Immune phenotyping study revealing caveats regarding a switch from fingolimod to cladribine

•Relapsing remitting multiple sclerosis•Cladribine•memory B cells•hyperrepopulation•immune phenotyping, disease activity Background: Recent data support a key role of B cells in the pathogenesis of multiple sclerosis. Due to the pronounced effect of cladribine on memory B cells, we initiated an immune phenotyping study, which included monitoring of memory B cells of patients newly assigned to this treatment option. A patient with ongoing disease activity in the first year of cladribine after a long-standing fingolimod treatment caught our attention. Objective: To report about differences in the immune phenotype of the case compared to patients without disease activity and to discuss possible causes for the deviations as caveats regarding treatment sequelae. Methods: Clinical data and immune phenotyping data collected at baseline (before treatment) and after three, six and ten/twelve months after cladribine initiation were compared between our case and six patients with a stable disease course (controls). Results: Both, the case and controls showed similar reductions of memory B cells in response to cladribine. The case however, showed an accelerated repopulation dynamic of naïve B cells with an almost 3-fold hyperrepopulation compared to baseline levels, and lower pre-treatment levels of CD4+ and CD8+ T cells and memory B cells compared to controls. Conclusion: We propose a prolonged pre-treatment with fingolimod as possible cause for the lack of response to cladribine. Autoreactive cells sequestrated within lymph nodes may have evaded cladribine depletion on top of a delay of recirculating regulatory T cells. In addition, we want to raise awareness of the importance of monitoring T and B cells for bridging the current lack of evidence regarding sequencing therapies in the real life setting.