Treatment choice of immunotherapy or further chemotherapy for Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis

Background: Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) leads to an aggressive and often fatal course without appropriate treatment. Etoposide therapy is crucial for the better prognosis, although it remains unknown what patients need cytotoxic agents. Since we have complied with step-up strategy in a tertiary center, treatment outcomes were studied to search predictors for disease course. Methods: The study enrolled 22 EBV-HLH patients treated between 1999 and 2010 in Kyushu University. Immunotherapy, chemotherapy and stem cell transplantation (SCT) proceeded in stages unless patients attained a consecutive >21 days-afebrile remission. Clinical and laboratory data and outcomes were retrospectively analyzed. Results: Median age of 9 males and 13 females was 5 years (range: 9 months-41 years). Sixteen patients (73%) presented at age <15 years. Two patients remitted spontaneously, 12 attained remissions after immunotherapy, 5 after chemotherapy, and 1 after successful SCT. The remaining two patients died after chemotherapy and SCT, respectively. Median EBV load was 1×10 ⁵copies/ml of peripheral blood (range: 200-5×10 ⁷). T-cells were exclusively targeted (94%; 15/16 examined) often with EBV/T-cell receptor clonality. EBV status indicated 19 primary infections and 3 reactivations. Either death occurred in EBV-reactivated patients who underwent chemotherapy±SCT. Age at primary infection in pediatric patients increased in the last 5 years. Patients having prolonged fever (P=0.017) or high soluble CD25 levels (P=0.017) at diagnosis were at higher risk for requiring chemotherapy assessed by multivariate analyses. Conclusions: No cytotoxic agents were needed for >60% of EBV-HLH patients. Early immunotherapy may modulate T-cell activation and reduce the chance of unnecessary chemotherapy.