A 40-year-old previously healthy woman presented with rapidly progressive altered mental status, respiratory failure, pancytopenia and hemophagocytic lymphohistiocytosis (HLH) requiring ICU admission. Initial laboratory evaluation demonstrated a ferritin of 40,000 µg/L, fibrinogen 81 mg/dL, LDH 2,140 u/L and a platelet count of 30 000/L. CT imaging revealed bilateral pleural effusions, ascites, and splenomegaly. MRI of the brain showed acute bilateral frontotemporal subdural hematomas. Bone marrow biopsy revealed an aggressive EBV-positive NK-cell neoplasm expressing CD30 and involving 40–50% of marrow cellularity with hemophagocytosis. Next-generation sequencing revealed no actionable mutations. PET-CT did not reveal FDG-avid lymphadenopathy. Her clinical condition remained critical, and she was started on methylprednisolone 1 g daily. Her HLH parameters improved with steroids, and she was extubated but remained persistently encephalopathic. Standard methotrexate-based therapy was contraindicated due to large pleural effusions and ascites, and peg-asparaginase could not be given because of acute subdural hematomas. She was also considered to be too weak to tolerate gemcitabine, oxaliplatin or other chemotherapy agents. Ruxolitinib 5 mg BID, later escalated to 10 mg BID was initiated and led to steady improvement in HLH markers and mental status, with ferritin decreasing to 3,000 µg/L within two weeks. Given her improvement she received nivolumab 240 mg, followed by brentuximab vedotin 1.8 mg/m², with further clinical and biochemical improvement. Ultimately, she recovered sufficiently to be discharged for continued outpatient therapy.
Aggressive NK-cell neoplasms frequently present with critical illness and secondary HLH, making treatment particularly challenging. This case illustrates that non-chemotherapy, targeted therapeutic approaches can achieve meaningful disease control even in critically ill patients with newly diagnosed disease.
