The multi-center randomized phase 3 NHL-004 study compared etoposide, dexamethasone and pegaspargase (ESA) versus methotrexate, etoposide, dexamethasone and pegaspargase (MESA) regimen, combined with sandwiched radiotherapy, in newly diagnosed early-stage nasal natural killer/T-cell lymphoma (NKTCL). Here we report the long-term outcomes (median follow-up, 64 months) and biomarker analysis. 256 eligible patients aged 14-70 years were randomly assigned (1:1) to ESA or MESA arm. The 5-year progression-free survival (PFS) rates were 80.3% and 74.9% in ESA and MESA arms (hazard ratio [HR] = 0.78 [95%CI, 0.46-1.33], p = 0.371), and the 5-year overall survival (OS) rates were 85.1% and 80.9% (HR = 0.74 [95%CI, 0.40-1.37], p = 0.332), respectively. No new safety signals related to treatments were observed. Interim plasma Epstein-Barr virus (EBV) DNA positivity and stable disease/progression disease response were independent predictors of inferior PFS and OS. No prognostic significance was observed according to molecular subtypes. Interim EBV DNA positivity correlated with upregulated chromatin remodeling alterations, immune escape related genes, and decreased infiltrating monocytes/M1 macrophages. With low toxicity, non-intravenous and outpatient design, ESA with sandwiched radiotherapy achieved long-term durable response in patients with newly diagnosed early-stage NKTCL. Dynamic monitoring of plasma EBV DNA provided clinical rationale in future mechanism-based therapy of NKTCL.