Peak CAR T-Cell Expansion Associated With Reduced Relapse Risk Following Brexu-Cel Consolidation in B-ALL

High chimeric antigen receptor (CAR) T-cell expansion was associated with a lower likelihood of disease relapse after consolidation therapy with brexucabtagene autoleucel (brexu-cel; Tecartus) in real-world patients with B-cell acute lymphoblastic leukemia (B-ALL) who have low disease burden, according to findings from a retrospective analysis presented during the 2025 SOHO Annual Meeting.1

At a median follow-up of 16.1 months, patients with 5% or fewer marrow blasts in the overall cohort (n = 52) achieved 12-month overall survival (OS) and relapse-free survival (RFS) rates of 89% and 66%, respectively. Further analysis of RFS and OS by pre–CAR T-cell next-generation sequencing (NGS) minimal residual disease (MRD) status and CAR T-cell expansion showed favorable long-term outcomes among patients who achieved peak CAR T-cell expansion of 15 cells/µL or greater (n = 25); only 2 relapses were reported among patients meeting these criteria.

The 12-month RFS rates were 81% vs 71% in NGS MRD-negative patients with peak CAR T-cell expansion of 15 cells/µL or greater (n = 17) vs less than 15 cells/µL (n = 21), respectively. Among NGS MRD-positive patients with a peak CAR T-cell expansion of 15 cells/µL or greater (n = 8) vs less than 15 cells/µL (n = 6), the respective 12-month OS rates were 69% and 0%.

The respective 12-month OS rates in NGS MRD-negative patients with a peak CAR T-cell expansion of 15 cells/µL or greater vs less than 15 cells/µL were 87% and 100%. In NGS MRD-positive patients with a peak CAR T-cell expansion of 15 cells/µL or greater vs less than 15 cells/µL, these rates were 86% vs 67%, respectively.

Treatment with brexu-cel was also associated with low rates of grade 3/4 cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS).

“It is clear that the patients who underwent CAR T-cell infusion while MRD positive had rapid relapse events if they did not have any peak CAR T-cell expression greater than 15 [cells/µL],” Niranjan Khaire, MBBS, MD, DM, a first-year fellow in the Leukemia Clinical Fellowship Program at The University of Texas MD Anderson Cancer Center in Houston, stated in a presentation of the data. “This is a very high-risk cohort for which some additional therapy is warranted once we see that there is not adequate CAR T-cell expansion. [Therefore], we feel that even in the clinical settings, CAR T[-cell] expansion should be monitored to help guide post–CAR T[-cell] treatment decisions.”

Rationale and Study Overview

In October 2021, brexu-cel was approved by the FDA for adult patients with relapsed or refractory B-cell precursor ALL based on findings from the registrational ZUMA-3 trial (NCT02614066).2 Among efficacy-evaluable patients (n = 54), the complete response (CR) rate within 3 months was 52% (95% CI, 38%-66%), and the median duration of CR was not reached at the time of approval.

“[Of note,] patients in ZUMA-3 were required to have active disease, which is greater than 5% bone marrow blast at the time of study entry. However, as the product has entered standard-of-care settings, more and more patients have received this product while being in remission,” Khaire noted.1 “Real-world studies in children with relapsed/refractory B-ALL have shown improved efficacy and lower toxicity when tisagenlecleucel [Kymriah] was given in a low tumor burden setting.”

Accordingly, investigators conducted a retrospective analysis of adult patients with low tumor burden who were treated with brexu-cel in a real-world setting. Patients must have received commercial brexu-cel between February 2022 and February 2025 at The University of Texas MD Anderson Cancer Center. Other key eligibility criteria included less than 5% marrow blasts at the time of most recent evaluation prior to lymphodepletion; the absence of any active extramedullary (EMD) or central nervous system (CNS) disease; and availability of NGS MRD and CAR T expansion data. Prior receipt of brexu-cel on clinical trials excluded patients from enrollment. Of note, serial CAR T-cell levels were monitored in peripheral blood using flow cytometry.

