Brexucabtagene Autoleucel for Relapsed or Refractory Mantle Cell Lymphoma in Standard-of-Care Practice: Results From the US Lymphoma CAR T Consortium

Abstract

Purpose: Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication.

Patients and methods: Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines.

Results: Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis.

Conclusion: In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.

FIG 1.

Patient flow diagram. CAR, chimeric antigen receptor; CR, complete response; IND, investigational new drug.

FIG 2.

Efficacy of brexu-cel. (A) Best response rate (n = 168). (B) Forest plot of ORR and CR rates in subgroups. (C) Duration of response in patients who achieved an objective response. (D) PFS in patients who received brexu-cel infusion. (E) OS in patients who received brexu-cel infusion. (F) Cumulative incidence of nonrelapse mortality. Tick marks above the x-axis indicate censoring; shading around the curves indicates 95% CI. (G) ITT analysis of PFS in patients who underwent leukapheresis. (H) ITT analysis of OS in patients who underwent leukapheresis. brexu-cel, brexucabtagene autoleucel; BTKi, Bruton's tyrosine kinase inhibitor; CR, complete response; ITT, intention-to-treat; MIPI, mantle cell lymphoma international prognostic index; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; POD24, progression of disease within 24 months; PR, partial response.

FIG 3.

PFS according to prognostic subgroups. PFS by (A) simplified MIPI, (B) Ki-67, (C) TP53, (D) complex karyotype, (E) morphology, (F) POD24, and (G) CNS involvement. MIPI, mantle cell lymphoma international prognostic index; PFS, progression-free survival; POD24, progression of disease within 24 months.

FIG 4.

Efficacy by BTKi exposure, ZUMA-2 eligibility, bridging therapy, and bendamustine exposure. PFS by (A) prior BTKi exposure, (B) ZUMA-2 eligibility, and (C) bridging therapy. (D) Rates of failure to infuse and manufacturing failure by prior bendamustine exposure. Cycles were denoted in mean ± standard deviation. (E) ITT analysis of best response rate by prior bendamustine exposure. (F) ITT analysis of PFS from leukapheresis by prior bendamustine exposure. BTKi, Bruton's tyrosine kinase inhibitor; CR, complete response; ITT, intention-to-treat; ORR, objective response rate; PFS, progression-free survival.

FIG A1.

Case numbers contributed by each center.

FIG A2.

OS according to prognostic subgroups. OS by (A) simplified MIPI, (B) Ki-67, (C) TP53, (D) complex karyotype, (E) morphology, (F) POD24, and (G) CNS involvement. MIPI, mantle cell lymphoma international prognostic index; OS, overall survival; POD24, progression of disease within 24 months.

FIG A3.

OS by (A) prior BTKi exposure, (B) ZUMA-2 eligibility, and (C) bridging therapy. (D) PFS by response to bridging therapy. (E) OS by response to bridging therapy. (F) ITT analysis of OS from leukapheresis by prior bendamustine exposure. BTKi, Bruton's tyrosine kinase inhibitor; CR, complete response; ITT, intention-to-treat; OS, overall survival; PD, progression of disease; PFS, progression-free survival; PR, partial response; SD, stable disease.