Effects of cladribine tablets on peripheral lymphocyte subtypes implicated in multiple sclerosis immunopathogenesis: surface marker analysis for a subset of patients from the 96-week, phase III, double-blind, placebo-controlled CLARITY study

BACKGROUND: Cladribine is activated specifically in lymphocyte sub-types resulting in targeted and sustained immunomodulation, whichprovides the rationale for use of cladribine tablets as a short-courseannual treatment in multiple sclerosis (MS). This was explored furtherthrough investigation of blood cell surface markers in a subset ofpatients from the CLARITY (CLAdRIbine tablets Treating multiplesclerosis orallY) study.METHODS: 1326 patients with RRMS (McDonald criteria; ExpandedDisability Status Scale [EDSS] score 0-5.5) were randomised 1:1:1 tocladribine tablets (cumulative dose of 5.25 or 3.5 mg/kg), or matchingplacebo. Cladribine tablets were given in short courses (once daily for4-5 days) in 4 or 2 consecutive months (28-day periods) in the first 48weeks, then 2 short courses at 48 and 52 weeks (both groups).Lymphocyte surface markers were analysed for a subset of patientsusing blood samples obtained at baseline and at Weeks 5, 9, 13, 16,24, 44, 48, 52, 72 and 96.RESULTS: Samples for lymphocyte surface marker analyses were avail-able from 80, 81 and 79 patients in the 5.25 mg/kg, 3.5 mg/kg orplacebo groups, respectively. T-cell counts (CD3, CD4 and CD8, incells/uL), decreased linearly after cladribine treatment, from baselinemedian 1362, 8312 and 395 (5.25 mg/kg group) and 1325, 856 and355 (3.5 mg/kg group), respectively, to nadir values at Week 16 weeks edian change -780, -610 and -214 [5.25 mg/kg] and -534, -404 and-122 [3.5 mg/kg], respectively). Levels subsequently recovered slightlyuntil redosing at Week 48, followed by a second (comparable) nadir.Lower CD4/CD8 ratios were due to preferential reductions in CD4versus CD8 cells. Reductions were also observed in CD4 naı¨ve andmemory (CD45RA and CD45RO) T-helper cells, and to a lesserextent in CD8 naı¨ve and memory cytotoxic T cells. B-cell (CD19)marker also revealed rapid reductions to nadir values at Weeks 9and 16, followed by more marked recovery than observed with T-cells.CONCLUSIONS: Treatment with cladribine tablets differentiallyaffected CD4, CD8 and CD19 subpopulations. These findings maysuggest a direct effect on T-cell function, humoral B cell activity andantigen-presenting cell activity, which may be involved in immune-mediated disease pathogenesis