**Background:** Neutropenia, defined as a reduction in absolute neutrophil count (ANC) below age- and ethnicity-adjusted normal limits, encompasses a wide spectrum of acquired or congenital, benign or premalignant disorders. Recent genomic advances have identified novel causative genes and mechanisms, yet real-world evidence from a survey across 28 European countries, Armenia, Israel, Turkey, and the USA showed that diagnosis and management remain largely based on physician experience and local practices rather than standardized evidence. The European Hematology Association (EHA) collaborated with the EuNet-INNOCHRON COST Action to produce these guidelines.
**Methods:** The guidelines working group comprised 17 members from the Severe Chronic Neutropenia International registry, all active in EuNet-INNOCHRON. Five main topics were identified: (1) definition and classification, (2) diagnostic approach, (3) natural history and follow-up, (4) treatment, and (5) special situations. Literature review for topics 1–3 and 5 included case-control and cohort studies; treatment was reviewed separately by Cochrane Hematology. Expert recommendations were developed using a Delphi approach, with consensus defined as >75% agreement among panelists.
**Key Results:** The guidelines establish ANC thresholds for neutropenia: <1.0 × 10⁹/L for infants 14 days to 1 year; <1.5 × 10⁹/L for children >1 year to adulthood; and <1.8 × 10⁹/L for adults. The term ACKR1/DARC-associated neutropenia (ADAN) is introduced to replace 'ethnic neutropenia,' emphasizing the genetic basis (rs2814778 polymorphism in the ACKR1/DARC gene). A pathogenesis-based classification divides neutropenias into congenital (with subcategories: isolated, associated with extrahematological manifestations, immunodeficiency/immune dysregulation, metabolic disorders, bone marrow failure syndromes) and acquired (primary/idiopathic, secondary to infections, autoimmune diseases, drugs, nutritional deficiencies, hypersplenism, or hematologic diseases). Key diagnostic recommendations include: detailed patient/family history; clinical examination for extrahematological manifestations; first-level investigations (CBC, differential, autoimmune serology, viral serology, nutritional assessments); second-level investigations (bone marrow aspiration with cytogenetics, flow cytometry, antineutrophil antibody testing, genetic testing). Genetic testing is highly recommended in children, young adults, and selected adults, with Sanger sequencing of ELANE (mutated in ~45% of severe CN) as first approach, followed by multigene NGS panels or whole exome sequencing. Annual bone marrow examination (aspiration, trephine biopsy, cytogenetics, somatic NGS) is recommended for congenital neutropenia and other bone marrow failure syndromes. Key markers of malignant transformation include: acquisition of CSF3R, RUNX1, TP53, SETBP1, ASXL1, PTPN11 mutations; cytogenetic abnormalities (trisomy 21, monosomy 7); and dysplastic features. For special situations: G-CSF use during pregnancy is supported by limited data showing safety; neonatal neutropenia requires consideration of gestational age-specific ANC norms, with detailed algorithms for immune neutropenias (neonatal alloimmune neutropenia occurs in 1:6000 newborns, with serious infections in 1 of 5 patients).
**Clinical Implications:** These guidelines provide the first comprehensive, consensus-based framework for standardizing the diagnosis and management of chronic neutropenias across Europe. They emphasize the critical role of genetic testing for accurate diagnosis, risk stratification for MDS/AML transformation, and guidance for special populations including pregnant women and neonates. The recommendations aim to reduce practice variability, improve early detection of malignant transformation, and optimize treatment decisions including G-CSF therapy and hematopoietic stem cell transplantation.