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.