Long-lasting Rituximab-associated Hypogammaglobulinemia: Is It All About Time?

Background: Rituximab-associated hypogammaglobulinemia may be reversible but some patients develop long-lasting hypogammaglobulinemia(LLH). We aim to describe clinical features and evolution of LLH patients and identify clinical and immunophenotyping features suggestive of Inborn Errors of Immunity(IEI).
Material and methods: Dynamic retrospective cohort from 1997 to 2022 conducted at the Immunology Unit of Hospital C.G.Durand including patients without previous IEI diagnosis who received rituximab and developed LLH for more than a year. We classified patients as highly suspicious of IEI considering refractory autoimmune cytopenias, inflammatory bowel disease, benign lymphoproliferation, respiratory infections or hypogammaglobulinemia before rituximab, or family history.
Results: We included 41 patients with LLH and a median follow-up of 4 years (IQR 2-8) since diagnosis of hypogammaglobulinemia and 5 years (IQR 2-10) since rituximab last infusion. Seventy-five percent were female with a median age of 48 (IQR 40-58) when they started rituximab. Hematological malignancies were identified in 32/41 patients, ANCA-associated vasculitis in 5/41 and autoimmune cytopenias in 4/41. Only 2 out of 41 patients normalized IgG levels but they had impaired pneumococcal response. Immunophenotype abnormalities included CD19+ cells<1% in 12/41 patients, 9/41 had decreased non-switched memory B-cells, 13/41 decreased class-switched memory B-cells, 6/41 increased transitional B-cells and 5/41 increased CD21low cells. We did not find statistical association between these findings and cumulative dose of rituximab or baseline disease. Highly suspicious IEI patients showed longer periods of hypogammaglobulinemia since the last infusion (5.7 vs 10 years,p=0.03) even though they received lower doses of rituximab (4 vs 7.2 g,p=0.002). This group showed more patients with increased CD21low (4/5) and less patients with CD19<1% (3/12) yet they had longer periods since last infusion (3 vs. 10 years,p=0.002).
Conclusion: B-cell reconstitution after rituximab may extend for years and flow cytometry may help to identify IEI patients. Further genetic information is needed for better understanding

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