IFN-γ driven hepatic injury exacerbates mortality in NK/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis

Abstract 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. 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), alanine 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). 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. 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.