High-Grade Toxicity of Brexu-Cel in R/R B-ALL Persists in Real-World Use

Data from a retrospective, real-world evidence study appearing in Blood Immunology & Cellular Therapy demonstrate that the toxicity profile of the chimeric antigen receptor T-cell (CAR-T) therapy brexucabtagene autoleucel (Tecartus; brexu-cel) in patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) largely parallels results previously reported in clinical trials.¹

In a population of 292 adult patients treated with brexu-cel as standard-of-care therapy between October 2021 and June 2024, rates of grade 3 or higher cases of immune effector cell-associated neurotoxicity syndrome (ICANS) were found to be numerically comparable (28.8%) with those reported in the pivotal phase 2 ZUMA-3 study (NCT02614066), which supported brexu-cel’s clinical use in this setting.^2,3 Notably, the real-world study population had numerically lower (9.8%) rates of grade 3 or higher cytokine release syndrome (CRS) than the ZUMA-3 population.

Management of these toxicities involved intensive supportive care. Approximately 71% of patients received tocilizumab (Actemra), and 64% were treated with corticosteroids. The use of these agents did not appear to negatively impact the overall efficacy of the CAR T product in this real-world setting.

A critical finding is the identification of risk factors associated with severe adverse events. Multivariable analysis revealed that there was a numerical increase in the risk of grade 3 or higher ICANS (HR, 1.012; 95% CI, 0.996-1.028; P =.15) and CRS (HR, 1.006; 95% CI, 0.995-1.017; P =.30) with higher disease burden—measured as the percentage of bone marrow blasts—although no significant correlations were observed.

About Brexu-Cel and the ZUMA-3 Study

Brexu-cel is an anti-CD19 autologous CAR-T therapy indicated for treatment of adult patients with R/R precursor B-ALL and R/R mantle cell lymphoma.^3,4 Its October 2021 FDA approval in B-ALL was based on results from the ZUMA-3 study,⁴ a single-arm multicenter trial that evaluated brexu-cel’s efficacy and safety in 71 adults with R/R precursor B-ALL.⁵

Here, data indicated high and rapid responses with brexu-cel, with the majority of treated patients achieving complete remission (CR) or CR with incomplete hematologic recovery (71%; 95% CI, 57%-82%; P <.0001). These findings were instrumental in establishing brexu-cel as a highly active treatment option for adults with R/R B-ALL, particularly in a population with otherwise limited therapeutic alternatives.

In the trial, the rate of any-grade CRS was 92%, with 26% being grade 3 or higher. Neurologic toxicities occurred in 87%, with 35% grade 3 or higher.³ Per brexu-cel’s prescribing information, the therapy carries a boxed warning for both CRS and neurologic toxicities.

Clinical Implications

After nearly 5 years of being on the market, the findings from this study suggest that the real-world experience of brexu-cel largely reflects the safety data that led to its initial FDA approval. The data specifically reaffirm brexu-cel’s significant risk of high-grade toxicity, particularly ICANS and CRS, underscoring the current need for careful monitoring as well as consideration of less toxic CAR T alternatives such as obecabtagene autoleucel (Aucatzyl; obe-cel).

Authors acknowledged the retrospective nature of the study as a key limitation, noting that the findings are hypothesis generating and should be interpreted with caution.

“Ultimately, these data are hypothesis generating, and further efforts to leverage these observations to identify mechanisms and mitigable risk factors for these toxicities are warranted,” wrote study authors Kopmar et al.¹ “This becomes more important given the availability of an alternative agent (obe-cel) that may have a more favorable toxicity profile with comparable short-term and long-term disease outcomes.”

Ongoing vigilance, adherence to established toxicity management protocols, and careful patient selection for brexu-cel remain pertinent to optimize patient outcomes in the postmarketing setting.

REFERENCES

1. Kopmar NE, Gooley TA, Roloff GW, et al. Real-world toxicity of brexucabtagene autoleucel in adults with relapsed/refractory B-cell acute lymphoblastic leukemia. Blood ICT. 2026;2(1):100028. doi:10.1016/j.bict.2025.100028

2. Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021;398(10299):491-502. doi:10.1016/S0140-6736(21)01222-8

3. FDA approves brexucabtagene autoleucel for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. News release. United States Food and Drug Administration. October 1, 2021. Accessed March 18, 2026. https://tinyurl.com/mst38s39

4. FDA approves brexucabtagene autoleucel for relapsed or refractory mantle cell lymphoma.News release. United States Food and Drug Administration. July 27, 2020. Accessed March 18, 2026. https://tinyurl.com/5xfp8eaf

5. A study evaluating the safety and efficacy of brexucabtagene autoleucel (KTE-X19) in adult subjects with relapsed/refractory B-precursor acute lymphoblastic leukemia (ZUMA-3) (ZUMA-3). ClinicalTrials.gov. Updated November 19, 2024. Accessed March 18, 2026. https://clinicaltrials.gov/study/NCT02614066