Exploring Synergistic Approaches to Enhance Blinatumomab's Efficacy in Acute Lymphoblastic Leukemia

Abstract

Resistance to blinatumomab (CD19-CD3 BiTE) is a significant obstacle in the treatment of B-cell precursor acute lymphoblastic leukemia (BCP-ALL), prompting the investigation of novel drug combinations. We aimed to generate an "in vitro" model capable of identifying synergistic combinations to enhance blinatumomab's efficacy in BCP-ALL treatment. Drug response profiling used annexin V/propidium iodide/CD3 staining and flow cytometry analysis in 28 patient samples and 4 cell lines. Co-cultured with healthy donor T-cells, samples were treated for 24h with blinatumomab and/or other inhibitors. Differential sensitivity to blinatumomab was observed among patient samples and cell lines. Idelalisib (tyrosin kinase inhibitor; TKi) combined with blinatumomab exhibited potential antagonistic effects. Birinapant (SMAC mimetic) and venetoclax (BCL2 inhibitor) demonstrated increased efficacy in BCP-ALL cell lines, displaying synergistic potential with blinatumomab. Our findings support TKi and SMAC mimetics' immunomodulatory effects, in accordance to prior anti-CD19 CAR T cell reports. Venetoclax emerges as a promising candidate for combination therapy against blinatumomab resistance.