Emapalumab in pediatric relapsed/refractory hemophagocytic lymphohistiocytosis: clinical responses, attenuated efficacy upon retreatment, and role in bridging to HSCT

Relapsed/refractory hemophagocytic lymphohistiocytosis (R/R HLH) represents a hyperinflammatory state driven largely by IFN-γ dysregulation and carries a high risk of early mortality and failure to bridge to hematopoietic stem cell transplantation (HSCT). Emapalumab, a fully human anti–IFN-γ monoclonal antibody, has emerged as a targeted option, but evidence in heterogeneous real-world pediatric populations remains limited. We retrospectively reviewed pediatric patients with R/R HLH who received emapalumab at our center from April 2023 to July 2025. Clinical responses, cytokine kinetics, virologic parameters, survival outcomes, and HSCT feasibility were assessed. Ten children were included: primary HLH (n = 3), EBV-HLH (n = 5), and malignancy-associated HLH (n = 2). Early clinical improvement was observed in most patients, with an ORR of 70% (3 pHLH, 3 EBV-HLH, and 1 M-HLH). IFN-γ, IL-6 and CXCL9 levels declined markedly among responders. Five (3 pHLH and 2 EBV-HLH) successfully proceeded to HSCT, four of whom achieved sustained remission. Patients requiring a second course of emapalumab exhibited attenuated fever resolution and reduced cytokine clearance. During a median follow-up of 3.8 months, the 6-month OS was 45.3 \(\:\text{±}\) 29.2%. Five patients (3 pHLH and 2 EBV-HLH) remained alive at the time of last follow-up. No newly emerged treatment-related toxicities were observed. In conclusion, emapalumab rapidly controls hyperinflammation in pediatric R/R HLH and enables HSCT in a substantial subset of patients. Diminished responsiveness during retreatment underscores the need for timely disease-modifying therapy. Integrated evidence supports IFN-γ blockade as a key component of multimodal HLH management.