Giancarlo Comi1, Stuart Cook2, Gavin Giovannoni3, Peter Rieckmann4, Per Soelberg Sørensen5, Patrick Vermersch6, Andrew Galazka7, Axel Nolting8, Christine Hicking8, Fernando Dangond9. 1. Department of Neurology and Institute of Experimental Neurology, Università Vita-Salute San Raffaele, Ospedale San Raffaele, Milan, Italy. 2. Rutgers, The State University of New Jersey, New Jersey Medical School, Department of Neurology & Neurosciences, Medical Science Building, 185 South Orange Avenue, MSB, H506, Newark, NJ 07101-1709, United States. Electronic address: cooksd@ca.rutgers.edu. 3. Queen Mary University of London, Blizard Institute, Barts and The London School of Medicine and Dentistry, London, United Kingdom. 4. Department of Neurology, Medical Park Loipl and University of Erlangen, Erlangen, Germany. 5. Danish MS Center, Department of Neurology, University of Copenhagen, Rigshospitalet, Copenhagen, Denmark. 6. University of Lille, CHU Lille, LIRIC-INSERM U995, FHU Imminent, Lille, France. 7. Merck, Aubonne, Switzerland. 8. Merck KGaA, Darmstadt, Germany. 9. EMD Serono Research & Development Institute Inc., Billerica, MA, United States.
Abstract
BACKGROUND:Immune reconstitution therapies (IRT) for patients with multiple sclerosis are used for short, intermittent treatment periods to induce immune resetting and allow subsequent treatment-free periods. Cladribine tablets are postulated to be an IRT that causes selective and transient reductions in CD19+ B cells and T cells, followed by reconstitution of adaptive immune function. OBJECTIVE: To characterize long-term lymphocyte count changes in pooled data from the 2-year CLARITY and subsequent 2-year CLARITY Extension studies, and the PREMIERE registry (Long-term CLARITY cohort). METHODS: Data from patients randomized to placebo (n = 435) or cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg; n = 685) in CLARITY or CLARITY Extension, including time spent in the PREMIERE registry were pooled to provide long-term follow-up data. The study investigated absolute lymphocyte counts (ALC) up to 312 weeks and B and T cell subsets up to 240 weeks after the first dose, in patients receiving placebo or cladribine tablets 3.5 mg/kg administered as two short (4 or 5 days) weekly treatments at the start of months 1 and 2 in each treatment year, followed by no further active treatment. RESULTS: Treatment with cladribine tablets 3.5 mg/kg resulted in selective reductions in B and T lymphocytes. Lymphocyte recovery began soon after treatment in each of years 1 and 2. Median ALC recovered to the normal range and CD19+ B cells recovered to threshold values by week 84, approximately 30 weeks after the last dose of cladribine tablets in year 2. Median CD4+ T cell counts recovered to threshold values by week 96 (approximately 43 weeks after the last dose of cladribine tablets in year 2). Median CD8+ cell counts never dropped below the threshold value. CONCLUSION: These results show the dynamics of lymphocyte count changes following treatment with cladribine tablets 3.5 mg/kg. The immune cell repopulation results provide further evidence that cladribine tablets may represent a form of IRT.
RCT Entities:
BACKGROUND: Immune reconstitution therapies (IRT) for patients with multiple sclerosis are used for short, intermittent treatment periods to induce immune resetting and allow subsequent treatment-free periods. Cladribine tablets are postulated to be an IRT that causes selective and transient reductions in CD19+ B cells and T cells, followed by reconstitution of adaptive immune function. OBJECTIVE: To characterize long-term lymphocyte count changes in pooled data from the 2-year CLARITY and subsequent 2-year CLARITY Extension studies, and the PREMIERE registry (Long-term CLARITY cohort). METHODS: Data from patients randomized to placebo (n = 435) or cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg; n = 685) in CLARITY or CLARITY Extension, including time spent in the PREMIERE registry were pooled to provide long-term follow-up data. The study investigated absolute lymphocyte counts (ALC) up to 312 weeks and B and T cell subsets up to 240 weeks after the first dose, in patients receiving placebo or cladribine tablets 3.5 mg/kg administered as two short (4 or 5 days) weekly treatments at the start of months 1 and 2 in each treatment year, followed by no further active treatment. RESULTS: Treatment with cladribine tablets 3.5 mg/kg resulted in selective reductions in B and T lymphocytes. Lymphocyte recovery began soon after treatment in each of years 1 and 2. Median ALC recovered to the normal range and CD19+ B cells recovered to threshold values by week 84, approximately 30 weeks after the last dose of cladribine tablets in year 2. Median CD4+ T cell counts recovered to threshold values by week 96 (approximately 43 weeks after the last dose of cladribine tablets in year 2). Median CD8+ cell counts never dropped below the threshold value. CONCLUSION: These results show the dynamics of lymphocyte count changes following treatment with cladribine tablets 3.5 mg/kg. The immune cell repopulation results provide further evidence that cladribine tablets may represent a form of IRT.
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