Immunoglobulins as replacement therapy in hematological malignancies: from historical hypogammaglobulinemia to the era of T-cell-engaging therapies

INTRODUCTION: Secondary immunodeficiency (SID) with hypogammaglobulinemia is a frequent complication of B-cell hematological malignancies, arising from the disease and from an expanding range of B-cell-depleting and T-cell-engaging therapies. Immunoglobulin replacement therapy (IgRT) is widely used to prevent infection, yet the evidence underpinning this practice is surprisingly weak. AREAS COVERED: The randomized trials, almost all conducted before 2000 and confined to chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), show a reduction in clinically documented infection (pooled relative risk [RR] 0.72) but no effect on mortality and an increased risk of adverse events. When high-risk-of-bias trials are excluded, even the infection benefit loses statistical significance (RR 0.80; 95% CI, 0.62-1.04). Contemporary real-world CLL data found no association between regular IgRT and fewer infection-related hospitalizations. EXPERT OPINION: Against this backdrop, IgRT use continues to rise, driven partly by the profound hypogammaglobulinemia that follows CAR-T cells and bispecific antibodies, settings supported only by observational data. This narrative review synthesizes the mechanisms, setting-specific evidence, and practical management of IgRT, argues for a critical, stewardship-minded stance in which IgRT is reserved (severe hypogammaglobulinemia with recurrent or severe bacterial infection failing simpler measures), and outlines the adequately powered, modern-era trials needed to resolve the uncertainty.