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January 2020; 7 (1) ArticleOpen Access

Lymphocyte pharmacodynamics are not associated with autoimmunity or efficacy after alemtuzumab

Heinz Wiendl, Matthew Carraro, Giancarlo Comi, Guillermo Izquierdo, Ho Jin Kim, Basil Sharrack, Carlo Tornatore, Nadia Daizadeh, Luke Chung, Alan K. Jacobs, Richard J. Hogan, Linda V. Wychowski, Bart Van Wijmeersch
First published October 29, 2019, DOI: https://doi.org/10.1212/NXI.0000000000000635
Heinz Wiendl
From the University of Münster (H.W.), Münster, Germany; Novant Health (M.C.), Charlotte, NC; University Vita-Salute San Raffaele (G.C.), Milan, Italy; Virgen Macarena University Hospital (G.I.), Seville, Spain; Research Institute and Hospital of National Cancer Center (H.J.K.), Goyang, South Korea; NIHR Sheffield Biomedical Research Centre, Sheffield Teaching Hospitals, University of Sheffield (B.S.), Sheffield, United Kingdom; Georgetown University Medical Center (C.T.), Washington, DC; Sanofi (N.D., L.C., A.K.J.), Cambridge, MA; Eloquent Scientific Solutions (R.J.H.), Sydney, NSW, Australia; Eloquent Scientific Solutions (L.V.W.), Philadelphia, PA; and Rehabilitation & MS-Centre Overpelt (B.V.W.), BIOMED, Hasselt University, Hasselt, Belgium.
MD, PhD
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Matthew Carraro
From the University of Münster (H.W.), Münster, Germany; Novant Health (M.C.), Charlotte, NC; University Vita-Salute San Raffaele (G.C.), Milan, Italy; Virgen Macarena University Hospital (G.I.), Seville, Spain; Research Institute and Hospital of National Cancer Center (H.J.K.), Goyang, South Korea; NIHR Sheffield Biomedical Research Centre, Sheffield Teaching Hospitals, University of Sheffield (B.S.), Sheffield, United Kingdom; Georgetown University Medical Center (C.T.), Washington, DC; Sanofi (N.D., L.C., A.K.J.), Cambridge, MA; Eloquent Scientific Solutions (R.J.H.), Sydney, NSW, Australia; Eloquent Scientific Solutions (L.V.W.), Philadelphia, PA; and Rehabilitation & MS-Centre Overpelt (B.V.W.), BIOMED, Hasselt University, Hasselt, Belgium.
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Giancarlo Comi
From the University of Münster (H.W.), Münster, Germany; Novant Health (M.C.), Charlotte, NC; University Vita-Salute San Raffaele (G.C.), Milan, Italy; Virgen Macarena University Hospital (G.I.), Seville, Spain; Research Institute and Hospital of National Cancer Center (H.J.K.), Goyang, South Korea; NIHR Sheffield Biomedical Research Centre, Sheffield Teaching Hospitals, University of Sheffield (B.S.), Sheffield, United Kingdom; Georgetown University Medical Center (C.T.), Washington, DC; Sanofi (N.D., L.C., A.K.J.), Cambridge, MA; Eloquent Scientific Solutions (R.J.H.), Sydney, NSW, Australia; Eloquent Scientific Solutions (L.V.W.), Philadelphia, PA; and Rehabilitation & MS-Centre Overpelt (B.V.W.), BIOMED, Hasselt University, Hasselt, Belgium.
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Guillermo Izquierdo
From the University of Münster (H.W.), Münster, Germany; Novant Health (M.C.), Charlotte, NC; University Vita-Salute San Raffaele (G.C.), Milan, Italy; Virgen Macarena University Hospital (G.I.), Seville, Spain; Research Institute and Hospital of National Cancer Center (H.J.K.), Goyang, South Korea; NIHR Sheffield Biomedical Research Centre, Sheffield Teaching Hospitals, University of Sheffield (B.S.), Sheffield, United Kingdom; Georgetown University Medical Center (C.T.), Washington, DC; Sanofi (N.D., L.C., A.K.J.), Cambridge, MA; Eloquent Scientific Solutions (R.J.H.), Sydney, NSW, Australia; Eloquent Scientific Solutions (L.V.W.), Philadelphia, PA; and Rehabilitation & MS-Centre Overpelt (B.V.W.), BIOMED, Hasselt University, Hasselt, Belgium.
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Ho Jin Kim
From the University of Münster (H.W.), Münster, Germany; Novant Health (M.C.), Charlotte, NC; University Vita-Salute San Raffaele (G.C.), Milan, Italy; Virgen Macarena University Hospital (G.I.), Seville, Spain; Research Institute and Hospital of National Cancer Center (H.J.K.), Goyang, South Korea; NIHR Sheffield Biomedical Research Centre, Sheffield Teaching Hospitals, University of Sheffield (B.S.), Sheffield, United Kingdom; Georgetown University Medical Center (C.T.), Washington, DC; Sanofi (N.D., L.C., A.K.J.), Cambridge, MA; Eloquent Scientific Solutions (R.J.H.), Sydney, NSW, Australia; Eloquent Scientific Solutions (L.V.W.), Philadelphia, PA; and Rehabilitation & MS-Centre Overpelt (B.V.W.), BIOMED, Hasselt University, Hasselt, Belgium.
