Incidence, Clinical Features, and Outcomes of Late‐onset Neutropenia from Rituximab for Autoimmune Disease

OBJECTIVE Late-onset neutropenia (LON) is an underrecognized complication of rituximab. Our objective is to describe its incidence, risk factors, clinical features, management, and recurrence. METHODS We conducted a single-center retrospective cohort study of 738 adult patients with autoimmune disease treated with rituximab-induced continuous B cell depletion. The primary outcome was LON, defined as an unexplained absolute neutrophil count < 1000 cells/µL during B cell depletion. Secondary outcomes included incidental diagnosis, fever, sepsis, filgrastim use, and recurrent LON. We assessed predictors of LON using Cox regression models. RESULTS We identified 107 episodes of LON in 71 patients. The cumulative incidence at 1 year was 6.6% (95% CI, 5.0 - 8.7). The incidence rate in the first year was higher compared to thereafter (7.2 (95% CI, 5.4 - 9.6) vs. 1.5 (95% CI, 1.0 - 2.3) per 100 person-years, respectively). Systemic lupus erythematosus and combination therapy with cyclophosphamide were each independently associated with an increased risk of LON (adjusted hazards ratios 2.96, (95% CI, 1.10 - 8.01) and 1.98 (95% CI, 1.06 - 3.71), respectively). LON was not observed with minimal change disease / focal segmental glomerulosclerosis. 59.4% of episodes were asymptomatic. Fever and sepsis complicated 31.3% and 8.5% of episodes, respectively. Most patients (69%) were treated with filgrastim. Rituximab rechallenge occurred in 87% of patients, of whom 21% developed recurrent LON. CONCLUSION LON is common and often incidental. Most cases are reversible and respond well to filgrastim. However, it can be associated with serious infections and thus warrants vigilant monitoring.