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.

Clinical efficacy and safety of chimeric antigen receptor T‐cell therapy for mantle cell lymphoma with secondary central nervous system involvement

“…As in the recent US Lymphoma CAR T Consortium retrospective study of brexu-cel, 9 we found that CAR T-cell therapy was effective in heavily pre-treated, refractory patients (4 median lines of prior therapy in our cohort; 90% with POD24). The systemic disease CR rate in our cohort of 90% (9/10) is comparable to the 82% reported in the consortium study 9 and the 68% reported in ZUMA-2. 7 Likewise, durable disease control was similar with a 12-month PFS in our cohort of 47% compared to 59% in the recently published real-world cohort 9 and 61% in ZUMA-2.…”

“…In these patients, CAR T-cell therapy was feasible with a similar toxicity profile compared to that observed for patients without CNS involvement. 8,9 However, given the limited number of patients reported, additional data are needed to confirm these findings and guide clinical management for this uncommon patient subgroup. In this retrospective study, we report the efficacy and safety of anti-CD19 CAR T-cell therapy in 10 patients from three US academic centres with MCL and SCNS involvement.…”

Challenges and solutions to superior chimeric antigen receptor‐T design and deployment for B‐cell lymphomas

“…20 The 6-month PFS was 69%, and 12-month PFS was 59%. 20 RW patients could receive bridging therapy ranging from venetoclax to radiation whereas patients in the ZUMA-2 study could only receive BTKi or corticosteroids. The difference in bridging therapy could account for the different CR rates in RW patients compared to patients from registration trials.…”

“…Similarly, 168 RW patients with mantle cell lymphoma who received brexu‐cel experienced similar efficacy and toxicity when compared to patients enrolled in the ZUMA‐2 trial 20 . The 6‐month PFS was 69%, and 12‐month PFS was 59% 20 . RW patients could receive bridging therapy ranging from venetoclax to radiation whereas patients in the ZUMA‐2 study could only receive BTKi or corticosteroids.…”

“…At 12 months, the survival rate for RW patients was 59%, while the rate from clinical trials for tisa‐cel, axi‐cel and liso‐cel were 49%, 59% and 58%, respectively 19 . Similarly, 168 RW patients with mantle cell lymphoma who received brexu‐cel experienced similar efficacy and toxicity when compared to patients enrolled in the ZUMA‐2 trial 20 . The 6‐month PFS was 69%, and 12‐month PFS was 59% 20 .…”