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Basil Sharrack
From the University of Münster (H.W.), Münster, Germany; Novant Health (M.C.), Charlotte, NC; University Vita-Salute San Raffaele (G.C.), Milan, Italy; Virgen Macarena University Hospital (G.I.), Seville, Spain; Research Institute and Hospital of National Cancer Center (H.J.K.), Goyang, South Korea; NIHR Sheffield Biomedical Research Centre, Sheffield Teaching Hospitals, University of Sheffield (B.S.), Sheffield, United Kingdom; Georgetown University Medical Center (C.T.), Washington, DC; Sanofi (N.D., L.C., A.K.J.), Cambridge, MA; Eloquent Scientific Solutions (R.J.H.), Sydney, NSW, Australia; Eloquent Scientific Solutions (L.V.W.), Philadelphia, PA; and Rehabilitation & MS-Centre Overpelt (B.V.W.), BIOMED, Hasselt University, Hasselt, Belgium.
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Carlo Tornatore
From the University of Münster (H.W.), Münster, Germany; Novant Health (M.C.), Charlotte, NC; University Vita-Salute San Raffaele (G.C.), Milan, Italy; Virgen Macarena University Hospital (G.I.), Seville, Spain; Research Institute and Hospital of National Cancer Center (H.J.K.), Goyang, South Korea; NIHR Sheffield Biomedical Research Centre, Sheffield Teaching Hospitals, University of Sheffield (B.S.), Sheffield, United Kingdom; Georgetown University Medical Center (C.T.), Washington, DC; Sanofi (N.D., L.C., A.K.J.), Cambridge, MA; Eloquent Scientific Solutions (R.J.H.), Sydney, NSW, Australia; Eloquent Scientific Solutions (L.V.W.), Philadelphia, PA; and Rehabilitation & MS-Centre Overpelt (B.V.W.), BIOMED, Hasselt University, Hasselt, Belgium.
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Nadia Daizadeh
From the University of Münster (H.W.), Münster, Germany; Novant Health (M.C.), Charlotte, NC; University Vita-Salute San Raffaele (G.C.), Milan, Italy; Virgen Macarena University Hospital (G.I.), Seville, Spain; Research Institute and Hospital of National Cancer Center (H.J.K.), Goyang, South Korea; NIHR Sheffield Biomedical Research Centre, Sheffield Teaching Hospitals, University of Sheffield (B.S.), Sheffield, United Kingdom; Georgetown University Medical Center (C.T.), Washington, DC; Sanofi (N.D., L.C., A.K.J.), Cambridge, MA; Eloquent Scientific Solutions (R.J.H.), Sydney, NSW, Australia; Eloquent Scientific Solutions (L.V.W.), Philadelphia, PA; and Rehabilitation & MS-Centre Overpelt (B.V.W.), BIOMED, Hasselt University, Hasselt, Belgium.
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Luke Chung
From the University of Münster (H.W.), Münster, Germany; Novant Health (M.C.), Charlotte, NC; University Vita-Salute San Raffaele (G.C.), Milan, Italy; Virgen Macarena University Hospital (G.I.), Seville, Spain; Research Institute and Hospital of National Cancer Center (H.J.K.), Goyang, South Korea; NIHR Sheffield Biomedical Research Centre, Sheffield Teaching Hospitals, University of Sheffield (B.S.), Sheffield, United Kingdom; Georgetown University Medical Center (C.T.), Washington, DC; Sanofi (N.D., L.C., A.K.J.), Cambridge, MA; Eloquent Scientific Solutions (R.J.H.), Sydney, NSW, Australia; Eloquent Scientific Solutions (L.V.W.), Philadelphia, PA; and Rehabilitation & MS-Centre Overpelt (B.V.W.), BIOMED, Hasselt University, Hasselt, Belgium.
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Alan K. Jacobs
From the University of Münster (H.W.), Münster, Germany; Novant Health (M.C.), Charlotte, NC; University Vita-Salute San Raffaele (G.C.), Milan, Italy; Virgen Macarena University Hospital (G.I.), Seville, Spain; Research Institute and Hospital of National Cancer Center (H.J.K.), Goyang, South Korea; NIHR Sheffield Biomedical Research Centre, Sheffield Teaching Hospitals, University of Sheffield (B.S.), Sheffield, United Kingdom; Georgetown University Medical Center (C.T.), Washington, DC; Sanofi (N.D., L.C., A.K.J.), Cambridge, MA; Eloquent Scientific Solutions (R.J.H.), Sydney, NSW, Australia; Eloquent Scientific Solutions (L.V.W.), Philadelphia, PA; and Rehabilitation & MS-Centre Overpelt (B.V.W.), BIOMED, Hasselt University, Hasselt, Belgium.
