Obecabtagene Autoleucel: A New Frontier in Treating Relapsed/Refractory Adult B-Cell Acute Lymphoblastic Leukemia

A new chimeric antigen receptor T-cell (CAR T) therapy is providing hope for a type of acute lymphoblastic leukemia that has been notoriously difficult to treat in the past.

Relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL) presents significant treatment challenges, particularly in adult populations where durable remissions are hard to achieve with existing therapies. While significant progress has been made in the treatment of pediatric ALL, adult patients continue to face poor outcomes, especially in the relapsed or refractory setting. Those who work in the field know that traditional chemotherapy regimens often fail to induce lasting remissions, and allogeneic stem cell transplantation is not feasible or successful for all patients due to factors like age, comorbidities, and donor availability.

The advent of CAR T-cell therapy has revolutionized the treatment landscape for certain hematologic malignancies — and recently, the U.S. Food and Drug Administration (FDA) approved obecabtagene autoleucel (obe-cel; Aucatzyl) for the treatment of adult patients with r/r B-cell precursor ALL.

“This therapy offers other options to these patients because often when they relapse, they’ve already been heavily pretreated and are at risk for additional toxicity with any treatment … with obe-cel, there was less CRS (Cytokine Release Syndrome) and ICANS (Immune Effector Cell-Associated Neurotoxicity Syndrome) seen compared to other CAR T cell therapies. Now, while there’s no head to head comparison amongst the CAR T-cell treatments, it does seem to be encouraging that this had less toxicity,” Dr. Catherine E. Lai, Physician Leader at the Leukemia Clinical Research Unit at University of Pennsylvania, tells SurvivorNet Connect.

What to Know About CAR T-Cell Therapy in B-ALL

CAR T-cell therapy has revolutionized the management of B-cell malignancies, with CD19 as a critical target for B-ALL. Previous CAR T-cell therapies, such as tisagenlecleucel (brand name Kymriah) and brexucabtagene autoleucel (brand name Tecartus), have demonstrated substantial clinical efficacy but are often associated with significant immune-related toxicities, including CRS and ICANS.

Unlike its predecessors, obe-cel (brand name Aucatzyl) uses an intermediate-affinity CD19-binding domain with a fast binding off-rate, which reduces the risk of overactivation while enhancing CAR T-cell persistence. This makes Aucatzyl particularly promising for adult patients who are at higher risk of severe immune-related toxicities.

The pivotal FELIX trial (NCT04404660) was an open-label, multi-center, global Phase Ib/II study designed to evaluate the safety and efficacy of Aucatzyl in adult patients with r/r B-cell ALL. The study has been published on the New England Journal of Medicine.

Study Population and Design

-153 patients were enrolled, with 127 receiving at least one infusion of Aucatzyl
-Median age: 47 years (range: 20–81 years)
-Median follow-up: 21.5 months
-52% of patients were refractory to their last line of therapy
-41.7% of patients had prior exposure to blinatumomab, 31.5% to inotuzumab ozogamicin, and 44.1% had previously undergone allogeneic stem-cell transplantation

Efficacy Outcomes

As of the latest analysis, 153 patients were enrolled, and 127 (83.0%) received at least one infusion of Aucatzyl and were evaluable for efficacy and safety. The median follow-up was 21.5 months.

Cohort 2A Results (Patients with Morphologic Disease)

-Number of Patients: 94
-Median Follow-up: 20.3 months
-Overall Remission Rate: 77% (95% CI, 67% to 85%)
-Complete Remission (CR): 55% (95% CI, 45% to 66%)
-Complete Remission with Incomplete Hematologic Recovery (CRi): 21% (95% CI, 14% to 31%)

Statistical Significance: The prespecified null hypotheses for overall remission rate (≤40%) and complete remission rate (≤20%) were rejected (P<0.001), indicating a statistically significant improvement over expected outcomes.

All Infused Patients (N=127)

-Median Event-Free Survival (EFS): 11.9 months (95% CI, 8.0 to 22.1 months)
-Estimated 6-Month EFS: 65.4%
-Estimated 12-Month EFS: 49.5%

-Median Overall Survival (OS): 15.6 months (95% CI, 12.9 months to not evaluable)
-Estimated 6-Month OS: 80.3%
-Estimated 12-Month OS: 61.1%

These results demonstrate a high incidence of durable responses in a heavily pretreated adult population with r/r B-cell ALL.

Safety Profile

Aucatzyl exhibited a favorable safety profile with a low incidence of severe immune-related toxicities.

Cytokine Release Syndrome (CRS)

-Any Grade CRS: Occurred in 68.5% of patients
-Grade 3 or Higher CRS: Reported in 2.4% of patients
-Median Time to Onset: 8 days post-infusion (range, 1 to 23)
-Median Duration: 5 days (range, 1 to 21)

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

-Any Grade ICANS: Occurred in 22.8% of patients
-Grade 3 or Higher ICANS: Reported in 7.1% of patients
-Median Time to Onset: 12 days post-infusion (range, 1 to 31)
-Median Duration: 8 days (range, 1 to 53)

Other Adverse Events

-Febrile Neutropenia: in the 60 days after obe-cel infusion, febrile neutropenia occurred in 31 of 127 patients (24.4%), with five deaths from infections.
-ICU Admissions: Twenty of 127 patients (15.7%) were admitted to an intensive care unit for a median of 5.5 days (range, 1 to 37). Seven of the 20 patients were admitted for the management of immunotoxic effects (5 patients with ICANS and 2 with cytokine release syndrome).

The low rates of severe CRS and ICANS suggest that the intermediate-affinity CAR and fast off-rate CD19 binding domain of Aucatzyl may mitigate immunotoxicity, enhancing patient tolerability and safety.

FDA Approval and Clinical Implications

On November 8, 2024, the FDA approved Aucatzyl for the treatment of adults with r/r B-cell precursor ALL. The approval was based on the significant clinical benefits demonstrated in the FELIX trial.

Dr. Elias Jabbour, the U.S. lead investigator of the FELIX study and Professor of Medicine in the Department of Leukemia at MD Anderson Cancer Center, notes, “Adult ALL is an extremely aggressive cancer, and there is a high unmet medical need that exists in the treatment of patients with this disease once they relapse, where historically they suffer from poor outcomes.

“This milestone approval, based on the demonstrated clinical benefit of obe-cel, brings new hope for adult patients with relapsed/refractory B-cell ALL.”

Implications for Clinical Practice

The approval of Aucatzyl represents a significant advancement in the treatment of adult patients with r/r B-cell ALL. Key implications include:

• Enhanced Efficacy: High rates of overall remission and durable responses offer improved outcomes for patients who have limited treatment options.
• Manageable Safety Profile: The low incidence of severe CRS and ICANS may allow for broader use of CAR-T therapy in clinical settings, including outpatient administration in select cases.
• Shift in Treatment Paradigm: Aucatzyl provides an alternative to allogeneic stem cell transplantation and may become a preferred option for suitable patients.