Outcomes Following Brexucabtagene Autoleucel Administered as an FDA-Approved Therapy for Adults with Relapsed/Refractory B-ALL

Background: In October 2021, brexucabtagene autoleucel (brexu-cel) became the first CAR-T cell therapy to receive FDA approval for adults (≥18 yrs) with relapsed/refractory (r/r) B-ALL. Approval was based on Phase II results of ZUMA-3, a single-arm, open-label, multicenter trial which reported on 55 treated patients with CR/CRi achieved in 71%; cytokine release syndrome (CRS) and neurologic toxicities occurred in 89% (grade 3-4, 24%) and 60% (grade 3-4, 25%), respectively. Here, we report outcomes of 76 adults with r/r B-ALL treated with post-approval brexu-cel at 13 U.S. centers.

Methods: Retrospective data were collected across centers participating in a real-world outcomes collaborative of CAR-T in ALL (ROCCA). Descriptive statistics, Kaplan-Meier methodologies and cumulative incidence functions were used to summarize outcomes.

Results: Among 76 patients infused, median age was 44 yrs (range, 18-81); 54% were male, 57% were non-Hispanic White (25% Hispanic), and 71% had Ph-neg disease. Median number of previous lines of therapy was 3.5 (range, 1-9) including blinatumomab in 53% and inotuzumab in 37%; 46% had relapsed post-transplant. Prior to apheresis, 69% of patients had active disease ( > 5% marrow blasts or presence of extramedullary disease), including 8 patients with CNS3 disease, 19% had detectable measurable residual disease (MRD) only, and 12% were MRD-neg. Median time from apheresis to infusion was 31 days. Lymphodepletion was predominantly with flu/cy (88%); 5 received cy/cladribine, and one patient each received single agent cy, single agent cladribine, and single agent bendamustine. Among 65 patients at least 28 days post-CAR-T with response assessed, 90.8% achieved CR/CRi, of whom 83% were MRD-neg, including CNS disease clearance in 7/8 CNS3 patients. CRS and ICANS (ASTCT criteria) occurred in 81.6% (grade 3-4, 6.6%) and 59% (grade 3-4, 38.6%), respectively. Median follow-up for survivors was 196.5 days (IQR 135.5-284.5). At last follow-up, 21 patients progressed/relapsed and 13 had died (7 of B-ALL; 6 of neurotoxicity/infection). Cumulative incidence of relapse and death in remission at 180 days were 31.5% (95% CI: 19.7%-44.1%) and 8.9% (95% CI: 3.5%-17.5%), respectively, while six-month PFS and OS were 58.8% (95% CI: 44.6%-70.5%) and 86.7% (95% CI: 75.8%-92.9%), respectively. Eleven patients underwent allogeneic transplant in CR/CRi after brexu-cel; all of whom remain in remission at last follow-up.

Conclusions: These data are the first to demonstrate post-approval efficacy and toxicity rates of brexu-cel in adults with r/r B-ALL. Unlike the ZUMA-3 population, 31% of patients infused in this real-world cohort lacked morphologically detectable disease and 8 had CNS3 prior to apheresis. Our data confirm high response rates associated with brexu-cel in adult ALL, but also highlight the need for interventions to reduce associated toxicities.