Comparative Real-World Outcomes of Commercial CD19-Directed CAR T-Cell Therapies in Large B-Cell Lymphoma

Introduction: Although the US FDA has approved 3 commercial CAR T-cell therapies for large B-cell lymphoma (LBCL), there are no randomized clinical trials directly comparing their efficacy and safety. Recent studies have supported the higher efficacy, but higher toxicity, of axicabtagene ciloleucel (axi-cel) compared to tisagenlecleucel (tisa-cel). However, there is no such comparison with lisocabtagene maraleucel (liso-cel). Here, we compare the real-world clinical outcomes of patients treated for LBCL with the 3 commercially available CAR T-cell products. Methods: We conducted a retrospective multicenter cohort study involving 501 patients from 4 centers in the USA and Israel, treated for LBCL between April 2016 and January 2024. We included only patients treated with commercially available CAR T-cells outside of prospective clinical trials. Patient characteristics between the cohorts were compared using Pearson's Chi-squared test, Fisher's exact test, or Kruskal-Wallis rank sum test. Multivariable analyses using Cox proportional hazards models were conducted to adjust for age, performance status, LBCL subtype, refractory vs. relapse status, stage at apheresis, bridging therapy, disease response pre-infusion, LDH, and line of treatment. Results: Among all patients, 96 (19%), 133 (27%), and 272 (54%) received liso-cel, tisa-cel, and axi-cel, respectively. Patients who received liso-cel and tisa-cel were older compared to those treated with axi-cel (median ages: 70, 71, 62 years, respectively; p˂0.001) and had a poorer performance status at cell infusion (KPS˂90 in 75%, 59%, 56%, respectively; p=0.004). Patients treated with liso-cel and tisa-cel had less aggressive disease biology compared to those treated with axi-cel, respectively: refractory disease pre-apheresis (35%, 33%, 49%; p=0.002) and bulky disease pre-apheresis (12%, 10%, 21%; p=0.013). Most patients received tisa-cel in the ≥ 3rd line of treatment (liso-cel 78%, tisa-cel 96%, and axi-cel 81%; p<0.001). The time from apheresis to cell infusion was longer with liso-cel and tisa-cel compared to axi-cel (41, 44, 35 days, respectively; p˂0.001). Other baseline characteristics, including use of bridging therapy and LDH pre-lymphodepletion, were similar. The median follow-up among patients in the cohort was 19 months. The objective response (OR) rate with liso-cel was higher than with tisa-cel and axi-cel (91%, 66%, 82%, respectively; p<0.001), and a higher percentage reached complete remission (CR) (75%, 53%, 68%, respectively; p=0.001). The median duration of CR was not reached for liso cell but was 18 months (95% CI: 7.4-NR months) for tisa-cel and 27 months (95% CI: 19-NR months) for axi-cel. After adjusting for baseline clinical covariates, there was no significant difference in progression-free survival (PFS) between liso-cel and axi-cel (HR 0.87; p=0.5) in the multivariable model but tisa-cel was associated with inferior PFS compared to axi-cel (HR 2.0; p<0.001) and liso-cel (HR 2.31; p<0.001); 2-year estimated PFS was 52% (95% CI: 39-70%) for liso-cel, 27% (95% CI: 20-37%) for tisa-cel, and 44% (95% CI: 37-52%) for axi-cel. There were no statistically significant differences in overall survival (OS) between the 3 products after adjusting for clinical covariates; 2-year estimated OS was 52% (95% CI: 39-70%) for liso-cel, 44% (95% CI: 35-54%) for tisa-cel, and 60% (95% CI: 53-67%) for axi-cel. Lower rates of any-grade CRS were observed with liso-cel compared to tisa-cel and axi-cel (54%, 71%, and 89%, respectively; p<0.001). Additionally, liso-cel was associated with less high-grade CRS (grade ≥2: liso-cel 16%, tisa-cel 33%, axi-cel 43%; p<0.001), any-grade ICANS (liso-cel 17%, tisa-cel 18%, axi-cel 38%; p<0.001), and high-grade ICANS (grade ≥2: liso-cel 10%, tisa-cel 9.8%, axi-cel 25%; p<0.001). Conclusion: In this real-world comparison, we observed that tisa-cel was associated with inferior efficacy compared to axi-cel and liso-cel. While OR and CR rates were higher in patients receiving liso-cel versus axi-cel, PFS and OS rates were similar. Additionally, liso-cel demonstrated the most favorable toxicity profile. These findings provide valuable insights into product selection and suggest that liso-cel, often preferred for older and frail patients, could also be considered for younger and fitter patients.

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