Baseline Characteristics

The cohort for this analysis comprised a total of 52 adults. The median age among all patients was 36.5 (range, 20-84), and 62% of patients were male. Disease subtypes included Philadelphia chromosome (Ph)–positive (35%), CK (25%), Ph-like (19%), TP53 mutant (19%), therapy-related ALL (10%), and KMT2A rearranged (2%). Prior EMD/CNS disease was observed in 37% of patients. Most patients had previously received 2 lines of therapy (48%), followed by 1 (19%), 3 (19%), and 4 or more prior lines (14%). Prior therapies included blinatumomab (Blincyto; 98%), inotuzumab ozogamicin (Besponsa; 77%), allogeneic stem cell transplant (allo-SCT; 15%), and CD19 CAR T-cell therapy (4%).

Five patients underwent consolidation allo-SCT after CAR T-cell infusion at the discretion of the treating physician, and 15 received a tyrosine kinase inhibitor (TKI) as post–CAR T-cell consolidation. The median time from CAR T-cell infusion to allo-SCT or TKI therapy was 3.5 months (range, 1.6-4.2) and 1 month (range, 0.6-2.6), respectively.

Patterns of CAR T Expansion By NGS MRD Status and Other Patient Characteristics

Based on previously reported data from an interim analysis, a critical threshold for peak CAR T-cell expansion was established at 15 cells/µL, serving to classify patients into categories of high (≥ 15 cells/µL) and low (< 15 cells/µL) expansion. Overall, 48% of patients in the entire cohort achieved a peak CAR T-cell expansion of at least 15 cells/µL, and the median peak CAR T-cell expansion in the whole cohort was 11.5 cells/µL (range, 1-2222).

Further stratification by pre–CAR T-cell bone marrow MRD status, as assessed by the clonoSEQ NGS assay, revealed distinct patterns of CAR T-cell expansion. Among the 38 patients who were identified as NGS MRD negative at the time of CAR T infusion, 44% exhibited a peak CAR T-cell expansion of 15 cells/µL or greater. The median peak CAR T-cell expansion in this subgroup was 11 cells/µL (range, 1-2222). In contrast, among the 14 patients who were NGS MRD positive prior to CAR T infusion, 57% achieved a peak CAR T-cell expansion of 15 cells/µL or greater. The median peak CAR T-cell expansion in this subgroup was significantly higher than in the NGS MRD–negative subgroup, at 36.5 cells/µL (range, 1-573).

“We know that the amount of disease burden at the time of CAR T-cell expansion influences the amount of CAR T-cell expansion, which was something we could see in the whole cohort. There was a dose-response relationship,” Khaire noted.

Analysis of patient characteristics revealed that Ph-positive disease (P = .019) and the absence of prior inotuzumab exposure (P = .008) were significantly associated with higher CAR T-cell expansion. Among patients with Ph-positive ALL, 72% of Ph-positive patients (n = 18) demonstrated a peak CAR T-cell expansion of 15 cells/µL or greater. Conversely, among the 40 patients who received prior inotuzumab, only 38% achieved a peak expansion of 15 cells/µL or greater.

Post-CAR T-Cell Safety Data

Regarding safety, the agent had generally manageable toxicity in this patient population. Any-grade CRS was observed in 54% of patients, 2% of which was grade 3. No grade 4 CRS events were reported. ICANS events were reported in 21% of patients, 6% of which were grade 3 and 4% of which were grade 4. Notably, patients with grade 2/4 CRS or ICANS had high CAR T expansion (102, 124, 573, 1270 and 2222 cell/µL) and 2 of 5 had recent CNS disease.

Post–CAR T-cell therapy, grade 3/4 neutropenia was observed in 10% of patients at day 28 and 6% at day 42. The incidence of grade 3/4 thrombocytopenia was 33% at day 28 and 27% at day 42. Notably, severe acute graft-vs-host disease was reported in 1 patient (2%). CRS/ICANS events were managed with tocilizumab (Actemra) in 42% of patients, dexamethasone in 25%, and intensive care support in 13%.

References

1. Khaire N, Jabbour E, Short N, et al. Brexucabtagene autoleucel (brexu-cel) as consolidation treatment in adults with B-cell acute lymphoblastic leukemia (B-ALL): efficacy and toxicity in a real-world setting. Presented at: 2025 SOHO Annual Meeting; September 3-6, 2025; Houston, TX. Poster ALL-1052
2. FDA approves brexucabtagene autoleucel for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. October 1, 2021. Accessed September 4, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-b-cell-precursor-acute-lymphoblastic#:~:text=On%20October%201%2C%202021%2C%20the,acute%20lymphoblastic%20leukemia%20(ALL)