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Publication Detail
Specific Patterns of Immune Cell Dynamics May Explain the Early Onset and Prolonged Efficacy of Cladribine Tablets: A MAGNIFY-MS Substudy
  • Publication Type:
    Journal article
  • Authors:
    Wiendl H, Schmierer K, Hodgkinson S, Derfuss T, Chan A, Sellebjerg F, Achiron A, Montalban X, Prat A, De Stefano N, Barkhof F, Leocani L, Vermersch P, Chudecka A, Mwape C, Holmberg KH, Boschert U, Roy S, MAGNIFY-MS Study Group
  • Publisher:
    Ovid Technologies (Wolters Kluwer Health)
  • Publication date:
  • Journal:
    Neurology: Neuroimmunology & Neuroinflammation
  • Volume:
  • Issue:
  • Article number:
  • Medium:
  • Status:
  • Country:
    United States
  • Print ISSN:
  • PII:
  • Language:
  • Keywords:
    Humans, Cladribine, Leukocytes, Mononuclear, CD8-Positive T-Lymphocytes, Multiple Sclerosis, Tablets, Antigens, CD20, Antigens, CD19, Immunoglobulin G, Immunoglobulin M
  • Notes:
    Copyright © 2022 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) (http://creativecommons.org/licenses/by-nc-nd/4.0/), 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.
BACKGROUND AND OBJECTIVES: Cladribine tablets cause a reduction in lymphocytes with a predominant effect on B-cell and T-cell counts. The MAGNIFY-MS substudy reports the dynamic changes on multiple peripheral blood mononuclear cell (PBMC) subtypes and immunoglobulin (Ig) levels over 12 months after the first course of cladribine tablets in patients with highly active relapsing multiple sclerosis (MS). METHODS: Immunophenotyping was performed at baseline (predose) and at the end of months 1, 2, 3, 6, and 12 after initiating treatment with cladribine tablets. Assessments included lymphocyte subtype counts of CD19+ B cells, CD4+ and CD8+ T cells, CD16+ natural killer cells, plasmablasts, and Igs. Immune cell subtypes were analyzed by flow cytometry, and serum IgG and IgM were analyzed by nephelometric assay. Absolute cell counts and percentage change from baseline were assessed. RESULTS: The full analysis set included 57 patients. Rapid reductions in median CD19+, CD20+, memory, activated, and naive B-cell counts were detected, reaching nadir by month 2. Thereafter, total CD19+, CD20+, and naive B-cell counts subsequently reconstituted, but memory B cells remained reduced by 93%-87% for the remainder of the study. The decrease in plasmablasts was slower, reaching nadir at month 3. Decrease in T-cell subtypes was also slower and more moderate compared with B-cell subtypes, reaching nadir between months 3 and 6. IgG and IgM levels remained within the normal range over the 12-month study period. DISCUSSION: Cladribine tablets induce a specific pattern of early and sustained PBMC subtype dynamics in the absence of relevant Ig changes: While total B cells were reduced dramatically, T cells were affected significantly less. Naive B cells recovered toward baseline, naive CD4 and CD8 T cells did not, and memory B cells remained reduced. The results help to explain the unique immune depletion and repopulation architecture regarding onset of action and durability of effects of cladribine tablets while largely maintaining immune competence. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03364036. Date registered: December 06, 2017.
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