Early Versus Late CAR-T Therapy in Large B-Cell Lymphoma: Real-World Outcomes

Introduction Recent randomized controlled trials have established CD19-chimeric antigen receptor T-cell (CAR-T) therapy as second-line treatment in large B-cell lymphoma (LBCL). However, it is uncertain whether earlier CAR-T therapy administration improves safety and efficacy compared to later administrations. Thus, we aimed to compare these outcomes based on the timing of CAR-T therapy in a real-world setting. Methods In this retrospective analysis we included 368 patients diagnosed with LBCL who underwent CD19 CAR-T therapy from two medical centers. We categorized CAR-T treatment for primary refractory disease or relapse occurring within 12 months after the initial line of treatment as "early indication" (EI), and treatment administered after two lines of prior therapy as "late indication" (LI). Results Patients in the LI group exhibited several distinguishing characteristics, including elevated pre-lymphodepletion LDH levels (p= <0.001), and the use of 41BB-based CAR-T (p=0.008), while the EI group presented higher pre-CART age (p=0.021) and systemic bridging therapy (p=0.034).With a median follow-up period of 24.6 months (IQR 7.7-34.7) for the LI group and 8.9 months (4.5-12.5) for the EI, no statistically significant differences were observed for overall (74% vs. 88%, p=0.068) or complete response rate (57% vs 68%, p=0.2). Specifically, the 1-year progression-free survival (PFS) rates were 40% (95% CI: 34-46%) in the LI group and 42% (26%-67%) in the EI group (p=0.4), and the 1-year overall survival (OS) rates were 66% (61%-72%) and 86% (73%-100%), respectively (p=0.045) (Figure 1A and 1B).In a multivariable Cox regression analysis, reduced OS was associated with an elevated pre-lymphodepletion LDH (p<0.001) and age (p=0.007); lower PFS was associated with elevated pre-lymphodepletion LDH (p= <0.001) and Tisagenlecleucel (p= <0.001). However, the indication time was not associated with OS (p=0.26) or PFS (p=0.28); a sensitivity analysis restricted to patients receiving axi-cel demonstrated similar results.The cumulative incidence of severe neutropenia (neutrophils < 0.5 × 109/L) within 30 days after infusion was higher in the LI group than in the EI group (65% [59%-70%] vs. 47% [31%-61%], p=0.013). The incidence of severe thrombocytopenia (platelets < 20,000/mm3) was similar across both groups, as were the rates of grade 2-4 cytokine release syndrome (CRS) (p=0.41) and grade 2-4 immune effector cell-associated neurotoxicity syndrome (ICANS) (p=0.48). Conclusions This is the first study to compare outcomes based on the timing of CAR-T treatment in LBCL. While earlier administration demonstrated a lower incidence of severe neutropenia, key efficacy metrics remained similar across early versus late introduction of CAR-T. Importantly, additional follow-up is needed to determine whether the benefit of earlier exposure to CAR-T endures over time.