BCMA-CD19 Dual-Targeted CAR-T Cell Therapy for Relapsed or Refractory AL Amyloidosis

Background: The potential efficacy of CAR-T cells for the treatment of relapsed/refractory systemic light chain (AL) amyloidosis remains elusive. This study aimed to investigate the efficacy and safety of BCMA-CD19 dual-targeted CAR-T cell therapy in patients with refractory/relapsed AL amyloidosis in a single-center exploratory trial. Methods: The key eligibility criteria of this trial were patients with AL amyloidosis and at least one major organ involvement who were refractory to or had relapsed from at least two lines of therapy. The primary outcome was the safety of CAR-T therapy. All eligible patients received a single infusion of 0.3×10 6 /kg the BCMA-CD19 dual-targeted CAR-T cells after preconditioning with fludarabine (30 mg/m 2 /d for 3 days) and cyclophosphamide (300 mg/m 2 /d for 3 days). Results: Notably, 6 patients with refractory/relapsed AL amyloidosis were enrolled, all of whom had kidney involvement, and one of whom had cardiac involvement with Mayo stage 3a disease. After a median follow-up of 640 (range, 563 to 745) days, all 6 patients achieved hematological complete response (100%, 95%CI: 54%-100%) and renal response (100%, 95%CI: 54%-100%). The median time to hematological response and renal response were 9 (IQR: 6-11) and 75 (IQR: 18-180) days, respectively. One patient relapsed at month 6, while the other patients remained in remission. Grade 1 cytokine release syndrome occurred in 2 patients, and no immune effector cell-associated neurotoxicity syndrome was identified. Pneumonia occurred in 2 of the 6 patients. One patient had grade 3 urticaria and grade 2 acute kidney injury. One patient developed acute promyelocytic leukemia 15 months post-CAR-T cell therapy. Single-cell RNA/BCR sequencing confirmed that BCMA-CD19 dual-targeted CAR-T cells enabled the comprehensive clearance of pathogenic plasma cells and aberrant B cells, while also promoting endogenous immune reconstitution in AL amyloidosis. Conclusions: This study provides preliminary evidence for the feasibility and tolerability of BCMA-CD19 dual-targeting CAR-T cell therapy, and it showed promising activity in patients with relapsed/refractory AL amyloidosis.