Late-Onset Neutropenia and Hypogammaglobulinemia After Dose-Adjusted R-EPOCH in Unfavorable Diffuse Large B-Cell Lymphoma

Background: Late-onset neutropenia (LON) and hypogammaglobulinemia are recognized sequelae of rituximab therapy in B-cell non-Hodgkin lymphoma, and both may leave patients vulnerable to infection once treatment has ended. Methods: Fifty-three patients with newly diagnosed, unfavorable diffuse large B-cell lymphoma (DLBCL) who entered remission on dose-adjusted (DA) R-EPOCH immunochemotherapy were retrospectively evaluated. Neutropenia (absolute neutrophil count < 1.5 × 109/L, CTCAE-graded), hypogammaglobulinemia and infections were registered at treatment completion and 6 and 12 months later. Results: All laboratory parameters changed significantly over time. Most reached their nadir at the end of treatment, whereas the absolute neutrophil count alone reached its lowest value later, at 6 months. Neutropenia, largely mild to moderate, affected 17.6% of patients at treatment completion, 22.4% at 6 months and 7.9% at 12 months. Neutropenia at 6 months was a new event, with no overlap with end-of-treatment neutropenia, and was mostly transient. Hypogammaglobulinemia (IgG < 5 g/L) occurred in 33.3%, 16.7% and 20.0%, respectively; median IgG declined to a nadir at the end of treatment and recovered thereafter, although the deficit tended to persist in the same patients. Post-treatment infections were recorded in 73.6% of patients (mostly respiratory); neutropenia was not associated with infection at any time point, whereas end-of-treatment hypogammaglobulinemia was associated with respiratory infection (p = 0.040). The independent predictors of 6-month neutropenia were a greater number of dose-escalated cycles, lower baseline leukocyte count and the absence of on-treatment infection, whereas 6-month hypogammaglobulinemia was predicted by autologous transplantation and the absence of B symptoms. In exploratory body composition analyses, lower baseline psoas muscle mass was associated with end-of-treatment neutropenia (p = 0.042) and greater muscle loss with other site (skin and gastrointestinal) infection (p = 0.004). Conclusions: After DA-R-EPOCH, LON is a delayed and largely transient event separate from end-of-treatment neutropenia, whereas hypogammaglobulinemia is more persistent and clinically relevant for respiratory infections.