Risk-Stratified Phase II Clinical Trial for Epstein–Barr Virus-Associated Hemophagocytic Lymphohistiocytosis in Pediatric, Adolescent, and Young Adult Patients in Japan

Introduction: Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is highly prevalent in Asia. This study evaluated the safety and efficacy of a risk-stratified treatment guided by dexamethasone (DEX) response and plasma EBV-DNA levels. Our goal was to optimize etoposide dosing and establish a safer EBV-HLH treatment. Methods: We conducted a single-arm, multicenter, risk-stratified Phase II clinical trial, EBV-HLH15, for EBV-HLH. Patients were classified into three groups based on age, DEX response, and plasma EBV-DNA load. In the low-risk (LR) group, etoposide was eliminated from the treatment regimen. In the intermediate-risk and high-risk group (IR/HR group), etoposide dosing was reduced by up to 60% compared with the HLH-2004 study to attenuate treatment intensity, whereas rituximab was added in the HR group to maintain it. Results: Of 56 patients suspected of EBV-HLH enrolled, 26 (14 in LR, eight in IR, and four in HR group) were eligible for EBV-HLH15. The median age was 3.5 years (range: 1.0–8.0). The 1-year overall survival of the LR and IR/HR groups was 100% and 81.5% (95% confidence interval [CI] = 43.5–95.1), respectively. The event-free survival of the LR and IR/HR groups was 78.6% (95% CI = 47.2–92.5) and 58.3% (95% CI = 27.0–80.1), respectively. Most events (9/10, mainly deterioration or recurrence of HLH) occurred within 3 weeks of treatment initiation. No patients received rituximab as scheduled in Weeks 5 and 6. Conclusion: Risk-stratified treatment for EBV-HLH guided by DEX response and plasma EBV-DNA levels after 2 weeks of treatment was safe and effective.