Clinical significance of blood EBV-DNA in peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) and EBV-positive nodal T-cell lymphoma

Abstract Background: Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), is a predominantly nodal, diagnosis-of-exclusion entity that encompasses clinically and molecularly heterogeneous lymphomas not meeting WHO criteria for any other specific subtype. A subset previously grouped as PTCL-NOS, characterized by EBV-encoded small RNA in situ hybridization (EBER-ISH) positivity within neoplastic cells, has recently been recognized as EBV-positive nodal T-cell lymphoma (EBV+ nPTCL), a distinct entity with poor prognosis. However, the clinical and prognostic implications of blood EBV-DNA in PTCL-NOS and EBV+ nPTCL remain unclear. Methods: Patients diagnosed with PTCL-NOS under the 4th edition of the WHO classification of haematolymphoid neoplasms (WHO-HAEM4) who were treated at Asan Medical Center, Seoul, Korea between January 1, 2007, and January 31, 2023, were included. Availability of tumor EBER-ISH and blood EBV-DNA PCR (whole blood or plasma) was required for inclusion. Among EBER-ISH-positive cases, pathology reports were reviewed to reclassify EBV+ nPTCL per contemporary criteria (i.e. WHO-HAEM5); cases with indeterminate reclassification based on report review were excluded. Blood EBV-DNA positivity was defined as detectable EBV-DNA by PCR in either whole blood or plasma. Baseline characteristics and clinical outcomes to first-line chemotherapy were compared by blood EBV-DNA status within the PTCL-NOS and EBV+ nPTCL groups, separately. Results: A total of 91 patients were included; 14 were reclassified as EBV+ nPTCL and 77 remained PTCL-NOS. Blood EBV-DNA was positive in 31/77 (40.3%) in PTCL-NOS and 11/14 (78.6%) in EBV+ nPTCL. In both groups, baseline characteristics did not differ by EBV-DNA status, except for higher frequency of bone marrow involvement (41.9% vs. 17.4%; P = 0.018) and higher Prognostic Index for T-cell lymphoma (PIT) scores (P = 0.010) in EBV-DNA-positive patients within PTCL-NOS. The median follow-up duration was 106.3 months (95% CI, 89.5–169.0). Compared with PTCL-NOS, the EBV+ nPTCL group had worse survival outcomes (median PFS, 5.4 vs. 7.3 months; P = 0.138; EFS, 4.9 vs. 5.8 months; P = 0.152; OS, 10.1 vs. 20.4 months; P = 0.012). Within PTCL-NOS, EBV-DNA-positive patients had numerically shorter median PFS (5.4 vs. 8.1 months; P = 0.116), EFS (4.6 vs. 7.3 months; P = 0.125), and OS (17.4 vs. 22.7 months; P = 0.133) than EBV-DNA-negative patients; however, none of these differences reached statistical significance. Within EBV+ nPTCL, survival did not differ significantly by EBV-DNA status (median PFS, 5.3 vs. 8.2 months; P = 0.334; EFS, 4.7 vs. 8.2 months; P = 0.152; OS, 8.6 vs. 11.6 months; P = 0.825). Conclusions: In PTCL-NOS, blood EBV-DNA positivity was associated with a non-significant trend toward poorer survival outcomes, while no association was observed in EBV+ nPTCL. Further prospective studies in larger, WHO-HAEM5-defined cohorts are warranted.