Survival Trends in Diffuse Large B-Cell Lymphoma (DLBCL) in the CAR-T Cell Therapy Era Vs Pre-CAR-T Cell Therapy Era in the United States: A Population-Based Study
Authors: Wasifuddin Mustafa , Ilerhunmwuwa Nosakhare Paul , Becerra Henry , Hakobyan Narek , Uche Ifeanyi Nnamdi , Yadav Ruchi , Pokhrel Akriti , Zheng Jin , Abowali Hesham Ali , Heravi Omid , Aroshidze Beka , Enayati Ladan , Manvar Kapilkumar , Saparov Dosbai , Yadav Siddharth , Wang Jen-Chin 
Published: December 2023

Background
Chimeric Antigen Receptors (CARs) are novel engineered proteins that alter T-cell antigen specificity. CAR-T cell therapy is a novel form of immunotherapy that uses T-cells engineered with CARs to target tumor-associated antigens. The Food and Drug Administration (FDA) granted approval to the first CAR-T therapeutic agents in 2017. Axicabtagene ciloleucel (axicel) is one such therapy currently in use that was developed to target CD19 - a pan-B cell marker for the treatment of Diffuse Large B-Cell Lymphoma (DLBCL). 1 Previous population-based studies have shown improvements in Overall Survival (OS) after the introduction of rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with DLBCL. 2 However, there is limited data on survival after the introduction of CAR-T cell therapy at the population level. With this study, we hypothesized that improvements in survival have been made in recent years with the introduction of CAR-T cell therapy for the treatment of DLBC and aim to demonstrate these outcomes.
Methods
We used the Surveillance, Epidemiology and End-Results (SEER-17) research program data to conduct a retrospective study of patients diagnosed with DLBCL between 2013-2020. This period was divided into two cohorts: pre-CAR-T approval (2013-2016) and post-CAR-T approval eras (2017-2020). Statistical analysis was performed using SPSS version 25. Patient characteristics were expressed as number (N) and percentages (%). Categorical variables were compared using the Chi-Square Test. The Kaplan Meier method was used to compare OS of both eras. OS was defined as the time from diagnosis to death. Cox proportional hazard regression was used to compare both cohorts and expressed as hazard ratios. A p-value ≤0.05 was considered statistically significant.
Results
All results are highlighted in Table 1. A total of 41219 DLBCL patients were identified between 2013 and 2020. Splitting by cohorts, 20139 DLBCL patients were identified in the pre-CAR-T cohort and 21080 DLBCL patients were identified in the post-CAR-T approval cohort. Patients in the post-CAR-T era demonstrated a higher proportion of patients ≥65 years (56.6% vs 53.7%) and distant stage disease (53.4% vs 52.1%) at the end of the time period.. The pre-CAR-T era demonstrated a higher proportion of people dead attributable to DLBCL (33% vs 23.5%). Figure 1 depicts OS for each group, with the post-CAR-T era (2017-2020) demonstrating a statistically significant higher OS (0.031). The post-CAR-T era cohort was associated with an improvement in overall survival (HR = 0.951, 95% CI: 0.913-0.990, p-value ≤0.014). Other independent prognostic variables found in our study were, ≥age 65 (HR = 2.351 95% CI: 2.251-2.455, p-value ≤0.001), male sex (HR = 1.260, 95% CI: 1.212-1.311, p-value ≤0.001), distant stage disease (HR = 1.653, 95% CI: 1.573-1.737, p-value ≤0.001), which indicated worse prognosis. Chemotherapy (HR = 0.331, 95% CI: 0.314-0.349, p-value ≤0.001) was found to be an independent prognostic factor for improvement of OS in DLBCL.
Conclusion:
To the best of our knowledge, our study is the first US population-based study to evaluate survival outcomes in DLBCL patients after the introduction of CAR-T cell therapy. The survival in patients in the CAR-T era improved compared with the pre-CAR-T era. A limitation of our study is that the SEER database does not contain data on the type of chemotherapy given to patients. Also, due to the relatively recent introduction of CAR-T cell therapy as a treatment modality further studies over longer time periods are required to better characterize its association with improvements in survival.
References:
Neelapu SS, Dickinson M, Munoz J, et al. Axicabtagene ciloleucel as first-line therapy in high-risk large B-cell lymphoma: the phase 2 ZUMA-12 trial. Nature Medicine. 2022;28(4):735-742. doi:10.1038/s41591-022-01731-4
Epperla N, Vaughn JL, Othus M, Hallack A, Costa LJ. Recent survival trends in diffuse large B-cell lymphoma–Have we made any progress beyond rituximab? Cancer Medicine. 2020;9(15):5519-5525. doi:10.1002/cam4.3237