Prior Ibrutinib Exposure Linked to Improved CAR T-Cell Outcomes in Mantle Cell Lymphoma

Previous exposure to ibrutinib among patients with mantle cell lymphoma was associated with improved efficacy after treatment with the chimeric antigen receptor T-cell therapy brexucabtagene autoleucel, a retrospective analysis of the ZUMA-2 trial suggested.

In patients with relapsed/refractory disease treated with brexu-cel, median progression-free survival was 26.51 months for those with previous exposure to ibrutinib compared with 6.57 months for those previously treated with acalabrutinib (P=0.0067). At 24 months after brexu-cel infusion, 53% of ibrutinib-exposed patients remained progression free compared with 23% of acalabrutinib-exposed patients.

The analysis stratified patients from ZUMA-2 into subgroups by Bruton's tyrosine kinase inhibitor exposure to assess the effects on outcomes to brexu-cel. Of the 68 evaluable patients treated with brexu-cel in ZUMA-2, all were previously treated with a BTK inhibitor—52 who received ibrutinib, 10 who received acalabrutinib, and six who received both. Median age was 65 in the ibrutinib group, and 85% had stage IV disease, while median age in the acalabrutinib group was 56.5, and 90% had stage IV disease.

In addition to the improved efficacy seen with ibrutinib exposure, there was greater peripheral blood CAR T-cell expansion in the ibrutinib group compared with the acalabrutinib group. However, the enhanced efficacy of brexu-cel seen with prior ibrutinib was accompanied by a higher incidence of high-grade cytokine release syndrome and neurotoxicity.

The improved efficacy and increased toxicity associated with ibrutinib exposure was potentially due to a more proliferative and effector-polarized CAR T-cell compartment. These findings could reflect ibrutinib-specific priming of T cells prior to manufacturing into CAR T cells.

Ibrutinib inhibits BTK, as well as the T-cell-specific kinase interleukin-2-inducible tyrosine kinase, while acalabrutinib selectively targets BTK. Ibrutinib received accelerated approval for relapsed/refractory mantle cell lymphoma in 2013. However, that approval was withdrawn from the market in 2023, based on results from confirmatory phase III trials. Acalabrutinib, which received accelerated approval in 2017, and zanubrutinib, which received accelerated approval in 2019, have been increasingly preferred to ibrutinib due to their reduced toxicity.

Although introduction of brexu-cel in earlier lines of treatment for BTK inhibitor-naive patients is anticipated to improve clinical outcomes, determining the optimal selection of BTK inhibitor for mantle cell lymphoma is important, as most patients will be exposed to a BTK inhibitor in a line of therapy before CAR T-cell therapy in the current treatment landscape.

In the ZUMA-2 trial, which led to the approval of brexu-cel for relapsed/refractory mantle cell lymphoma, the CAR-T therapy resulted in an objective response rate of 87%, including complete responses in 62% of patients.

The study was limited by its retrospective nature and small sample size. Prospective studies are needed to confirm whether the findings translate to larger patient populations. Furthermore, ex vivo strategies to include BTK inhibitors in the CAR T-cell manufacturing process, or genetic modification of the ITK gene within CAR T cells could be appealing methodologies that ascertain the impact of BTK inhibitors.