Brexucabtagene Achieves High Central Nervous System Remission Rates in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia with Active Central Nervous System Involvement

Brexucabtagene Achieves High Central Nervous System Remission Rates in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia with Active Central Nervous System Involvement

According to a retrospective study presented at the 2024 Transplantation & Cellular Therapy Meetings, a single infusion of brexucabtagene autoleucel (brexu-cel) achieved a higher rate of central nervous system (CNS) remission in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) and active CNS involvement.

Regarding systemic disease status, most patients were in active disease at the time of leukapheresis (47.0%; n=16/34), followed by complete remission (CR) with minimal residual disease (MRD) positive (29.4%; n=10/34), CR and MRD negative (20.6%; n=7/34), and CR (3.0%; n=1). At the first disease assessment, 85% (n=29/34) of patients reported CR, including 76.5% (n=26/34) with sustained CR and MRD negativity. Additionally, 81% (n=13/16) of patients with active disease achieved CR.

At the time of leukapheresis, 50% (n=17/34) of patients had CNS2 involvement (defined as detectable blasts in the cerebrospinal fluid [CSF] with white blood cell count <5/μL), and 50% (n=17/34) had CNS3 involvement (defined as detectable blasts in the CNS with white blood cell count ≥5/μL). Among the 9 evaluable patients who received bridging therapy, 8 patients achieved CNS1 disease status, defined as no identifiable CNS disease. Five patients received intrathecal chemotherapy in combination with systemic treatment. After bridging therapy, 8 out of 9 patients achieved remission.

The researchers reported that among the patients who underwent CSF evaluation, 88% (n=22/25) achieved remission, including 12 CNS3 patients and 10 CNS2 patients who had no CNS involvement at the first disease re-assessment. Of the 10 patients who did not receive bridging therapy, 9 achieved CNS remission after receiving CAR-T cell therapy.

It was reported that 26.5% (n=9/34) of patients received additional treatment after CAR-T cell therapy to prolong remission or prevent relapse. Furthermore, 38.2% (13/34) of patients relapsed, with a median time to relapse of 100 days (range, 6–263 days), and 4 patients relapsed within 3 months.

It is noteworthy that while based on the data from the phase 2 ZUMA-3 trial (NCT02614066), brexucabtagene is currently the only FDA-approved CAR-T cell therapy for R/R B-ALL patients, the trial included only 5 patients with CNS involvement and excluded patients with symptomatic CNS disease or high CSF white blood cell counts. Therefore, the safety and efficacy data for CAR-T cell therapy in treating CNS B-ALL appear to be limited.

The researchers collected data from the CAR-T Real-World Outcomes Consortium for ALL (ROCCA) to evaluate the outcomes of patients with R/R B-ALL treated with brexucabtagene between October 2021 and October 2023. The data came from 226 patients who received brexucabtagene at 31 academic institutions and community practices across the United States.

The primary endpoints of the study were safety and CNS remission. The researchers assessed immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS) according to the standards of the American Society for Transplantation and Cellular Therapy (ASTCT).

Patients were categorized as having CNS1 (including no identifiable CNS disease), CNS2, or CNS3 disease. A total of 17 CNS2 patients and 17 CNS3 patients received brexucabtagene and were included in the analysis.

The median age at the time of CAR-T cell therapy was 47 years (range, 24–76 years). Additionally, most patients were male (55.9%), Philadelphia chromosome-positive (41.2%; n=14), had CNS1 disease at diagnosis (73.5%; n=25), and had an unknown extramedullary disease status (64.7%; n=22). Fifty-three percent of patients (n=18) achieved systemic CR at the time of leukapheresis, including 7 MRD-negative patients.

The median number of prior lines of therapy was 4 (range, 2–12), and most patients had previously undergone allogeneic hematopoietic stem cell transplantation (53.0%; n=18). Furthermore, 88% of patients (n=30) received brexu-cel in combination with intrathecal chemotherapy.

The data showed that 67% of patients received bridging therapy, with the most common types being systemic therapy alone (48%), systemic therapy + intrathecal chemotherapy (35%), and intrathecal chemotherapy alone (17%). The median time from bridging to infusion was 33 days (range, 5–194 days).

Overall, 73.5% (n=25) of patients experienced any-grade CRS, with 3% (n=1) experiencing grade 3/4 CRS. The median time to CRS onset was 5 days (range, 1–10 days), and the median duration of the event was 4 days (range, 1–10 days). Notably, 26.5% (n=9) of patients did not experience any CRS event.

Additionally, 76.6% (n=23) of patients experienced any-grade ICANS, with 35.3% (n=12) experiencing grade 3/4 ICANS. The median time to ICANS onset was 7 days (range, 3-15 days), and the median duration was 3 days (range, 1–30 days). Toxicities were generally managed with steroids (73.5%; n=25), followed by tocilizumab (58.8%; n=20) and anakinra (20.6%; n=7).

The incidence of grade 3/4 CRS was 3% (n=1/34) in patients with CNS disease, 12% (n=19/155) in patients without CNS disease from the ROCCA pooled analysis, and 24% (n=13/55) in patients from the ZUMA-3 trial. The incidence of grade 3/4 ICANS was 35.3% (n=12/34), 30% (n=47/155), and 24% (n=13/55), respectively, in these groups.

References:

1. Muhsen IN, Roloff G, Kopmar NE, et al. Assessment of central nervous system responses in adults with relapsed/refractory B-cell acute lymphoblastic leukemia receiving brexucabtagene autoleucel as an FDA-approved standard of care. Transplantation and Cellular Therapy. 2024;30(2):S7-S8. doi:10.1016/j.jtct.2023.12.028

2. FDA approves brexucabtagene autoleucel for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. News release. October 1, 2021. Accessed February 22, 2024. https://bit.ly/3irFWFV

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