Annals of neurology · 2025
Effect of Cumulative Exposure to Ocrelizumab on Memory B-Cell Repopulation Dynamics in Multiple Sclerosis.
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Disanto Giulio, Sacco Rosaria, Mallucci Giulia, Zecca Chiara, Gobbi Claudio
Аннотация
OBJECTIVE: Extended interval dosing protocols of B-cell-depleting therapies in multiple sclerosis (MS) are being developed, but intervals between infusions are often arbitrary. We describe total and memory B-cell repopulation dynamics in MS patients on a memory B-cell-guided extended interval dosing ocrelizumab (OCR) protocol.
METHODS: OCR was administered on peripheral CD19+ CD27+ memory B-cell repopulation (≥1 cell/μL), monitored using fluorescence-activated cell sorting. Associations with CD19+ B cells and CD19+ CD27+ memory B cells were tested using mixed-effect hurdle models, with rate ratios (RR) predicting cell counts and odds ratios (OR) predicting cell depletion.
RESULTS: We collected 1,369 samples from 101 patients, 61.4% women, aged 42.2 years (IQR 32.3-51.1 years) and follow up 4.1 years (IQR 2.9-5.2 years). The median time between samples and previous OCR infusion was 6.6 months (IQR 4.7-8.8 months). Time since previous OCR infusion was positively associated with CD19+ B cells (RR = 1.11, 95% CI 1.10-1.11, p < 0.001) and CD19+ CD27+ memory B-cell counts (RR = 1.11, 95% CI 1.09-1.13, p < 0.001). A greater cumulative OCR dose was associated with persistent CD19+ CD27+ memory B-cell depletion (OR 1.90, 1.57-2.31, p < 0.001). CD19+ B-cell repopulation was inversely associated with age (RR = 0.82, 95% CI 0.71-0.95, p = 0.010). Female patients showed a lower ratio of CD19+ CD27+ memory B cells/total CD19+ B cells (RR = 0.42, 95% CI 0.26-0.69, p = 0.001). Disease activity was low, with most radiological activity observed within the first year of OCR treatment.
INTERPRETATION: Memory B-cell repopulation becomes slower with increasing cumulative OCR dose. Age- and sex-related mechanisms probably influence repopulation dynamics. Given the evidence for a pathogenic role of memory B cells, these observations could be considered when planning extended interval dosing strategies of OCR treatment. ANN NEUROL 2025;98:603-615.
METHODS: OCR was administered on peripheral CD19+ CD27+ memory B-cell repopulation (≥1 cell/μL), monitored using fluorescence-activated cell sorting. Associations with CD19+ B cells and CD19+ CD27+ memory B cells were tested using mixed-effect hurdle models, with rate ratios (RR) predicting cell counts and odds ratios (OR) predicting cell depletion.
RESULTS: We collected 1,369 samples from 101 patients, 61.4% women, aged 42.2 years (IQR 32.3-51.1 years) and follow up 4.1 years (IQR 2.9-5.2 years). The median time between samples and previous OCR infusion was 6.6 months (IQR 4.7-8.8 months). Time since previous OCR infusion was positively associated with CD19+ B cells (RR = 1.11, 95% CI 1.10-1.11, p < 0.001) and CD19+ CD27+ memory B-cell counts (RR = 1.11, 95% CI 1.09-1.13, p < 0.001). A greater cumulative OCR dose was associated with persistent CD19+ CD27+ memory B-cell depletion (OR 1.90, 1.57-2.31, p < 0.001). CD19+ B-cell repopulation was inversely associated with age (RR = 0.82, 95% CI 0.71-0.95, p = 0.010). Female patients showed a lower ratio of CD19+ CD27+ memory B cells/total CD19+ B cells (RR = 0.42, 95% CI 0.26-0.69, p = 0.001). Disease activity was low, with most radiological activity observed within the first year of OCR treatment.
INTERPRETATION: Memory B-cell repopulation becomes slower with increasing cumulative OCR dose. Age- and sex-related mechanisms probably influence repopulation dynamics. Given the evidence for a pathogenic role of memory B cells, these observations could be considered when planning extended interval dosing strategies of OCR treatment. ANN NEUROL 2025;98:603-615.