Table 5.

Main strategies adopted for the up-front management of ENKTCL, R/R disease, and novel therapies.

ENKTCL clinical presentation	Main therapeutic strategies
1. Early stage (IE-IIE)	1.1. Very elderly (≥80 years old), unfit cases, or primary cutaneous presentation • Isolated EF-RT with 50–60 Gy 1.2. Fit patients • Chemoradiotherapy (CRT)—concurrent, sequential, or sandwiched modalities - 2 × P-GEMOX/EF-RT/2 × P-GEMOX - RT plus weekly cisplatin followed by 3 × VIPD (Korean protocol) - RT followed by 2/3 DeVIC
2. Advanced-stage (III-IV) or extranasal disease (except cutaneous localized disease)	- 2/3 × SMILE - 6 × DDGP - 4/6 × AspMetDex - 4 × P-GEMOX - 4/6 × GDP * Consider up-front consolidation with ASCT for cases presenting high-risk PINK or PINK-E scores
3. Relapsed/refractory (R/R) disease	- Anti-MDR-based chemotherapy (SMILE, DDGP, and P-GEMOX) followed by ASCT consolidation or allo-SCT (in cases previously submitted to ASCT)
4. Novel therapies	- Clinical trials - Anti-PD-1/PD-L1: nivolumab, pembrolizumab, tislelizumab, sintilimab, avelumab - Anti-CD30: brentuximab-vedotin - Anti-CD38: daratumumab - JAK/STAT inhibitors: ruxolitinib, tofacitinib - HDACi: chidamide - Antiviral agents: valganciclovir plus nanatinostat - CAR-T therapies

ENKTCL, extranodal NK-/T-cell lymphoma; EF-RT, extended-field radiotherapy; CRT, chemoradiotherapy; RT, radiotherapy, P-GEMOX, peg-asparaginase, gemcitabine, and oxaliplatin; VIPD, etoposide, ifosfamide, cisplatin, and dexamethasone; DeVIC, dexamethasone, etoposide, ifosfamide, and carboplatin; SMILE, methylprednisolone, methotrexate, ifosfamide, l-asparaginase, and etoposide; DDGP, dexamethasone, cisplatin, gemcitabine, and peg-asparaginase; AspMetDex, l-asparaginase, methotrexate, and dexamethasone; GDP, gemcitabine, dexamethasone, and cisplatin; ASCT, autologous stem cell transplantation; allo-SCT, allogeneic stem cell transplantation; HDACi, histone deacetylase inhibitors; CAR-T, chimeric antigen T-cell receptor.