab-treate... more Supplemental material, sj-pdf-1-mso-10.1177_2055217320972137 for Proportion of alemtuzumab-treated patients converting from relapsing-remitting multiple sclerosis to secondary progressive multiple sclerosis over 6 years by Dana Horáková, Aaron Boster, Antonio Bertolotto, Mark S Freedman, Isabel Firmino*, Steven J Cavalier, Alan K Jacobs*, Karthinathan Thangavelu*, Nadia Daizadeh, Elizabeth M Poole*, Darren P Baker, David H Margolin*, Tjalf Ziemssen and on behalf of the CARE-MS I, CARE-MS II, and CAMMS03409 Investigators in Multiple Sclerosis Journal—Experimental, Translational and Clinical
ObjectiveTo examine the association between peripheral blood lymphocyte pharmacodynamics and auto... more ObjectiveTo examine the association between peripheral blood lymphocyte pharmacodynamics and autoimmune adverse events (AEs) or return of disease activity in alemtuzumab-treated patients with relapsing-remitting MS.MethodsPatients received 2 alemtuzumab courses (12 mg/d IV; 5 days at baseline, 3 days 12 months later) in the 2-year Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis studies (NCT00530348 and NCT00548405) and could then receive as-needed alemtuzumab or other disease-modifying therapy in a 4-year extension (NCT00930553). Lymphocytes were phenotyped quarterly over 2 years using fluorescence-activated cell sorting. Pharmacodynamic assessments included counts of total lymphocytes, CD3+ T cells, CD4+/CD8+ T cells (total/naive/memory/regulatory [Treg]), and CD19+ B cells (total/immature/mature/memory) and ratios of CD19+ (total/immature/mature/memory) to Treg (CD4+/CD8+) counts. Assessed autoimmune AEs included immune thrombocytopenia, nephropathies, and thyro...
Two cases of headache during pregnancy were associated with MRI findings suggestive of venous sin... more Two cases of headache during pregnancy were associated with MRI findings suggestive of venous sinus thrombosis. The findings, however, were atypical, and of uncertain clinical significance. Venous sinus thrombosis typically does not occur during the first and second trimesters (less than 10 percent of reported cases). Thus, these two cases are doubly unusual. The correct significance of these equivocal MRI findings of possible venous sinus thrombosis must be understood so that unnecessary and potentially harmful therapies are not employed, and so that appropriate management of what may otherwise be a typical vascular headache syndrome may be undertaken.
Multiple Sclerosis Journal - Experimental, Translational and Clinical, 2020
Background Few data exist concerning conversion to secondary progressive MS in patients treated w... more Background Few data exist concerning conversion to secondary progressive MS in patients treated with disease-modifying therapies. Objective Determine the proportion of alemtuzumab-treated patients converting from relapsing-remitting to secondary progressive MS during the CARE-MS core and extension studies. Methods Patients ( N = 811) were analyzed post hoc for secondary progressive MS conversion. Optimal conversion definition: Expanded Disability Status Scale (EDSS) score ≥4, pyramidal functional system score ≥2, and confirmed progression over ≥3 months including confirmation within the functional system leading to progression, independent of relapse. Results Over 6.2 years median follow-up, 20 alemtuzumab-treated patients converted (Kaplan-Meier estimate, 2.7%; 95% confidence interval, 1.8%–4.2%). Sensitivity analysis accounting for dropouts showed similar results (3%), as did analyses using alternative definitions with different EDSS thresholds and/or confirmation periods, and ana...
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Papers by Alan Jacobs