Successful treatment of refractory hemophagocytic lymphohistiocytosis complicating Epstein-Barr virus-positive classic Hodgkin lymphoma with rituximab.

Hemophagocytic lymphohistiocytosis (HLH) complicating classic Hodgkin lymphoma (HL-HLH) is a rare but frequently life-threatening condition that is strongly associated with Epstein-Barr virus (EBV) infection, particularly in the mixed-cellularity and lymphocyte-depleted subtypes. No consensus has been reached regarding treatment for HL-HLH, and the myelotoxicity induced by etoposide-based HLH-directed therapy precludes its safe addition to intensive lymphoma-directed chemotherapy, particularly in older patients. We here report the case of a male in his early 70s with advanced EBV-positive mixed-cellularity classic Hodgkin lymphoma (CHL) who presented with cervical lymphadenopathy, fever, hepatosplenomegaly, and a markedly elevated soluble interleukin-2 receptor (sIL-2R) level, along with a high peripheral blood EBV DNA load. EBV-encoded small RNA in situ hybridization confirmed EBV positivity in lymphoma cells. His fever was steroid-refractory, and chemotherapy with brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (BV-AVD) was initiated immediately following the diagnosis was confirmed. However, the persistent high fever did not resolve, and progressive cytopenia, marked hyperferritinemia, and further increase in sIL-2R levels were observed. Repeat bone marrow examinations revealed macrophage activation with hemophagocytosis, confirming HLH as a complication. Rituximab was promptly administered, and the fever resolved within 3 days. Furthermore, ferritin, sIL-2R, and lactate dehydrogenase levels substantially declined within 1 week, with peripheral blood EBV DNA becoming undetectable. BV-AVD was continued without major complications and led to a complete response after six cycles. Rituximab may represent a strategically timed and reasonable adjunctive intervention for EBV-driven HL-HLH that is refractory to, or develops following, chemotherapy for CHL.