Clinical and biological characteristics of autoimmune neutropenia in adults according to the presence of anti-granulocyte antibodies: A multicenter retrospective Study of 79 cases

Abstract Introduction: Autoimmune neutropenia (AIN) is a rare and poorly described condition in adults. It may be associated or not with autoantibodies directed against granulocyte lineage antigens, although their detection remains challenging in clinical practice. The aim of this study was to characterize the clinical and biological features of adult patients with AIN based on the presence or absence of anti-granulocyte antibodies. Patients and Methods: This was a retrospective, multicenter study across three french hospitals. Clinical records from all patients with at least one anti-granulocyte antibody testing between January 2014 and October 2024 at Etablissement Français du Sang (EFS) Créteil were reviewed. Testing included screening by Granulocyte Indirect Fluorescence Test [GIFT] and Granulocyte Agglutination Test [GAT], followed by Monoclonal Antibody Immobilization of Granulocyte Antigens [MAIGA] in case of positive screening. Patients were included if they had absolute neutrophil count (ANC) <1 × 109/L (confirmed on at least 2 separate counts one month apart). Clinical, biological, and therapeutical data were retrospectively collected using a standardized form. Patients were excluded if they had myeloid malignancy, lymphoid malignancy with >50% bone marrow infiltration, constitutional, toxic, or drug-induced neutropenia, or if follow-up was less than one year. Symptomatic neutropenia was defined as ANC < 0,5 x 109/L with infection requiring hospitalization or aphthous stomatitis . Therapeutic response was defined as ANC >1 × 109/L within one month after treatment initiation. Results: Among the 216 patients tested for anti-granulocyte antibodies, 137 were excluded (ANC > 1 × 109/L, n=44; myeloid malignancy, n=33; follow-up < 1 year, n=28; toxic or drug-induced neutropenia, n=24; neutropenia duration <1 month, n=6; constitutional neutropenia, n=2). Seventy-nine patients (median age 45 years [range 18–90], 63% female) were included in the study, with an ANC nadir of 0,42 x 109/L. In 42 patients (53%), AIN was secondary to Evans syndrome (n=19, 45%) and/or connective tissue disease (n=19, 45%) or lymphoid malignancy (n=12, 29%, including 7 patients with a large granular lymphocyte (LGL) leukemia). Overall, 45 (57%) patients had positive screening for anti-granulocyte antibodies, including 17 (22%) with positive MAIGA (MAIGA+). Main specificity of antibodies in MAIGA+ patients was CD16 in 65%. Four patients with initial negative MAIGA were tested positive after repetition of the assay. ANC < 0.5 × 109 was more frequently found in MAIGA+ patients (82%) as compared to antibody-negative patients (58%, p<0.03).All MAIGA+ patients had secondary AIN (100%, vs. 32% in antibody-negative patients, p<0.001). After a median follow-up of 3 years [range 1–28], 16 patients (20%) had symptomatic neutropenia (infection requiring hospitalization, n=15, including 1 admission in intensive care unit, and aphtous stomatitis, n=3). Three deaths unrelated to AIN were reported. Twelve patients (15%) received a treatment for AIN, including granulocyte colony-stimulating factor (G-CSF, n=10) leading to a short-term response in 80%, and/or an immunosuppressive agent (including corticosteroids, n=10) with an overall response rate of 86%. AIN treatment was more frequently initiated in MAIGA+ patients (35% vs. 6% in antibody-negative patients, p<0.0001), but the rate of infection-related hospitalizations was similar between the two groups (18% vs. 19%). Conclusion: Our results suggest that AIN is a heterogeneous and generally mildly symptomatic condition with favorable outcome in most patients. MAIGA+ patients more frequently had profound neutropenia, associated conditions (particularly Evans syndrome), and had more treatment initiation for neutropenia.