Chronic active Epstein-Barr virus disease in children: Clinical outcomes and prognostic risk factors from a 149-patient cohort.

Chronic active Epstein-Barr virus disease (CAEBV), an Epstein-Barr virus (EBV)+ T/Natural Killer (NK)-cell lymphoproliferative disorder, remains critically undefined in treatment and prognostic stratification due to its rarity. We analysed 149 paediatric systemic CAEBV patients, of whom 134 received LDEP (liposomal doxorubicin, etoposide, pegylated asparaginase and methylprednisolone) chemotherapy as a bridge to haematopoietic stem cell transplantation (HSCT). Diagnostic delay was common (median 6.0 months), with 41.6% presenting atypically with localized symptoms at onset. Haemophagocytic lymphohistiocytosis developed in 50.3%. EBV infection involved pan-lymphoid lineages in 85.2%, with NK-cell predominance (44.3%) enriched in the hydroa vacciniforme/severe mosquito bite allergy subtype. LDEP induced favourable response in 59.0%, significantly improving HSCT rates (98.7% vs. 69.1%). Overall, 127 patients (85.2%) underwent HSCT, with 3-year post-transplant survival of 84.5% ± 3.5%. Inferior post-HSCT survival was independently associated with active disease at transplantation (hazard ratio [HR] = 6.17, p < 0.001) and also linked to longer chemotherapy-to-HSCT interval (>3.5 months) and poor LDEP response. Non-transplanted patient had 90.9% mortality. The entire cohort had a 3-year overall survival of 72.6% from diagnosis, with poor LDEP response, hepatic dysfunction and leucopenia as independent risk factors. This large paediatric cohort defines the clinical spectrum of CAEBV, establishes LDEP as an effective bridging regimen to HSCT-particularly in early-stage disease-and highlights the need for early disease activity control and timely transplantation.