Dr Ip on the Limitations of Real-World CAR T-Cell Therapy Research in LBCL

“This ongoing question of which CAR T-cell product is really better and which is safer for [a given patient] population is not always easy to answer [with] real-world data.”

Andrew Ip, MD, chief of the Division of Outcomes and a member of the Division of Lymphoma at Hackensack Meridian Health’s John Theurer Cancer Center, Hackensack University Medical Center, discussed the limitations of real-world research that may prompt future clinical trials comparing CAR T-cell therapies in patients with high-risk large B-cell lymphoma (LBCL).

Ip and colleagues conducted a real-world study comparing the efficacy of CD19-directed CAR T-cell therapies in patients with LBCL. This study included patients who had received axicabtagene ciloleucel (axi-cel; Yescarta; n = 272), tisagenlecleucel (tisa-cel; Kymriah; n = 233), and lisocabtagene maraleucel (liso-cel; Breyanzi; n = 96). The investigators found that tisa-cel was less effective compared with axi-cel and liso-cel; however, liso-cel had a more tolerable toxicity profile compared with axi-cel.

In this real-world study, selection bias was inherent to the practical application of CAR T-cell therapy in the study population, Ip explained. Specifically, the population of patients with LBCL who received axi-cel often presented with refractory disease, representing a more clinically compromised subgroup within the broader LBCL population, he noted. These patients typically exhibit poorer performance status and greater disease burden, which are associated with less favorable clinical outcomes compared with other patients receiving CAR T-cell therapy, he emphasized.

Future studies investigating CAR T-cell therapy in patients with refractory LBCL will require more sophisticated multivariate or statistical analyses to stratify subgroups more precisely and adequately account for baseline disparities in patient characteristics, according to Ip. However, many current real-world studies lack such methodological rigor, he said.

Given these limitations, there is a compelling case for conducting a randomized, controlled clinical trial specifically enrolling patients with more advanced or refractory disease, to better evaluate the comparative efficacy and safety of available CAR T-cell products in this higher-risk population, he stated. The broader question regarding which CAR T-cell therapy is most efficacious and safest for specific subsets of patients with LBCL continues to go unanswered, and may not adequately be resolved by real-world data alone.