Secondary Immunodeficiency After B-Cell Depletion: Mechanisms, Clinical Manifestations, Monitoring, and Management

The expanding use of B-cell-targeted therapies (BCTTs) across multiple clinical specialties has established secondary hypogammaglobulinemia (SHG) as a clinically significant and increasingly prevalent form of iatrogenic immunodeficiency. Estimated to be approximately 30 times more common than primary antibody deficiency, SHG following B-cell depletion carries measurable risks of severe infections and excess mortality that remain underrecognized in routine practice. This review provides a focused review of the immunological mechanisms underlying SHG after B-cell-directed therapy, examines agent-specific evidence for anti-CD20 monoclonal antibodies (rituximab, ocrelizumab), anti-CD38 agents (daratumumab), and CAR T-cell therapies targeting CD19 and B-cell maturation antigen (BCMA), and synthesizes current evidence-based recommendations for pre-treatment immunological screening, serial monitoring, and immunoglobulin replacement therapy (IgRT). A clinical department-stratified reference table of immunosuppressive agents associated with secondary B-cell dysfunction is provided.