IFN‐γ Driven Hepatic Injury Exacerbates Mortality in NK/T‐Cell Lymphoma‐Associated Hemophagocytic Lymphohistiocytosis

Background Hepatic involvement is a life‐threatening complication in natural killer/T‐cell lymphoma with hemophagocytic lymphohistiocytosis (NK/T‐HLH). Nevertheless, the prognostic implications of hepatic dysfunction and its underlying related factors are not fully elucidated. Methods We retrospectively analyzed the clinical and laboratory data of 53 NK/T patients, comprising 35 cases without HLH and 18 with HLH. All NK/T‐HLH patients exhibited hepatic injury, characterized by significantly elevated hepatic enzyme levels and bilirubin compared to those without HLH (all p < 0.001). Glutamyltransferase (GGT), aspartate aminotransferase (AST), and direct bilirubin (DBIL) individually predicted mortality with AUC > 0.8 in NKTCL patients, while their composite GSD index enhanced predictive accuracy (AUC = 0.87). Results Notably, NK/T‐HLH patients meeting the GSD index criteria had markedly reduced overall survival (OS) compared to non‐fulfillers (median OS: 2 vs 21 months; p = 0.003). Patients with hepatic involvement exhibited significantly higher levels of serum interferon‐γ(IFN‐γ) and interleukin‐10 (IL‐10). While, only IFN‐γ concentrations showed a strong positive correlation with the elevated levels of GGT, AST, and DBIL. To further validate the clinical relevance of these findings, we present two representative cases of NK/T‐HLH with severe hepatic injury. Both patients achieved rapid liver function recovery following a targeted regimen combining chemotherapy and emapalumab, a human anti‐IFN‐γ monoclonal antibody approved for primary HLH. Conclusion The GSD index emerges as a robust prognostic tool for NK/T‐HLH patients with hepatic dysfunction, reflecting underlying IFN‐γ‐mediated immunopathology. Early intervention with anti‐IFN‐γ monoclonal antibody may improve clinical outcomes in this high‐risk subgroup.