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The use of alemtuzumab in people with relapsing MS (pwRMS) is limited by the high risk of secondary B cell autoimmunity (SAI). Data describing the effect of alemtuzumab on lymphocyte subsets collected during the phase III trials has never been comprehensively reported. We hypothesised this data may reveal mechanisms explaining efficacy as well as SAI with alemtuzumab.Lymphocyte data from regulatory submissions of the pivotal CARE-MS I and II trials was obtained from the European Medicines Agency, and analysed.Alemtuzumab depleted CD4+ T cells by 95%, including regulatory (−80%) and CD8+ T cells (−85%), all remaining below normal throughout the trials. Whilst CD19+ B cells were initially depleted (−90%) marked (+180%) hyper-repopulation occurred of immature B cells, converting to mature B cells. This was associated with alemtuzumab-binding and neutralising antibodies and SAI. Hyper-repopulation of B cells masked long-term depletion of CD19+ memory B cells that may underpin efficacy in MS.Whilst depletion of memory T and B cells by alemtuzumab may limit MS, rapid CD19+ B cell subset repopulation in the absence of effective T cell regulation may reduce efficacy and cause SAI. Controlling B cell proliferation until T cell regulation recovers may limit SAI.