Real-World Outcomes of Brexucabtagene Autoleucel (Brexu-cel) for Relapsed or Refractory (R/R) Mantle Cell Lymphoma (MCL): A CIBMTR Subgroup Analysis of High-Risk Characteristics
Authors: Kambhampati Swetha , Ahmed Nausheen , Hamadani Mehdi , Kim Soyoung , Hemmer Michael T. , Grover Natalie S. , Shadman Mazyar , Beitinjaneh Amer , Budde L. Elizabeth , Gerson James , Jacobson Caron A. , Locke Frederick L. , Nasta Dwivedy S. , Wang Michael L. , Weng Wen-Kai , Yan Jiali , Nunes Ana , Dalton David , Wu James J. , Abdeldaim Amina , Hu Zhen-Huan , Pasquini Marcelo , Herrera Alex F. 
Published: December 2023

Background: Patients (pts) with R/R MCL and TP53 mutation/deletion, or high Ki-67 proliferation index (PI), have historically had limited treatment options with dismal outcomes. Brexu-cel is a CAR T-cell therapy approved in the US for adults with R/R MCL. Real-world data has been consistent with that of clinical trials (Kambhampati et al. 2023). In a 3-year follow-up of ZUMA-2 (Wang et al. 2022), outcomes were comparable across various high-risk subgroups (TP53 mutation, Ki-67 PI ≥ 30% or ≥ 50%). Here, we describe real-world outcomes of brexu-cel in R/R MCL by high-risk features, including deletion of TP53 or 17p, Ki-67 PI, and by ZUMA-2 eligibility.

Methods : A total of 500 pts receiving brexu-cel for R/R MCL from 84 US centers between 07/2020−12/2022 were prospectively enrolled in the CIBMTR observational database for a post-authorization safety study. In this analysis, 446 pts were included, excluding pts with prior non-transplant cellular therapy, missing data for analysis, or no follow-up. Effectiveness outcomes were overall response rate (ORR), complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), overall survival (OS) and relapse/progressive disease (REL/PD). Safety outcomes included cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), prolonged cytopenias, infections requiring treatment, subsequent neoplasms, and non-relapse mortality (NRM). Analyses conducted included univariate as well as multivariate logistic regression and Cox proportional hazard models fit to identify covariates with an impact on outcomes.

Results : Of the 446 pts included and who had available data, 20% (44/220) had deletion of TP53/17p at diagnosis; Ki-67 PI ≥ 50% at diagnosis was seen in 42% (107/252). Pts with deletion of TP53/17p were less likely to undergo prior autologous hematopoietic cell transplant (11% vs 30%). Pts with Ki-67 PI ≥ 50% were more likely to receive Bruton's tyrosine kinase inhibitor (BTKi) (92% vs 81%) and bridging therapy (52% vs 37%), but less likely to receive bendamustine (47% vs 62%). Pts with either high-risk feature tended to have a shorter time from diagnosis to brexu-cel infusion. Overall, 67% (297/446) of pts would not have met ZUMA-2 eligibility criteria, mainly due to pulmonary impairment (33%), cardiac impairment (21%), prior malignancy (21%), low platelet count (20%), and no prior BTKi (18%).

With a median follow-up of 12.2 mo, DOR, PFS and OS were evaluated at 12 mo. CR was 84% (ORR, 95%; DOR, 46%; PFS, 54%; OS, 55%) for pts with deletion of TP53/17p vs 80% (ORR, 90%; DOR, 65%; PFS, 61%; OS, 77%) in those without. CR for pts with Ki-67 PI ≥ 50% vs &lt; 50% was 84% (ORR, 93%; DOR, 60%; PFS, 58%; OS, 77%) vs 83% (ORR, 92%; DOR, 69%; PFS, 63%; OS, 73%); for pts eligible vs ineligible to ZUMA-2, CR was 84% (ORR, 92%; DOR, 73%; PFS, 70%; OS, 82%) vs 79% (ORR, 90%; DOR, 60%; PFS, 57%; OS, 71%). Safety endpoints were largely consistent among all subgroups. Prolonged neutropenia and thrombocytopenia occurred more frequently in pts with vs without deletion of TP53/17p (25% vs 12% and 28% vs 17%, respectively). Grade ≥ 3 CRS occurred more frequently in ZUMA-2-ineligible vs eligible pts (13% vs 7%).

After multivariable adjustment, all effectiveness and most safety outcomes were consistent regardless of deletion of TP53/17p. Deletion of TP53/17p approached an association with decreased OS (HR 1.79 [95% CI 0.99−3.25]), and was associated with more frequent prolonged neutropenia (OR 2.85 [1.30−6.27]) and prolonged thrombocytopenia (OR 2.18 [1.04−4.57]) although these did not result in significant difference in infections requiring treatment (HR 1.22 [0.79−1.90]) nor NRM (HR 2.00 [0.77−5.21]). The remaining outcomes were consistent regardless of deletion of TP53/17p. Comparable outcomes were observed between pts with Ki-67 PI ≥ 50% and &lt; 50%.

Conclusions: These real-world findings with 12 mo of follow-up suggest that outcomes of brexu-cel treatment are largely consistent, including a high CR rate, regardless of ZUMA-2 eligibility or the high-risk feature subgroups analyzed. Although pts without deletion of TP53/17p appeared to have longer OS than pts with deletion of TP53/17p, the data further support brexu-cel as the standard of care across pts with R/R MCL, including those with high-risk features. An updated dataset is planned to be analyzed and results can be presented at the conference.

*SK and NA are equal contributors.