Early time to relapse as a survival prognosticator in mature T-cell/NK-cell lymphomas: results from the PETAL Consortium Open Access

• Patients with nMTCL with TTR12 from initial therapy have worse survival and distinct subsequent therapeutic responses.

• Poor OS effect of TTR12 is consistent across sensitivity, validation, and subgroup analyses, including histological and high-risk subgroups.

We previously demonstrated that relapsed and refractory nodal-mature-T-cell-lymphomas (nMTCL) have distinct prognoses. Here, we assessed the overall survival (OS) impact of time-to-relapse (TTR) in multinational PETAL/LATAM cohorts with validation using observational and randomized independent cohorts. Patients with nMTCL with complete response to frontline treatment were assigned to TTR12 (<12m) or without TTR12 based on time-to-progression or time-to-next-therapy. OS was compared using modified landmark (m-LM) analysis. Sensitivity analyses included standard landmark (s-LM) and time-dependent Cox (td-Cox). Estimates were adjusted for age, histology, and Prognostic-Index-for-T-cell-lymphoma (PIT) score. Across 452 patients, 165 (36.5%) had TTR12, 181 (40%) relapsed ≥12m, and 106 (23.5%) remained relapse-free. TTR12 conferred worse OS using m-LM (HR 2.14; 95%CI: 1.58-2.90, p<0.001), s-LM (HR 1.92; 95%CI: 1.39-2.66, p<0.001), and td-Cox (HR 5.81; 95%CI: 2.94-11.46, p<0.001). Results were consistent in the independent validation cohorts with univariable and multivariable models. TTR12 consistently conferred worse OS irrespective of front-line hematopoietic stem-cell transplantation or PIT score, in peripheral-T-cell-lymphoma, not-otherwise-specified (m-LM: HR 2.32; 95%CI: 1.51-3.55, p<0.001; s-LM: HR 2.10; 95%CI: 1.33-3.31, p=0.001), anaplastic-large-cell-lymphoma (m-LM: HR 3.34; 95%CI: 1.18-9.50, p=0.023; s-LM: HR 2.96; 95%CI: 1.02-8.81, p=0.046), and angioimmunoblastic-T-cell/T-follicular-helper-cell-lymphoma (m-LM only: HR 1.92, 95%CI: 1.15-3.21; p=0.013). Second-line novel therapies improved OS (second-line start to death) versus chemotherapy in TTR12 (HR 0.60; 95%CI: 0.37-0.97, p=0.038) but not in patients without (HR 0.82; 95%CI: 0.51-1.32, p=0.407). TTR12 identified worse OS patients alongside, and compounding with, PIT score. TTR12 serves as a prognostic and potential OS surrogate marker, supporting stratification of new risk groups and need for their differential treatment.