Regardless of CNS Involvement, Patients With B-ALL Benefit From Brexu-Cel

This article was originally published by Targeted Oncology^®.

Brexucabtagene autoleucel (brexu-cel; Tecartus) demonstrates efficacy and manageable safety in relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL), even in patients with central nervous system (CNS) involvement—a population historically excluded from clinical trials, according to a new multi-institutional study published in Blood Advances.¹

The toxicity profile of brexu-cel was comparable between patients with (n = 31) and without (n = 158) CNS involvement. The researchers reported that brexu-cel is efficacious in patients with CNS B-ALL, resulting in high rates of CNS disease remission and progression-free and overall survival (OS) comparable with those of patients without CNS involvement.

Brexu-cel demonstrated efficacy and safety even in patients with B-cell acute lymphoblastic leukemia with central nervous system involvement.

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In the CNS group, 74.2% developed cytokine release syndrome (CRS), with only one case of grade 3/4 severity, while 64.5% experienced immune effector cell-associated neurotoxicity syndrome (ICANS), including 11 patients with grade 3/4. These rates mirrored the non–CNS cohort (n=158), in which 84.8% had CRS (12.0% were grade 3/4) and 54.4% had ICANS (30% were grade 3/4). No statistically significant differences were observed in toxicity severity between groups.

The safety findings are consistent with previous studies reporting a high rate of CRS and ICANS after brexu-cel. For example, 89% of patients enrolled in ZUMA-3 (NCT02614066) had CRS, and 60% had neurotoxicity, with about 25% of patients developing grade 3/4 CRS or ICANS.² The trial was an open-label single-arm phase 2 trial demonstrating a 71% complete remission (CR) rate in patients with R/R B-ALL.

Study Details

The Real-World Outcomes Collaborative for CAR T in ALL (ROCCA) consortium data were collected and evaluated from 31 US-based academic and community cellular therapy centers.

A total of 189 patients were infused with brexu-cel. In patients with CNS involvement, 15 had CNS-2 disease, defined as the presence of blasts in cerebrospinal fluid with 5 or fewer white blood cells (WBCs) per μL, and 16 had CNS-3 disease, defined as the presence of blasts with 5 or more WBCs per μL and/or clinical signs/symptoms.

The investigators reported that a total of 17 patients (54.8%) had CNS disease without morphological medullary disease. Among these patients, 11 had minimal residual disease (MRD)-positive or unknown CR, and 6 had MRD-negative CR. The other 14 patients had both morphological medullary and CNS disease at preapheresis assessment.

In the cohort with CNS involvement, the median age was 46.5 years (range, 24-76), and 58.1% were male. More patients had Ph-positive disease (45.2%) than Ph-negative disease (35.5%). Four patients had molecular mutations and included TP53, SLC16A3-NOTCH1, TP53/DNMT3A, and PPM1D/CDKN2A/MLL3.

The median age in patients with no CNS involvement was 46 years (range, 18-81); most were male (56.3%), and most had Ph-negative disease (54.4%).

The median follow-up was 13.8 months for the entire cohort. In the CNS group, 12 patients had R/R disease after brexu-cel, with a median time to relapse of 100 days. Of 12 relapses, 5 occurred in the CNS with or without systemic disease. The remaining relapses occurred in the BM (n = 2), were extramedullary (n = 1), or had no specified site of relapse documented (n = 4). The cumulative incidence of relapse at 1 year was 39% in the CNS group compared with 35% in patients without CNS disease (P = .54).

Survival and Relapse Data

The median follow-up was 13.8 months for the entire cohort. In the CNS group, 12 patients had R/R disease after brexu-cel, with a median time to relapse of 100 days. Of 12 relapses, 5 occurred in the CNS with or without systemic disease. The remaining relapses occurred in the bone marrow (n = 2), were extramedullary (n = 1), or had no specified site of relapse documented (n = 4). The cumulative incidence of relapse at 1 year was 39% in the CNS group compared with 35% in patients without CNS disease (P = .54).

A total of 8 patients (25.8%) in the CNS group and 56 patients (35.4%) in the non-CNS group died. In the CNS group, 4 of 8 patients died in the absence of leukemia relapse; 2 died because of CRS and ICANS, and 2 died because of infections and multiorgan failure. The 6- and 12-month PFS in the CNS group were 57% (95% CI, 38%-73%) and 47% (95% CI, 29%-34%), respectively. The median PFS was 263 days.

There was no statistically significant difference in PFS between the CNS and non-CNS groups (P = .83). The 6- and 12-month OS in the CNS group were 84% (95% CI, 65%-93%) and 76% (95% CI, 57%-88%), respectively. The median OS was not reached. There was no statistically significant difference in OS between the CNS and non-CNS groups (P = .14).

The investigators wrote that their findings were promising and suggest the benefit of including patients with CNS B-ALL in future CAR T-cell clinical trials while underscoring the ongoing work needed to optimize efficacy and reduce toxicity.

References

1. Muhsen IN, Roloff GW, Faramand R, et al. Outcomes of brexucabtagene autoleucel in patients with relapsed/refractory acute lymphoblastic leukemia with CNS involvement. Blood Adv. 2025;9(16):4081–4089. doi:10.1182/bloodadvances.2024015779

2. Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021;398(10299):491-502. doi:10.1016/S0140-6736(21)01222-8