Characterization of Peripheral Immune Cell Dynamics and Repopulation Patterns in the First 12 Months of Cladribine Tablets Treatment: MAGNIFY-MS Study
Heinz Wiendl1, Klaus Schmierer2,3, Suzanne Hodgkinson4, Tobias Derfuss5, Andrew Chan6, Finn Sellebjerg7, Anat Achiron8, Xavier Montalban9, Alexandre Prat10, Nicola De Stefano11, Frederik Barkhof12,13, Letizia Leocani14, Patrick Vermersch15, Anita Chudecka16, Sanjeev Roy17, Ursula Boschert18
1Department of Neurology, Institute of Translational Neurology, University of Münster, 2Blizard Institute, Centre for Neuroscience, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, 3Clinical Board Medicine (Neuroscience), The Royal London Hospital, Barts Health NHS Trust, 4Ingham Institute for Applied Medical Research, University of New South Wales Medicine, 5Department of Neurology, University Hospital Basel, 6University Hospital of Berne, University of Berne, 7Danish MS Center, Department of Neurology, University of Copenhagen, Rigshospitalet, 8Multiple Sclerosis Center, Sheba Academic Medical Center, 9Department of Neurology-Neuroimmunology, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitari Vall d’Hebron, 10Department of Neurosciences, Université de Montréal, 11Department of Medicine, Surgery and Neuroscience, University of Siena, 12Image Analysis Center, VU University Medical Center, 13UCL Institute of Neurology, London, UK, 14Experimental Neurophysiology Unit, Vita-Salute San Raffaele University, 15University of Lille, Inserm U1172 LilNCog, CHU Lille, FHU Imminent, 16Cytel Inc., 17Merck, Aubonne, Switzerland, a division of Merck KGaA, Darmstadt, Germany, 18Ares Trading S.A., Eysins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany
Objective:

To report on peripheral immune cell subset dynamics and immunoglobulin levels in the first 12 months of cladribine tablets (CT) therapy.

Background:
The action of CT on immune cells may be key for both onset and durability of its effect in people with multiple sclerosis (MS).
Design/Methods:

Longitudinal evaluation of peripheral blood immune cells in patients receiving CT in a sub-study of MAGNIFY-MS (NCT03364036). Absolute cell counts and %change from baseline were assessed for adaptive immune cell subtypes and immunoglobulins. Immunophenotyping was completed at baseline and months 1,2,3,6,12.

Results:
Full analysis set: 57 patients (median age 37 years; 61% female; ≥2 relapses in previous year, 70%). Effector and regulatory B cells were reduced from month 1 and showed a subtype-specific repopulation pattern. Change from baseline for CD19+ B cells: month 1,-77%; month 2,-90%; month 12,-35%. Memory B cells: month 1,-74%; month 3,-93%; month 12,-87%. Plasmablasts: month
1,-28%; month 3,-78%; month 12,-51%. Regulatory B cells (CD19+, CD24bright, and CD38bright): month 1,-45%; month 3,+176%; month 6,+171%; month 12,+50%. Naïve/transitional B cells: month 1,-79%/-61%; month 3,-69%/+35%; month 12,+35%/+23%. Decrease in T cell subsets was moderate and slower, nadir occurring between 3 and 6 months. T-helper 17 CD4+ and terminally differentiated effector memory CD8+ T cell counts reached nadir at month 3 (-35% and -25%, respectively). No clinically meaningful change in serum IgG or IgM was observed over 12 months.
Conclusions:
Assessment of lymphocyte dynamics following CT over 1 year demonstrates that effects occur from month 1, and are sustained in several immune cell subpopulations. CT exerts a pronounced effect on memory B cells, while immunoglobulin levels are unaffected over 12 months. Results suggest early onset of CT action, underpinned by MAGNIFY-MS MRI results, may be mediated through this specific pattern of sustained decrease and reconstitution of B and T cell subtypes in a highly active MS population.