Dynamic monitoring of circulating cell-free EBV-DNA for risk assessment in early-stage natural killer/T-cell lymphoma

While circulating tumor DNA (ctDNA) has shown promise in real-time monitoring of recurrence risk in various solid tumors, the clinical relevance of cell-free EBV-DNA (cfEBV-DNA) in natural killer/T-cell lymphoma (NKTCL) remains unclear. In this study, 710 consecutive patients with early-stage NKTCL were included from five hospitals between January 2014 and December 2022, all of whom underwent longitudinal monitoring of cfEBV-DNA. All patients received asparaginase-based induction chemotherapy (IC) followed by radiation therapy (RT). Pretreatment cfEBV-DNA was positive in 487 patients (68.6%), 258 of whom became negative after the first cycles of IC. During chemotherapy the percentage of patients becoming cfEBV-DNA-negative increased, whereas the velocity of cfEBV-DNA clearance decreased. Achieving cfEBV-DNA negative during different treatment phases (post-IC1 to post-IC6, and post-RT) was significantly associated with better progression-free survival (PFS) and overall survival (OS) compared with those who remained positive (all P < 0.01). Next, using unsupervised clustering analysis, patients were classified into four cfEBV-DNA response phenotypes: (1) consistently negative; (2) early response; (3) late response; and (4) no response. These cohorts had significantly different 5-year PFS (94%, 83%, 57% and 18%; P-value for trend < 0.001) and OS (98%, 91%, 70%, and 33%; P-value for trend < 0.001). In Cox multi-variable analyses cfEBV-DNA response phenotype was still independently correlated with PFS and OS. In conclusion, dynamic monitoring of on-treatment cfEBV-DNA provides longitudinally prognostic information in patients with early-stage NKTCL and may have therapy implications.