Drivers of Temporal Improvement in CAR T-Cell Therapy for Large B-Cell Lymphoma: A Japanese Nationwide Registry Analysis

Real-world CD19 chimeric antigen receptor (CAR) T-cell therapy for large B-cell lymphoma (LBCL) is characterized by expanded eligibility and evolving management practices. However, the prognostic impact of these changes remains inconsistent, and the specific drivers of the outcomes remain unclear. This study analyzed 913 patients with relapsed/refractory LBCL from a Japanese registry and compared the outcomes between two calendar periods (2019-2021 vs. 2022-2024). The 2022-2024 cohort was older, had more adverse baseline features, and was less pretreated. Treatment patterns have shifted toward higher utilization of second-line therapy, a growing preference for axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel), and improved disease control prior to infusion. Accordingly, the 2022-2024 cohort achieved a longer progression-free survival (PFS) (6-month PFS, 63.2% vs. 55.2%; P = .005), which persisted after adjusting for baseline characteristics using propensity score matching. Multivariable analysis identified second-line therapy, improved pre-infusion disease control, and a shift in product selection from tisagenlecleucel to axi-cel or liso-cel as the primary drivers of this improvement. This benefit was pronounced in high-risk populations, including patients with stable or progressive disease at infusion (6-month PFS: 54.6% vs. 43.8%; P = .012) and those who were refractory to first-line therapy (6-month PFS: 51.7% vs. 40.3%; P = .013). Despite broader use in higher-risk populations and greater axi-cel exposure, 6-month non-relapse mortality remained low (2.1% vs. 1.5%). Real-world outcomes of CD19 CAR T-cell therapy for r/r LBCL have improved, predominantly driven by second-line therapy, enhanced pre-infusion disease control, and increased use of more potent CAR T products.