Bruno PA, Barone S, Pascarella A, Lanza PL, Tinelli E, Gambardella A, Valentino P. B-cell-driven relapse and anti-CD20 rescue therapy after Alemtuzumab in RRMS: case report and literature review. Front Immunol. 2026;16:1710669.
Background: Alemtuzumab is an immune reconstitution therapy (IRT) approved for highly active relapsing-remitting multiple sclerosis (RRMS). Notably, the differential reconstitution of B and T cells after alemtuzumab may trigger paradoxical B-cell-mediated inflammation and secondary autoimmunity.
Case report: We describe the case of a 44-year-old woman with RRMS who experienced a severe, steroid-resistant relapse nine months after her second alemtuzumab cycle. Lymphocyte subtyping revealed disproportionate B-cell repopulation, suggesting a B-cell-mediated immunopathogenesis. Early ocrelizumab switch resulted in rapid clinical and radiological recovery and sustained stability.
Literature review: We conducted a narrative review of early and paradoxical disease reactivation after alemtuzumab, identifying common features: early onset, poor steroid response, large or tumefactive lesions, and marked B-cell hyperrepopulation. Anti-CD20 therapy often induced rapid remission. These findings may suggest a distinct B-cell-driven mechanism of inflammation. Prior exposure to fingolimod has been observed in several cases, but does not uniformly account for the observed phenotype.
Conclusion: This case contributes to the growing evidence that a subset of patients may experience B-cell-driven inflammatory reactivation after alemtuzumab treatment. Lymphocyte subtyping should be performed, and a predominance of CD19+ B cells can guide a timely therapeutic switch to anti-CD20 therapy. Further studies are needed to define whether this represents a distinct post-IRT immunopathological entity.
Alemtuzumab induced marked depletion of T cells and a marked depletion of B cells but because of the relatively low dose of the treatment it soon disappears, the B cells then start to repopulate and this is driven by transitional/immature and mature/naive B cells which are capable of inducing antibody responses. We have argued that this allows vaccine responses to be induced and perhaps the break through of antibody-mediated autoimmunities. In contrast there is a marked and long lasting depletion of memory B cells possibly associated with inhibition of relapse. These responses are very sterotyped and the B cell depletion and repletion is similar with cladribine and CD20-depleting antibodies although the kinetics (time frame) may vary. Possible because the B cells return when there is neither CD4 nor CD8 T cell regulation this occurs very quickly and overshoots the baseline response. This is typical and do if this is the signal for CD20 depletion then it will happen very often. With alemtuzumab about 50% of people show breakthrough but you can have another dose but you have to wait a year from the last dose because the anti-drug antibodies have to subside. So an quick bash of anti-CD20 will deplete pathogenic B cells and block further disease. Anti-CD20 depletion is a go to for switches….but
Source: multiple-sclerosis-research.org