The present case report describes the 15-year period of a female patient with aggressive RRMS who received GA, DMF, fingolimod, alemtuzumab and ocrelizumab, respectively. Switching from DMF to fingolimod and from fingolimod to alemtuzumab is not unusual in common clinical practice. However, high MS activity while on alemtuzumab is rather uncommon compared to moderate-efficacy drugs. Alemtuzumab depletes circulating T- and B-lymphocytes with the lowest cell counts observed at the first post-baseline assessment. B-cell counts normalise within 3 months of administration while T-cell counts recover over a longer period of time [
2]. After 6 months of therapy, patient’s immunological profile showed the expected decrease in CD4+ and CD8+ T-cells and, markedly increased values of CD19+ B-cells (3.4 times the upper reference limit of the laboratory). As expected, an increase in naïve B-lymphocytes was recorded (4.3 times the upper limit of the laboratory). However, high values of class-switched memory B-cells (3.5 times the upper limit of the laboratory) were detected. These results are unexpected when compared to the results of Baker et al. [
3], where after 6 months of treatment absolute CD19+ B lymphocytes were + 5% vs. baseline and memory B-cells – 80% vs. baseline. Previous works demonstrated that memory B-cells typically repopulate very slowly [
3‐
5] and according to Akgün et al. [
5] this process took years. Therefore, it is of interest that depletion of cells within this subset and controlling their repopulation have been associated with treatment efficacy [
4,
6]. Thus, the treatment was switched to ocrelizumab, which selectively targets the CD20-positive B-lymphocytes resulting in B-cell depletion whereas natural immunity and total T-cell count remain unaffected [
7,
8]. Whilst, a lack of CD4+ T-cell decrease in alemtuzumab-treated patients, or their rapid repopulation, has been suggested to lead to persistent relapses [
5,
9,
10], this has remains controversial [
11,
12]. Nevertheless, this study is consistent with disease breakthrough relating to B-cell activity [
6]. Therefore, we recommend testing B-lymphocytes in case of failure of alemtuzumab and considering early change of treatment to ocrelizumab.