When Can We Define Cure after CAR-T Therapy in LBCL? Insights from Serial Landmark Analyses

Background: While response rates to CD19-targeted CAR T cell therapies in large B cell lymphoma (LBCL) are high, up to 60% of patients ultimately relapse or progress. Consequently, determining the optimal time point to define a cure following CAR-T therapy remains challenging. To address this, we performed serial evaluations of the risk of relapse after CAR-T, contingent on patients remaining disease-free at specific time points. Methods: This retrospective multicenter study includes patients with LBCL treated with commercially available CD19 CAR-T products between April 2018 and June 2023. Primary endpoints were progression-free survival (PFS) and overall survival (OS) measured in patients who maintained a response from various landmarks after CAR-T infusion (Day 28, 3, 6, 12, 18, and 24 months). Response rate transitions were visualized using Sankey diagrams. Cox regression models were adjusted for age, NHL transformation, elevated vs. normal LDH, response at corresponding landmark time, CAR-T product, and bridging therapy to determine associations with PFS. Results: We included 477 patients treated with Axi-cel (n=260, 55%), Tisa-cel (n=130, 27%), and Liso-cel (n=87, 18%). Patients were heavily pre-treated, with 79% having received >3 lines of therapy. Overall response rate (ORR) at Day 28 was 78%, with 50% achieving complete response (CR) and 28% partial response (PR). With a median follow-up of 18 months for Axi-cel, 34 months for Tisa-cel, and 12 months for Liso-cel, median PFS was 12 months for Axi-cel, 3.2 months for Tisa-cel, and not reached for Liso-cel. Among patients in CR on day 28 (n=195), 1 and 2-year PFS from day 28 landmark was 64% and 53%, corresponding OS probability was 90% and 74%. Patients with a PR on day 28 (n=194) had lower PFS (1-year: 43%, 2-year: 40%) and OS (1-year 65%, 2-year 50%). Probabilities of 1 and 2-year PFS also varied by product in patients achieving response: Axi-cel (58%/52%), Tisa-cel (46%/35%), and Liso-cel (62%/57%). For patients in CR at 3 months (n=173), PFS from the 3-month landmark was 76% at one year and 66% at two years, while the corresponding OS probability was 92% and 81%. By product, PFS probabilities at one year and two years were, respectively, Axi-cel (83% /74%), Tisa-cel (66% /46%), and Liso-cel (75%/69%). For patients in CR at 6 months (n=148), the PFS from the 6-month landmark was 77% at one year and 64% at two years, while the corresponding OS probability was 89% and 81%. By product, PFS probabilities at one year and two years were, respectively, Axi-cel (81%/67%), Tisa-cel (66% / 49%), and Liso-cel (78%/78%). After one year in CR (n=128), patients treated with Axi-cel and Liso-cel have PFS rates for the year following the 1-year landmark of 89% and 100%, respectively. In patients treated with Tisa-cel, 1-year PFS was lower (83%) and only patients in CR at 2 years had a PFS from the landmark increased to over 90%. However, 1 year OS probability from 1-year landmark remains above 90% for all products: Axi-cel (94%), Tisa-cel (96%), and Liso-cel (100%). Finally, in a multivariable Cox regression model for PFS, elevated LDH levels before lymphodepletion were associated with an increased risk of loss of response at the day 28, 3 months and 6 months landmarks (HR 2.66 (95% CI: 1.84, 3.84), p < 0.001; 2.06 (95% CI: 1.12, 3.80), p = 0.024; 2,43(95% CI: 1,25,4,72), p = 0.011, respectively). From the 6-month landmark, Tisa-cel showed a higher risk of progression compared to Axi-cel (HR 3.58, 95% CI: 1.57-8.14; p = 0.009), while Liso-cel showed no significant difference (HR 1.23, 95% CI: 0.48-3.19) compared to Axi-cel. Conclusion: In this large real-world analysis of the three commercially available products for LBCL, we provide a benchmark for data-driven conversations about long-term survival with patients in remission. Our findings indicate that with Tisa-cel, a longer remission duration of two years post-CAR-T is required to determine a high likelihood of cure.Notably, we find that patients maintaining remission at 1 year following Axi-cel and Liso-cel have a very low probability of relapse, underscoring their curative potential.