Effects of cladribine tablets on lymphocyte subsets in patients with multiple sclerosis: an extended analysis of surface markers.

Background: Cladribine tablets 3.5 mg/kg cumulative over 2 years (CT3.5) had significant clinical/imaging effects in patients with clinically isolated syndrome (CIS; ORACLE-MS) or relapsing-remitting MS (RRMS; CLARITY and CLARITY Extension). This analysis compared the effect of cladribine tablets on the dynamics of immune cell reduction and reconstitution in ORACLE-MS, CLARITY, and CLARITY Extension during the first year of treatment (i.e. the first course of CT1.75) in patients randomized to CT3.5.
Methods: Lymphocyte subtypes were analyzed using multiparameter flow cytometry. Changes in cell counts and relative proportions of lymphocytes were evaluated at weeks 5, 13, 24, and 48.
Results: Across studies, consistent and comparable selective kinetics of immune cell populations occurred following the first treatment year with CT. A rapid reduction in CD16 ⁺ /CD56 ⁺ cells (week 5 nadir), a more marked reduction in CD19 ⁺ B cells (week 13 nadir), and a less-pronounced effect on CD4 ⁺ (week 13 nadir) and CD8 ⁺ T cells (week 24 nadir) was shown. There was little effect on neutrophils or monocytes. Lymphocyte recovery began after treatment with CT3.5. Regarding relative proportions of naïve and memory T-cell subtypes in ORACLE-MS, the proportion of naïve-like naturally occurring T-regulatory cells (nTregs) decreased, and the proportion of memory-like nTregs increased, relative to total CD4 ⁺ T cells.
Conclusions: CT3.5 has comparable effects on the immune systems of patients with CIS or RRMS. The pronounced reduction and recovery dynamics of CD19 ⁺ B cells and relative changes in the proportion of some immune cell subtypes may underlie the clinical effects of CT3.5.
Competing Interests: Conflict of interest statement: OS serves on the editorial boards of the Multiple Sclerosis Journal, and Therapeutic Advances in Neurological Disorders. He has served on data monitoring committees for Genentech-Roche, Pfizer, and TG Therapeutics without monetary compensation. He has advised EMD Serono, Celgene, Genzyme, and Serono. He currently receives grant support from Sanofi Genzyme. He received travel support from Shire PSS has served on advisory boards for Biogen, Merck KGaA, Novartis, Teva, MedDay Pharmaceuticals, and GSK; on steering committees or independent data monitoring boards in trials sponsored by Merck KGaA, Teva, GSK, and Novartis; has received speaker honoraria from Biogen Idec, Merck KGaA, Teva, Sanofi-Aventis, Genzyme, and Novartis. His department has received research support from Biogen, Merck KGaA, Teva, Novartis, Roche, and Genzyme. TL has received consultancy fees or clinical research grants from Acorda, Bayer, Biogen, Daiichi, EMD Serono, Novartis, ONO, Pfizer, and Teva Neuroscience. GG has received speaker honoraria and consulting fees from Abbvie, Actelion, Atara Bio, Almirall, Bayer Schering Pharma, Biogen Idec, FivePrime, GlaxoSmithKline, GW Pharma, Merck & Co., Merck KGaA, Pfizer Inc, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi-Genzyme, UCB, Vertex Pharmaceuticals, Ironwood, and Novartis; and has received research support unrelated to this study from Biogen Idec, Merck & Co, Novartis, and Ironwood. YH, DD, FD, and UB are employees of EMD Serono Research & Development Institute Inc., a business of Merck KGaA, Darmstadt, Germany.