Late-Onset Neutropenia After Rituximab in Multiple Sclerosis

BACKGROUND AND OBJECTIVES: Late-onset neutropenia (LON) is a rare, transient reduction in absolute neutrophil count (ANC) associated with anti-CD20 therapies. In multiple sclerosis (MS), data regarding severity, infectious outcomes, and predictors remain limited. We aimed to determine the incidence, characteristics, and predictors of LON in rituximab-treated people with MS (pwMS). METHODS: We conducted a registry-based retrospective multicenter cohort study of pwMS in Sweden exposed to rituximab between 2008 and 2024. Any LON was defined as ANC <1,500 cells/μL occurring at least 30 days after rituximab initiation. Grades 3-4 LON was defined as ANC <1,000 cells/μL, recording infectious complications for these events. Incidence rates (IRs) were calculated per 1,000 person-years, and event times were summarized as medians (interquartile range [IQR]). Predictors of LON events were evaluated using Cox regression with time-varying covariates and binary logistic regression. RESULTS: Among 2,686 rituximab-exposed pwMS, 6.2% (n = 165) experienced ≥1 LON event during a median follow-up of 7.8 years (IQR 5.7-9.8). The IR for any LON (grades 2-4) was 10.1/1,000 person-years (95% CI 8.6-11.8); the median time-to-first event was 360 days (IQR 112-1,017). Most events were mild, 5.3% (grade 2, n = 142). Grades 3-4 LON occurred for 1% (23 individuals; 36 events) and IR 2.1/1,000 person-years (95% CI 1.4-2.9). Ten infections occurred among LON grades 3-4 events, classifying 8 as severe. All individuals with infectious LON grades 3-4 events (48%) recovered after hospitalization, antibiotics/antivirals, and/or granulocyte colony-stimulating factor. Rituximab was rechallenged in 89% (32/36) of grades 3-4 events: 14 recurred and 2 complicated by infections. In time-dependent Cox models, higher accumulated rituximab exposure (HR 0.87, 95% CI 0.81-0.93) and prior injectable therapy (HR 0.66, 95% CI 0.45-0.96) were associated with a lower hazard of any LON. Exploratory binary analyses of LON grades 3-4 showed associations with prior natalizumab (odds ratio [OR] 2.8) and higher body mass index (OR 0.87), not confirmed in time-to-event models. DISCUSSION: In this large real-world cohort, high-grade LON (grades 3-4) events were rare and frequently complicated by infections. Mild (grade 2) LON events were often fluctuating and generally clinically uneventful. Rechallenge with rituximab was rarely complicated by serious adverse events. Prediction of LON remains challenging, highlighting the relevance of infection vigilance during anti-CD20 therapy.