PURPOSE: We sought to identify the clinical variables most critical to successful treatment of Epstein-Barr virus (EBV)–associated hemophagocytic lymphohistiocytosis (HLH). PATIENTS AND METHODS: Among the factors tested were age at diagnosis (< 2 years or ≥ 2 years), time from diagnosis to initiation of treatment with or without etoposide-containing regimens, timing of cyclosporin A (CSA) administration during induction therapy, and the presence or absence of etoposide. RESULTS: By Kaplan-Meier analysis, the overall survival rate for the entire cohort of 47 patients, most of whom had moderately severe to severe disease, was 78.3% ± 6.7% (SE) at 4 years. The probability of long-term survival was significantly higher when etoposide treatment was begun less than 4 weeks from diagnosis (90.2% ± 6.9% v 56.5% ± 12.6% for patients receiving this agent later or not at all; P < .01, log-rank test). Multivariate analysis with the Cox proportional hazards model demonstrated the independent prognostic significance of a short interval from EBV-HLH diagnosis to etoposide administration (relative risk of death for patients lacking this feature, 14.1; 95% confidence interval, 1.16 to 166.7; P = .04). None of the competing variables analyzed had significant predictive strength in the Cox model. However, concomitant use of CSA with etoposide in a subset of patients appears to have prevented serious complications from neutropenia during the first year of treatment. CONCLUSION: We conclude that early administration of etoposide, preferably with CSA, is the treatment of choice for patients with EBV-HLH.

The clinical features of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH) vary significantly, from mild to severe, at the time of the treatment decision. There are many reports of successful treatments, for example conservative treatment without etoposide, HLH-94/2004-type immunochemotherapy with etoposide, and hematopoietic stem cell transplantation. When considering the treatment of EBV-HLH, the most important factor is the finding that a survival benefit is obtained when etoposide-containing therapy is initiated within 4 weeks of diagnosis. This indicates that there may be a window for observation or conservative corticosteroid/cyclosporine A or intravenous immunoglobulin (IVIG) treatment; however, once the disease is defined as “high risk” and/or refractory to such therapy, prompt introduction of etoposide (ideally within 4 wk) is recommended. In deciding whether the disease is “high-risk,” evaluation of clinical staging, EBV genome copy numbers in the serum, cellular EBV tropism, chromosome analysis, and screening for hereditary immuno-deficient diseases such as familial HLH, are required.