Patient Dies After Receiving Monoclonal Antibody Lymphodepletion Regimen in LBCL Trial for Allogene’s Cema-Cel

A patient treated in Allogene Therapeutics’ phase 2 ALPHA3 clinical trial (NCT06500273), which is evaluating investigational CD19-directed allogeneic chimeric antigen receptor T-cell (CAR-T) therapy cemacabtagene ansegedleucel (cema-cel) as a first-line consolidation treatment for large B-cell lymphoma (LBCL), has died.¹

Notably, the patient was treated in an arm of the trial evaluating a lymphodepletion regimen consisting of fludarabine and cyclophosphamide and antiCD52 monoclonal antibody ALLO-647 (FCA arm), and the patient’s death was attributed to this lymphodepletion regimen rather than to cema-cel itself. Specifically, the patient’s death was attributed hepatic failure that was thought to have arisen from “disseminated adenovirus infection in the setting of immune suppression”. The patient’s death occurred 54 days after infusion and was attributed to ALLO-647 specifically.

ALPHA3 also includes a separate arm using only a standard fludarabine and cyclophosphamide (FC) lymphodepletion regimen, and Allogene noted that no adenoviral infections or hepatic failures have been reported in patients treated in the FC arm in ALPHA3, nor in any of the company’s other clinical trials utilizing an FC regimen. As such, Allogene stated that it has selected FC as the lymphodepletion regimen to be used going forward in ALPHA3, a decision it made following discussions with the FDA and along with the study’s data and safety monitoring board and steering committee.

“The loss of a patient is always deeply saddening, and we extend our heartfelt condolences to the patient’s family,” David Chang, MD, PhD, the president, chief executive officer, and cofounder of Allogene, said in a statement.¹ “This event, which prompted an early review of the trial data, compelled us to make a decisive choice - one that may ultimately help bring this potentially life-saving therapy to patients more quickly. The ability to administer cema-cel following standard FC lymphodepletion in an outpatient setting will simplify study treatment and has the potential to accelerate trial enrollment and streamline regulatory review, ultimately transforming care for patients.”

As a result of the change, ALPHA3 is now a 2 arm trial, in which patients are randomly assigned to receive either cema-cel with FC lymphodepletion or to undergo standard of care observation. The company stated that a futility analysis comparing minimal residual disease conversion for ALPHA3 is planned for the first half of next year, and that the trial currently has 50 active clinical sites in the United States and Canada. Allogene also pointed out that currently, none of its actively enrolling clinical trials for its therapeutic candidates include the use of ALLO-647.

Among Allogene’s other investigational CAR-T therapy products is ALLO-329, an investigational allogeneic CAR-T therapy that targets both CD19+ B-cells and CD70+ activated T-cells, with the intention of eliminating dysfunctional cells of both types in rheumatology indications including active refractory moderate-to-severe systemic lupus erythematous; active severe/refractory idiopathic inflammatory myopathy, specifically including dermatomyositis, immune mediated necrotizing myopathy, and antisynthetase syndrome; and active refractory diffuse systemic sclerosis.^2,3 Notably, ALLO-329 received fast track designation from the FDA for the aforementioned indications in April of this year. Furthermore, the CAR-T product utilizes the company’s Dagger technology, which is intended to reduce or eliminate the need for lymphodepletion by making the CAR-T more resistant to rejection by the patient’s immune system.

"Receiving these designations for ALLO-329 underscores the versatility and transformative promise of this next-generation allogeneic CAR-T investigational product in redefining the autoimmune treatment landscape," Zachary Roberts, MD, PhD, the executive vice president of research and development and the chief medical officer at Allogene, said in an April 2025 statement.² "Leveraging our extensive expertise, we've developed this off-the-shelf CAR T specifically for autoimmune diseases, prioritizing both scalability and the reduction or elimination of lymphodepletion – a key barrier in this patient population."

REFERENCES
1. Allogene Therapeutics moves forward with standard fludarabine and cyclophosphamide (FC) lymphodepletion regimen in the ALPHA3 trial for cemacabtageneansegedleucel (cema-cel) in first-line consolidation for large B-cell lymphoma. News release. Allogene Therapeutics, Inc. August 1, 2025. Accessed August 4, 2025. https://ir.allogene.com/news-releases/news-release-details/allogene-therapeutics-moves-forward-standard-fludarabine-and
2. Allogene Granted Three U.S. FDA Fast Track Designations (FTD) for ALLO-329, a Next-Generation Dual-Targeted CD19/CD70 Allogeneic CAR T, for the Treatment of Lupus, Myositis and Scleroderma. News release. Allogene Therapeutics, Inc. April 7, 2025. Accessed August 4, 2025. https://ir.allogene.com/news-releases/news-release-details/allogene-granted-three-us-fda-fast-track-designations-ftd-allo
3. Allogene Therapeutics secures U.S. FDA IND clearance for ALLO-329, advancing its next-generation allogeneic CAR T into autoimmune diseases. News release. Allogene Therapeutics, Inc. January 28, 2025. Accessed August 4, 2025. https://ir.allogene.com/news-releases/news-release-details/allogene-therapeutics-secures-us-fda-ind-clearance-allo-329