New study explores obecabtagene autoleucel for adults with hard-to-treat leukemia

By Vijay Kumar MalesuReviewed by Danielle Ellis, B.Sc.Dec 2 2024

Phase 1b–2 trial evaluates the potential of CAR T-cell therapy obe-cel in relapsed or refractory B-cell ALL patients.

In a recent study published in The New England Journal of Medicine, a group of researchers evaluated the efficacy, safety, and durability of the response of obecabtagene autoleucel (obe-cel) in adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) (a fast-growing cancer of immature B-cells in the blood and bone marrow).

Background

Chimeric antigen receptor (CAR) T-cell therapy has shown promise in inducing sustained responses in relapsed or refractory B-cell cancers, including ALL. Tisagenlecleucel (tisa-cel) is approved for patients ≤25 years, while brexucabtagene autoleucel (brexu-cel) is licensed for adults ≥18 years. obe-cel utilizes a novel intermediate-affinity anti-Cluster of Differentiation (CD)19 single-chain variable fragment, hypothesized to reduce toxic effects and enhance persistence.

Early trials in pediatric and adult populations demonstrated high efficacy, durable responses, and low severe toxicity rates. Further research is needed to optimize treatment protocols, improve long-term outcomes, and expand accessibility for diverse patient populations.

About the study

The FELIX study was conducted across 34 sites in Spain, the United Kingdom, and the United States in adults with relapsed or refractory CD19-positive B-cell ALL. Eligible patients were at least 18 years old and met specific inclusion criteria. The study followed ethical standards, including written informed consent and institutional review board approval, in accordance with the Declaration of Helsinki. The sponsor, Autolus Therapeutics, provided access to study data, ensuring transparency and adherence to protocol.

The study comprised two phases. Phase 1b included two cohorts, based on disease status: cohort 1A -morphologic disease (≥5% bone marrow blasts) and cohort 1B- measurable residual disease ((MRD), <5% blasts). Phase 2 included cohort 2A for morphologic disease, 2B for MRD, and 2C for isolated extramedullary disease.

Patients underwent leukapheresis (collecting white blood cells for therapy) to manufacture obe-cel. They received a bone marrow burden-adjusted split dose after lymphodepletion (reducing immune cells to aid CAR T-cell therapy), with dosing guided by pre-treatment bone marrow assessments. Bridging therapy was allowed, excluding blinatumomab.

Primary and secondary endpoints focused on remission rates, duration, survival outcomes, and safety, evaluated by independent committees using established criteria. Statistical analyses ensured accurate hypothesis testing, controlling for error rates.

Study results

The FELIX study enrolled 153 patients with relapsed or refractory B-cell ALL, and of these, 127 patients (83%) received at least one infusion and were evaluated for outcomes. Manufacturing of obe-cel was successful in 95.4% of cases, with a median production time of 21 days. Reasons for non-receipt of infusion included manufacturing failures, death, or uncontrolled disease progression. Patient demographics showed a median age of 47 years, with 52% refractory to their last line of therapy. Nearly 42% had prior treatment with blinatumomab, and 44% had undergone allogeneic stem-cell transplantation.

Bridging therapy was administered to 92.9% of infused patients, with chemotherapy being the most common approach. Bone marrow assessments before lymphodepletion indicated a high disease burden in many patients, with 59% having more than 20% bone marrow blasts. Patients with high blast burdens typically required more intensive bridging therapy. A bone marrow burden–adjusted split-dose regimen of obe-cel was implemented, and 94.5% of patients received the full planned doses.

The primary endpoint, overall remission, was achieved in 77% of patients in cohort 2A, with complete remission observed in 55%. Median response duration was 14.1 months, and event-free survival was 11.9 months. Importantly, the incidence of MRD-negative remission was high, reaching 94% in evaluable patients. Outcomes varied by disease burden, with lower bone marrow blasts correlating with better remission and survival rates.

Safety analysis revealed a favorable profile, with cytokine release syndrome (CRS) occurring in 68.5% of patients but severe cases (grade 3 or higher) limited to 2.4%. Immune effector cell–associated neurotoxicity syndrome (ICANS) was observed in 22.8% of patients, with 7.1% experiencing severe cases. Both CRS and ICANS were more common in patients with higher initial disease burden. Cytopenias and infections were manageable, with recovery of neutrophil and platelet counts occurring within a median of 21 days.

Five infection-related deaths were reported, two of which were attributed to neutropenic sepsis. CAR T-cell persistence was observed for a median duration of 17.8 months. Relapses were associated with loss of CD19 expression or waning CAR T-cell activity.

Conclusions

To summarize, In the FELIX study, obe-cel demonstrated high efficacy and safety in 127 adults with relapsed or refractory B-cell ALL. Among the pivotal cohort (2A), the overall remission rate was 77%, with a median event-free survival of 11.9 months and a 12-month event-free survival of 49.5%.

Grade 3 or higher CRS occurred in only 2.4% of patients and severe ICANS in 7.1%, both significantly lower than rates observed with other CAR T-cell therapies like brexu-cel. Patients with low-to-intermediate bone marrow burdens experienced better outcomes, indicating that optimizing tumor clearance before therapy may enhance efficacy and minimize toxicity.