Matched donor allogeneic CAR-T for adult B-ALL: toxicity, efficacy, repeat dosing, and the importance of lymphodepletion
Researchers at University College London and collaborators have determined that matched allogeneic donor CD19 CAR T-cell therapy, delivered as a CAR-modified donor lymphocyte infusion, is safe and clinically active for adults with relapsed B-ALL following allogeneic transplant. However, their findings only extend to when matched allogeneic donor CD19 CAR T-cell therapy is administered following lymphodepleting chemotherapy. In this Clinical Trials and Observations report, the presence or absence of fludarabine and cyclophosphamide lymphodepletion was the decisive factor for CAR engraftment, expansion, persistence, and survival. By contrast, repeating CAR-DLI doses for post-infusion relapse did not restore activity in this analysis.
The team developed a matched donor CAR product for patients who had failed prior allogeneic stem cell transplantation. Seventeen donors underwent leukapheresis and 14 recipients received an infusion, with a median age of 43 years and high baseline disease burden, ranging from measurable residual disease to 100 percent marrow blasts. Patients 1 through 7 received CAR-DLI alone, while patients 8 through 14 received CAR-DLI plus fludarabine and cyclophosphamide, with primary outcomes observed being toxicity and feasibility of manufacture. Secondary outcomes included CAR engraftment, expansion, and persistence, along with event-free and overall survival. The study is registered as NCT02893189.
Further, lymphodepletion transformed product performance without increasing toxicity. Compared with CAR-DLI alone, CAR-DLI plus lymphodepletion achieved higher peak engraftment at 93,134 versus 8,010 copies per microgram genomic DNA, greater 28-day expansion at 858,101 versus 39,038 copies per microgram, and longer persistence with a median of 197 versus 32 days. Safety remained acceptable, with no excess immunotoxicity and only grade 1 skin graft-versus-host disease in 2 of 14 patients. Twelve-month outcomes favored the lymphodepleted cohort for event-free survival at 57 percent versus 29 percent and overall survival at 83 percent versus 29 percent. Eight patients who relapsed had received repeat CAR-DLI on an escalating schedule, with minimal engraftment and clinical benefit. The results support a practical message for post-transplant B-ALL - pair matched allogeneic CAR-DLI with standard lymphodepletion unlocks efficacy, without reliance on repeat dosing or renewed conditioning.
Reference:
Roddie C, Dias J, O'Reilly MA, et al. Matched donor allogeneic CAR-T for adult B-ALL: toxicity, efficacy, repeat dosing, and the importance of lymphodepletion. Blood. 2025;146(14):1664-1676.