Specific Patterns of Immune Cell Dynamics May Explain the Early Onset and Prolonged Efficacy of Cladribine Tablets: A MAGNIFY-MS Substudy.

Heinz Wiendl Klaus Schmierer Suzanne Hodgkinson Tobias Derfuss Andrew Chan Finn Sellebjerg Anat Achiron Xavier Montalban Alexandre Prat Nicola De Stefano Frederik Barkhof Letizia Leocani Patrick Vermersch Anita Chudecka Claire Mwape Kristina H Holmberg Ursula Boschert Sanjeev Roy

Neurol Neuroimmunol Neuroinflamm

From the Department of Neurology with Institute of Translational Neurology (H.W.), University of Münster, Germany and Brain and Mind Center, University of Sydney, Australia; The Blizard Institute (K.S.), Centre for Neuroscience, Surgery & Trauma, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, UK; Clinical Board Medicine (Neuroscience) (K.S.), The Royal London Hospital, Barts Health NHS Trust, UK; Ingham Institute for Applied Medical Research (S.H.), University of New South Wales Medicine, Sydney, Australia; Department of Neurology (T.D.), University Hospital Basel, Switzerland; Department of Neurology (Andrew Chan), Inselspital, Bern University Hospital, University of Bern, Switzerland; Danish MS Center (F.S.), Department of Neurology, Copenhagen University Hospital-Rigshospitalet, Glostrup, Denmark; Department of Clinical Medicine (F.S.), University of Copenhagen, Denmark; Multiple Sclerosis Center (A.A.), Sheba Academic Medical Center, Ramat Gan, Israel; Sackler School of Medicine (A.A.), Tel-Aviv University, Israel; Department of Neurology-Neuroimmunology (X.M.), Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d'Hebron, Universitat Autonoma de Barcelona, Spain; Department of Neurosciences and CRCHUM (A.P.), Université de Montréal, QC, Canada; Department of Neurological and Behavioural Sciences (N.D.S.), University of Siena, Italy; Department of Radiology (F.B.), VU University Medical Center, Amsterdam, The Netherlands; UCL Institute of Neurology (F.B.), London, UK; Experimental Neurophysiology Unit (L.L.), Vita-Salute San Raffaele University, Milan, Italy; Univ. Lille (P.V.), Inserm U1172 LilNCog, CHU Lille, FHU Precise, France; Cytel Inc (Anita Chudecka), Geneva, Switzerland; InScience Communications (C.M.), Springer Healthcare Ltd, Chester, UK; EMD Serono (K.H.H.), Billerica, MA; and Ares Trading SA (U.B., S.R.), Eysins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany.

Published: January 2023

Cladribine tablets lead to significant decreases in B-cell and T-cell counts in patients with highly active relapsing multiple sclerosis, with the most pronounced effects on B-cell subtypes.* -
A study involving 57 patients tracked changes in immune cell counts over 12 months, showing that B-cell counts hit their lowest points by month 2 while T-cell changes were slower and less intense.* -
The findings indicate a unique immune response to cladribine, with notable B-cell depletion and slower recovery of certain T-cell populations, providing insights into the drug's effects on the immune system.*

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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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9679889	PMC
http://dx.doi.org/10.1212/NXI.0000000000200048	DOI Listing

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