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Richard J. Hogan
From the University of Münster (H.W.), Münster, Germany; Novant Health (M.C.), Charlotte, NC; University Vita-Salute San Raffaele (G.C.), Milan, Italy; Virgen Macarena University Hospital (G.I.), Seville, Spain; Research Institute and Hospital of National Cancer Center (H.J.K.), Goyang, South Korea; NIHR Sheffield Biomedical Research Centre, Sheffield Teaching Hospitals, University of Sheffield (B.S.), Sheffield, United Kingdom; Georgetown University Medical Center (C.T.), Washington, DC; Sanofi (N.D., L.C., A.K.J.), Cambridge, MA; Eloquent Scientific Solutions (R.J.H.), Sydney, NSW, Australia; Eloquent Scientific Solutions (L.V.W.), Philadelphia, PA; and Rehabilitation & MS-Centre Overpelt (B.V.W.), BIOMED, Hasselt University, Hasselt, Belgium.
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Linda V. Wychowski
From the University of Münster (H.W.), Münster, Germany; Novant Health (M.C.), Charlotte, NC; University Vita-Salute San Raffaele (G.C.), Milan, Italy; Virgen Macarena University Hospital (G.I.), Seville, Spain; Research Institute and Hospital of National Cancer Center (H.J.K.), Goyang, South Korea; NIHR Sheffield Biomedical Research Centre, Sheffield Teaching Hospitals, University of Sheffield (B.S.), Sheffield, United Kingdom; Georgetown University Medical Center (C.T.), Washington, DC; Sanofi (N.D., L.C., A.K.J.), Cambridge, MA; Eloquent Scientific Solutions (R.J.H.), Sydney, NSW, Australia; Eloquent Scientific Solutions (L.V.W.), Philadelphia, PA; and Rehabilitation & MS-Centre Overpelt (B.V.W.), BIOMED, Hasselt University, Hasselt, Belgium.
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Bart Van Wijmeersch
From the University of Münster (H.W.), Münster, Germany; Novant Health (M.C.), Charlotte, NC; University Vita-Salute San Raffaele (G.C.), Milan, Italy; Virgen Macarena University Hospital (G.I.), Seville, Spain; Research Institute and Hospital of National Cancer Center (H.J.K.), Goyang, South Korea; NIHR Sheffield Biomedical Research Centre, Sheffield Teaching Hospitals, University of Sheffield (B.S.), Sheffield, United Kingdom; Georgetown University Medical Center (C.T.), Washington, DC; Sanofi (N.D., L.C., A.K.J.), Cambridge, MA; Eloquent Scientific Solutions (R.J.H.), Sydney, NSW, Australia; Eloquent Scientific Solutions (L.V.W.), Philadelphia, PA; and Rehabilitation & MS-Centre Overpelt (B.V.W.), BIOMED, Hasselt University, Hasselt, Belgium.
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Citation
Lymphocyte pharmacodynamics are not associated with autoimmunity or efficacy after alemtuzumab
Heinz Wiendl, Matthew Carraro, Giancarlo Comi, Guillermo Izquierdo, Ho Jin Kim, Basil Sharrack, Carlo Tornatore, Nadia Daizadeh, Luke Chung, Alan K. Jacobs, Richard J. Hogan, Linda V. Wychowski, Bart Van Wijmeersch
Neurol Neuroimmunol Neuroinflamm Jan 2020, 7 (1) e635; DOI: 10.1212/NXI.0000000000000635

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Abstract

Objective 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.

Methods 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 [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 thyroid events. Efficacy assessments included relapses, 6-month confirmed disability worsening (CDW), and MRI disease activity.

Results Lymphocyte repopulation patterns, including ratios between distinct lymphocyte subsets (e.g., CD19+ to Treg 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.

Conclusions 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.

Glossary

AE=
adverse event;
Breg=
regulatory B;
CARE-MS=
Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis;
CDW=
confirmed disability worsening;
EDSS=
Expanded Disability Status Scale;
MMRM=
mixed-effects model for repeated measures;
NEDA=
no evidence of disease activity;
RRMS=
relapsing-remitting MS;
Treg=
regulatory T

Footnotes

  • Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.

  • The Article Processing Charge was funded by Sanofi.

  • CARE-MS I, CARE-MS II, and CAMMS03409 coinvestigators are listed at links.lww.com/NXI/A163.

  • Received May 15, 2019.
  • Accepted in final form September 5, 2019.
  • Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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