To 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.
Patients 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 [T reg]), and CD19 + B cells (total/immature/mature/memory) and ratios of CD19 + (total/immature/mature/memory) to T reg (CD4 +/CD8 +) counts. Assessed autoimmune AEs included immune thrombocytopenia, nephropathies, and thyroid events. Efficacy assessments included relapses, 6-month confirmed disability worsening (CDW), and MRI disease activity.
Lymphocyte repopulation patterns, including ratios between distinct lymphocyte subsets (e.g., CD19 + to T reg cell count ratios), showed no significant differences over 2 years in patients developing/not developing autoimmune AEs, relapses, CDW, or MRI activity through 6 years following alemtuzumab. Lymphocyte kinetics were also unrelated to multiple autoimmune AEs or extreme clinical phenotypes.
Repopulation kinetics of the evaluated peripheral lymphocyte subsets did not predict autoimmune AE occurrence or disease activity, including return of disease activity after 2 alemtuzumab courses. Further study is needed to investigate potential antigen-level markers of treatment response.
(1) Bayer Healthcare (2) Biogen Idec (3) Sanofi- Genzyme (4) Merck Serono (5) Novartis (6) Roche (7) Teva
(1) Bayer Vital GmbH (2) Bayer Schering AG (3) Biogen (4) CSL Behring (5) EMD Serono (6) Fresenius Medical Care (7) Sanofi - Genzyme (8) Merck Serono (9) Omniamed (10) Novartis (11) Teva (12) GlaxoSmithKline (13) GW Pharmaceuticals
(1) PLOS ONE, Editorial board member, since 2013 (2) Neurotherapeutics, since 2013 (3) Recent Patents on Inflammation & Allergy Drug Discovery
(1) Bayer Healthcare (2) Bayer Vital (3) Biogen (4) Merck Serono (5) Novartis (6) Sanofi – Genzyme (7) Sanofi US (8) TEVA Pharma
(1) German Ministry for Education and Research (BMBF), 01GI1601E, principal investigator, 2016-2019 (2)Interdisciplinary Centre of Clinical Research (IZKF) Muenster, principal investigator, 2015-2018 (4)PML Consortium, principal investigator, 2016-2018 (5) German Research Foundation, principal investigator,SFB 1009 TP A3 + SFB-TR CRC128 TP A09 + SFB TR CRC128 TP A10, TR CRC128 TP V, TR CRC128 TP Z02 2016- 2020
(1) Else Kröner Fresenius Foundation (2) Fresenius Foundation (3) Hertie Foundation (4) RE Children’s Foundation
Received personal fees from Novartis, Teva, Sanofi Genzyme, Merck, Biogen, Roche, Almirall, Celgene, Forward Pharma, Medday and Excemed
Received personal fees from Novartis, Teva, Sanofi Genzyme, Merck, Biogen, Roche, Almirall, Celgene, Forward Pharma, Medday and Excemed
Received personal fees from Novartis, Teva, Sanofi Genzyme, Merck, Biogen, Roche, Almirall, Celgene, Forward Pharma, Medday and Excemed
Received travel expenses and/or honoraria for lectures or educational activities from Bayer Schering Pharma, Celltrion, Eisai, HanAll BioPharma, MedImmune, Merck Serono, Novartis, Sanofi Genzyme, and Teva-Handok.
Multiple Sclerosis Journal – Experimental, Translational and Clinical, Coeditor, 2014 Journal of Clinical Neurology, Associate Editor, 2016
Bayer Schering Pharma, HanAll BioPharma, Medimmune, Merck, Novartis, Sanofi Genzyme, and Teva-Handok
National Research Foundation of Korea, M3A9B6069339, Co- Principal Investigator, 2015 National Research Foundation of Korea, 2018R1A5A2023127, Co- Principal Investigator, 2018
Sanofi Genzyme, Global Medical Lead - Lemtrada, 5 years I am currently an employee of Sanofi Genzyme, Sanofi.
I am an employee of Sanofi Genzyme as such I receive compensation in the form of stock or stock option Stock/Stock Options, Medical Equipment & Materials: I am an employee of Sanofi Genzyme as such I receive compensation in the form of stock or stock option
Actelion, Bayer-Schering, Biogen-Idec, Sanofi/Genzyme, Merck-Serono, Novartis, Roche and TEVA.
Speaker Honoraria from Actelion, Bayer-Schering, Biogen-Idec, Sanofi/Genzyme,Merck-Serono, Novartis, Roche and TEVA.
Research Grant from Biogen-Idec, Sanofi/Genzyme, Merck-Serono, Novartis, Roche
Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.
CARE-MS I, CARE-MS II, and CAMMS03409 coinvestigators are listed at links.lww.com/NXI/A163.
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