The FDA approved obecabtagene autoleucel (obe-cel; Aucatzyl) in November 2024 for adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). This approval marks a significant advancement in the treatment landscape, offering a new CAR T-cell therapy option with a unique split-dosing regimen and a potentially improved safety profile.
The approval was based on data from the phase 1/2 FELIX trial (NCT04404660), a global, multi-center, open-label, single-arm study. The trial's findings, published in the New England Journal of Medicine, demonstrated a high overall remission rate (ORR) of 77% (95% CI, 67%-85%) in patients with morphologic disease (n = 94) treated with obe-cel. The complete remission (CR) rate was 55% (95% CI, 45%-66%), and the CR with incomplete hematologic recovery rate was 21% (95% CI, 14%-31%). The median duration of response was 21.2 months (95% CI, 11.6-not evaluable).
Unique Design and Mechanism
Obe-cel stands out as the only FDA-approved CAR T-cell therapy administered via split dosing. The recommended dose is 410 × 106 CD19 CAR-positive viable T cells, infused on day 1 and day 10 (± 2 days) based on bone marrow blast assessment, following fludarabine and cyclophosphamide lymphodepleting chemotherapy.
According to Daniel J. DeAngelo, MD, PhD, chief of the Division of Leukemia at Dana-Farber Cancer Institute, obe-cel's construct differs slightly from other CAR T-cell agents. It features a 4-1BB construct and a mutagenized receptor antibody with a fast-off target effect. This design theoretically reduces T-cell exhaustion and cytokine activation, potentially leading to a better prognosis and lower rates of cytokine release syndrome (CRS) and neurotoxicity.
Safety and Efficacy Profile
In the FELIX trial, the rates of grade 3 or higher CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were notably low, at 2.4% and 7.1%, respectively. This favorable safety profile, combined with the high remission rates, led to the FDA approval of obe-cel in relapsed/refractory, CD19-positive ALL.
Elias Jabbour, MD, professor of leukemia at The University of Texas MD Anderson Cancer Center, emphasized the significance of the split-dosing regimen, stating that it allows for a safer CAR T-cell therapy with minimal complications and long-term effectiveness. He also highlighted the potential for obe-cel to be administered in an outpatient setting, which could significantly impact patients' lives and the healthcare system.
CAR-HT Risk Score and Treatment Outcomes
An analysis of the FELIX trial presented at the 2025 Transplantation and Cellular Therapy Meetings revealed that patients with low-risk CAR-HEMATOTOX (CAR-HT) scores experienced improved outcomes with obe-cel compared to those with high-risk scores. The CAR-HT model stratifies patients based on the risk of hematotoxicity prior to CAR T-cell therapy, considering factors such as platelet count, absolute neutrophil count, hemoglobin level, c-reactive protein level, and ferritin level.
Patients in the low-risk group (n = 25) had an ORR of 96.0% (95% CI, 79.6%-99.9%), while those in the high-risk group (n = 102) had an ORR of 73.5% (95% CI, 63.9%-81.8%). The median duration of remission (DOR), event-free survival (EFS), and overall survival (OS) were not evaluable in the low-risk group, while the high-risk group experienced a median DOR of 14.2 months (95% CI, 8.2-NE), a median EFS of 9.0 months (95% CI, 5.8-15.1), and a median OS of 14.1 months (95% CI, 10.7-17.1).
Future Directions
The approval of obe-cel expands the CAR T-cell therapy options for patients with relapsed/refractory ALL. Researchers are now focused on optimizing the use of CAR T-cell therapies, including exploring their potential as standalone treatments or in earlier lines of therapy. Ongoing studies aim to determine whether consolidation with stem cell transplant improves outcomes after CAR T-cell therapy and whether CAR T-cell agents can be used in patients with minimal residual disease (MRD) or even in MRD-agnostic settings to shorten the duration of chemotherapy.
