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Extranodal natural killer/T‐cell lymphoma, nasal type (ENKL) is a rare peripheral T‐cell lymphoma that predominantly occurs in Asian and South American populations. The treatment of ENKL has been a challenge for a long time. This study was conducted to compare the clinical efficacy and safety of cisplatin, dexamethasone, gemcitabine, and pegaspargase (DDGP) and methotrexate, dexamethasone, ifosfamide, L‐asparaginase, and etoposide (SMILE) regimens for relapsed/refractory ENKL and explore the prognostic factors. From October 2014 to July 2019, 54 patients with relapsed/refractory ENKL who received DDGP or SMILE chemotherapy were retrospectively assessed in this study. Thirty‐one patients received DDGP chemotherapy and 23 patients received SMILE chemotherapy. A higher complete response rate was observed in patients treated with DDGP regimen (61.3% vs. 30.4%,  P  = 0.025). The DDGP group (95% confidence interval (CI) of 5‐year progression‐free survival (PFS): 24.6–66.2%; 95% CI of 5‐year overall survival (OS): 8.5–91.7%) was also significantly associated with longer 5‐year PFS and 5‐year OS ( P  = 0.008 for 5‐year PFS,  P  = 0.023 for 5‐year OS). More serious leucopenia ( P  = 0.021), neutropenia ( P  = 0.041), and allergy ( P  = 0.040) were observed in the SMILE group. Post‐treatment Epstein–Barr virus (EBV)‐DNA status ( P  = 0.001 for PFS,  P  = 0.018 for OS) was identified as a significant prognostic factor for PFS and OS in multivariate analysis. The present research suggested that compared with SMILE chemotherapy, DDGP chemotherapy can significantly improve the response and survival of relapsed/refractory ENKL with better tolerance. Post‐treatment EBV‐DNA status was identified as a significant prognostic factor for PFS and OS in relapsed/refractory ENKL.

DDGP vs. SMILE in Relapsed/Refractory Extranodal Natural Killer/T‐cell Lymphoma, Nasal Type: A Retrospective Study of 54 Patients