Blood Biomarker Dynamics in Highly Active Relapsing Multiple Sclerosis Patients Treated With Cladribine Tablets: Results of the 2-Year MAGNIFY-MS Study
Heinz Wiendl1, Nicola De Stefano2, Frederik Barkhof3, Xavier Montalban4, Anat Achiron5, Tobias Derfuss6, Andrew Chan7, Suzanne Hodgkinson8, Alexandre Prat9, Letizia Leocani10, Klaus Schmierer11, Finn Sellebjerg12, Patrick Vermersch13, Hulin Jin14, Elina Jarvinen14, Anita Chudecka15, Lidia Gardner16
1Department of Neurology, Institute of Translational Neurology, University of Muenster, 2Department of Medicine, Surgery and Neuroscience, University of Siena, 3Department of Radiology, VU University Medical Center, 4Department of Neurology-Neuroimmunology, Centre d’Esclerosi Múltiple de Catalunya (Cemcat), Hospital Universitario Vall d’Hebron, Universitat Autonoma de Barcelona, 5Multiple Sclerosis Center, Sheba Academic Medical Center, 6Department of Neurology, University Hospital Basel, 7Department of Neurology, Inselspital, Bern University Hospital, University of Bern, 8Ingham Institute for Applied Medical Research, University of New South Wales Medicine, 9Department of Neurosciences, Université de Montréal, 10Experimental Neurophysiology Unit, Vita-Salute San Raffaele University, 11The Blizard Institute, Centre for Neuroscience, Surgery & Trauma, Barts and The London School of Medicine & Dentistry, Queen Mary University of London, 12Danish MS Center, Department of Neurology, Copenhagen University Hospital - Rigshospitalet, 13Inserm U1172 LilNCog, CHU Lille, FHU Precise, 14the healthcare business of Merck KGaA, Darmstadt, Germany, 15Cytel Inc. Geneva, Switzerland, 16EMD Serono, Billerica, MA, USA
Objective:
To describe blood biomarker (BB) dynamics over 2 years of treatment with cladribine tablets 3.5mg/kg (CladT), including immune cell subsets, serum proteins, and intracellular cytokines.
Background:
MAGNIFY-MS (NCT03364036) BB analysis was designed to characterize the effect of CladT on BB in patients with highly active relapsing multiple sclerosis.
Design/Methods:
Blood samples were collected at baseline and Months (M) 3, 6, 12, 15, 18, and 24 for immune cell characterization and serum protein analysis. Intracellular cytokine analyses were performed for a subset of patients in the BB sub-study.
Results:
A total of 270 patients enrolled in the main study were analyzed (BB sub-study, n=57). Quantitative immune cell changes were observed following each yearly treatment course. Median percentage change from baseline at M24: regulatory (+1.62%), transitional (+6.3%), naïve (+10.85%), memory (-89.29%) B-cells; total plasma cells: -62.47%; T cells remained below baseline levels (CD4+, -57.51%; CD8+, -45.93%). Increased levels above baseline from M12 onwards were detected for CD16lowCD56bright (M24, +17.21%) and NKp46 cells (M24, +77.7%). IgM and IgG levels remained within reference ranges. Compared with baseline, serum neurofilament levels were reduced at M12 (-25.22%) and M24 (-23.23%).
In the BB sub-study, reductions in pro-inflammatory cytokine-producing B-cells (IL-6) and CD4+ and CD8+ T-cells (GMCSF, TNFα, INFg), and increases in anti-inflammatory cytokine-producing CD19+ and memory B-cells (IL-10) and CD4+ and CD8+ T-cells (IL-4), were observed.
Conclusions:
Multifaceted immune changes were detected over a 2-year observation period following CladT treatment. Most dynamic changes were observed in the peripheral B-cell compartment (persistent reduction of B-memory cells), while IgM and IgG levels remained within reference ranges, helping to interpret efficacy and safety data in conjunction with changes in immune cells, serum proteins, clinical and MRI parameters.