Real-World (RW) Outcomes for Brexucabtagene Autoleucel (Brexu-Cel) Treatment in Patients (Pts) with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia (R/R B-ALL) By High-Risk Features and Prior Treatments: Updated Evidence from the CIBMTR® Registry
Authors: Wudhikarn Kitsada , Bezerra Evandro , Yang Yang , Perales Miguel-Angel , Jain Nitin , Gergis Usama , Aribi Ahmed , Hill LaQuisa , Leonard Jessica T. , Lutfi Forat , Kim Soyoung , Bye Matthew , Hu Zhen-Huan , Wang Hai-Lin , Luo Zhong-Cheng , Siddiqi Rubina , Damico Khalid Rita , Speiser Jessica , Pasquini Marcelo C. , Kebriaei Partow , Muffly Lori 
Published: December 2024

Introduction: Brexu-cel is an autologous anti-CD19 CAR T-cell therapy approved for adults with R/R B-ALL and demonstrated a high complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate (74%) and median overall survival (OS; 25.6 mo; N=78) with &gt;4 y follow-up (FU) in ZUMA-3 (Oluwole et al. ASCO 2024). In a RW study of brexu-cel in pts with R/R B-ALL in the CIBMTR registry (N=150; median FU 6.1 mo), CR/CRi and 6-mo OS rates were both 79%, with safety outcomes consistent with ZUMA-3 (Bezerra et al. ASH 2023). Here, we report updated RW outcomes with longer FU and more pts with key subgroups described.

Methods: Adults with R/R B-ALL treated with commercial brexu-cel from 10/01/2021-12/26/2023 were included from the CIBMTR registry. Key subgroups, including prior treatments, lines of therapy (LOT), pre-infusion MRD status, and high-risk features (e.g., aged ≥55 y, ECOG PS ≥2, &gt;50% pre-infusion bone marrow [BM] blasts, comorbidities, and poor cytogenetic risk score), were examined in univariate and multivariate analyses (MVA) for effectiveness and safety outcomes.

Results: A total of 242 pts were included (median FU 7.2 mo); median age 46.8 y (range 18.5-84.3), 8% &lt;26 y, 35% ≥55 y, 29% Hispanic, 8% ECOG PS ≥2, 81% had comorbidities (30% with moderate/severe pulmonary symptoms at infusion, 10% with history of cardiac comorbidity, and 9% with ongoing infection at infusion [despite a boxed warning in the US label instructing not to administer brexu-cel to pts with active infection or inflammatory disorders]), and 11% had &gt;50% pre-infusion BM blasts (70% had ≤5%). Pts were heavily pretreated, with median 3 prior LOT (interquartile range [IQR], 2-4; 62% blinatumomab [blina]; 44% inotuzumab ozogamicin [InO]) and 32% had prior allogeneic stem cell transplantation (alloSCT; median 25 mo alloSCT to infusion). Pre-infusion CR/CRi rate was 39% (24% MRD negative). Median vein-to-vein time was 32 d (IQR, 27-42) and 50% had bridging therapy.

CR/CRi rate (95% CI) in evaluable pts (n=239) after brexu-cel was 80% (75-85; 68% [60-76] for 145 pts not in CR/CRi pre-infusion). Estimated 6-mo rates (95% CI; n) of duration of remission (DOR), relapse-free survival (RFS), and OS were 67% (58-74; 192; 66% [51-77] in 99 pts not in CR/CRi pre-infusion), 55% (48-62; 242), and 80% (74-84; 242). Of responders, 29% had subsequent alloSCT (median time to alloSCT, 107.5 d [IQR, 84-157]). In MVA, prior blina, InO, and LOT had no significant effectiveness associations. Prior alloSCT was associated with improved DOR (hazard ratio [HR], 0.22 [95% CI, 0.10-0.49]) and RFS (HR, 0.62 [95% CI, 0.40-0.96]). Ongoing infection at infusion was associated with worse CR/CRi (odds ratio [OR], 0.31 [95% CI, 0.10-0.91]), RFS (HR, 1.80 [95% CI, 1.02-3.19]) and OS (HR, 2.67 [95% CI, 1.40-5.10]). There was increased risk of relapse/death for pts not in CR/CRi pre-infusion (HR, 2.08 [95% CI, 1.25-3.45]) vs pts with CR/CRi pre-infusion who were MRD negative.

Rates of any Grade (Gr) cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) at 100-d FU were 81% (13% Gr ≥3) and 46% (24% Gr ≥3). Day 30 prolonged thrombocytopenia and neutropenia rates (n=224) were 30% and 34%. Cumulative incidence of infection at 3 mo since infusion was 40%. In MVA, pts with prior alloSCT had higher risk of Gr ≥3 ICANS (OR, 2.25 [95% CI, 1.18-4.27]). Pts with &gt;50% pre-infusion BM blasts had higher risk (OR [95% CI]) of Gr ≥3 CRS (6.39 [2.10-19.47]) and infection (2.14 [1.13-4.05]). Other increased risks (OR) included primary refractory disease with any Gr (8.81) and Gr ≥3 (3.34) CRS; cardiac comorbidity with Gr ≥3 CRS (3.12); aged ≥55 y with any Gr ICANS (4.11); poor cytogenetics with any Gr (1.93) and Gr ≥3 (2.58) ICANS; moderate/severe pulmonary symptoms at infusion with Gr ≥3 ICANS (2.35); not in CR/CRi pre-infusion with prolonged neutropenia (3.78); and 12-24 mo from diagnosis to infusion with prolonged neutropenia (3.32 vs &lt;12 mo) and thrombocytopenia (3.99). Cumulative incidence of non-relapse mortality at 6 mo was 4%.

Conclusions: In the RW, brexu-cel demonstrated high effectiveness and a safety profile consistent with ZUMA-3 in a broader R/R B-ALL pt population than ZUMA-3. Effectiveness was consistent across prior treatments and most high-risk features. Age was not detrimental to safety while some high-risk features, like &gt;50% pre-infusion BM blasts, may require closer monitoring for safety risks.

KW, EB, and YY contributed equally.