Outcomes of CAR T-Cell Therapy in transformed indolent Non-Hodgkin Lymphomas and de novo DLBCL: A comparative analysis from the Italian CAR T-SIE study

Background Transformed indolent non-Hodgkin lymphoma (TiNHL) generally has poorer outcomes than de novo diffuse large B-cell lymphoma (dnDLBCL). Although anti-CD19 CAR T-cell therapy is standard for relapsed/refractory (R/R) large B-cell lymphoma (LBCL), its prognostic role across histologies remains unclear. Methods We conducted a multicenter, retrospective/prospective observational study comparing R/R TiNHL and R/R dnDLBCL patients treated with commercial CAR T-cell therapy and enrolled in the Italian CART-SIE study. Findings Among 438 patients, 107 had TiNHL (96 transformed follicular lymphoma [tFL], 11 transformed marginal zone lymphoma [tMZL]) and 331 had dnDLBCL. Baseline characteristics were comparable. TiNHL patients showed superior overall (83% vs 69%) and complete response rates (62% vs 53%) (both p ' 0·01), with better 2-year progression-free survival (PFS: 44% vs 31%) and overall survival (OS: 61% vs 48%) (both p ' 0·01). CAR-HEMATOTOX score predicted worse outcomes (PFS HR=2·10; OS HR=3·57). No significant differences were found between tFL and tMZL. Two-year relapse/progression incidence was lower in TiNHL (28% vs 47%, p ' 0·01), with similar non-relapse mortality (11% vs 4%, p = 0·12). Safety profiles, including cytokine release syndrome and ICANS rates, were comparable. Conclusion TiNHL patients receiving CAR T-cell therapy achieved better outcomes than dnDLBCL patients, with comparable safety, supporting its use as a standard treatment in TiNHL.