Confined B-Cell Reconstruction and High T-Cell Clonality Define Clinical Response to Cladribine Treatment

Cladribine tablets are approved for relapsing multiple sclerosis, mediating their clinical effect by moderately depleting lymphocytes. In a prospective, monocentric study including 22 patients completing 2 annual cycles of cladribine, B- and T-cell receptor repertoires and relapse activity were assessed at baseline and after 24 months. T-cell clonality increased, driven by loss of low-frequency, naive clonotypes, and re-expansion of dominant CD8 memory clonotypes, particularly in clinically stable patients. In contrast, B-cell receptor richness increased because of reconstruction by transitional and naive B cells with higher clonotype numbers observed in relapsing patients. Therefore, competing immune reconstitution following cladribine therapy could result in differential clinical responses. ANN NEUROL 2026;99:1166-1172.