ArticleFrontiers in immunology2026
Case Report: refractory hemophagocytic lymphohistiocytosis progression despite complete metabolic response in a patient with stage IV extranodal NK/T-cell lymphoma: clinical observation of "tumor-immune dissociation" phenomenon.
Article in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-associated mature T- and NK-cell neoplasm with a notably high prevalence in Asian populations. It is a leading malignant cause of secondary hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune hyperactivation syndrome associated with poor prognosis in ENKTCL patients. Current clinical guidelines lack evidence-based post-remission monitoring protocols for the early detection of HLH progression in ENKTCL patients who achieve complete metabolic response (CMR). We report the case of a 59-year-old woman with stage IVB extra-nasal ENKTCL and biopsy-confirmed secondary HLH at initial diagnosis, who achieved radiologic CMR following frontline HLH induction therapy and three cycles of lymphoma-specific chemotherapy. Despite persistent CMR, she developed refractory HLH progression, and ultimately died from progressive HLH and multiple organ failure. Serial dynamic monitoring of tumor biomarkers (plasma EBV-DNA), direct immune activation biomarkers (soluble CD25 [sCD25]), and HLH-specific disease activity biomarkers (serum ferritin, triglycerides) revealed a "tumor-immune dissociation" phenomenon-aberrant immune activation and HLH progression occurring independently of radiologic tumor progression, with sCD25 remaining persistently elevated throughout the disease course, though subclinical EBV reactivation or microscopic disease undetectable by PET/CT cannot be excluded. This case demonstrates that HLH can progress independently of radiologically detectable tumor burden even after achieving CMR, underscoring a critical limitation of current response-adapted follow-up strategies. The observed "tumor-immune dissociation" highlights the urgent need to incorporate immune activation biomarkers into routine surveillance for high-risk ENKTCL patients, as well as to conduct early evaluations of allogeneic hematopoietic stem cell transplantation for eligible individuals.
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