Clinical heterogeneity and outcome of acquired PRCA: a multicenter European study

Pure red cell aplasia (PRCA) is a rare single-lineage bone marrow (BM) failure characterized by anemia with profound reticulocytopenia and severe reduction of erythroid precursors. PRCA is heterogeneous, and diagnosis requires extensive evaluation to distinguish primary from secondary causes, such as thymoma, autoimmune diseases, T-cell large granular lymphocyte expansion, and myelodysplastic syndrome (MDS), the differential diagnosis of which is particularly challenging. Evidence guiding management remains limited because of the rarity of the disease and the lack of prospective studies. We analyzed 121 acquired adult PRCA (excluding Parvovirus B19-associated PRCA) cases across 14 European centers. Secondary forms accounted for 78% of diagnoses, mostly thymoma (23%) or MDS (21%). In a subset of patients, BM immunohistochemistry demonstrated significant depositions of C3, C4d, immunoglobulin M (IgM), and IgG, reducing after immunosuppression. Next-generation sequencing was performed in half of the patients, 36% of whom presented mutations predominantly related to clonal hematopoiesis, except in MDS-associated cases, which often carried multiple non-clonal hematopoiesis mutations. Immunosuppression represented the backbone of therapy: cyclosporine A (CyA) was the most effective agent, with 61% overall response rate (47% complete) and better outcomes when initiated earlier; mammalian target of rapamycin inhibitors (mTORi) showed promising activity as second-line therapy, with responses in 71% of the patients, including CyA-refractory cases. Mortality reached 30%, predominantly because of infectious complications, and was significantly higher in MDS-associated cases. PRCA remains a diagnostically challenging and clinically heterogeneous disorder in which integration of molecular analyses may refine diagnostic accuracy and patient stratification. Immunosuppression remains the mainstay of treatment, with CyA being a reliable first-line treatment and mTORi emerging as encouraging rescue options.