A Triple Oral Combination of Bendamustine, Acalabrutinib, and Venetoclax Demonstrates Efficacy Against Mantle Cell Lymphoma in Vitro and in Vivo.

Bendamustine (BEN) combined with Rituximab (RTX) remains a standard first-line therapy for transplant-ineligible patients with newly diagnosed mantle cell lymphoma (MCL). Meanwhile, novel targeted therapies such as Bruton tyrosine kinase inhibitors (BTKis) are increasingly used in the treatment of relapsed/refractory (R/R) MCL. We recently reported that a novel oral formu-lation of BEN exhibits comparable efficacy to the intravenous counterpart. In this study, we in-vestigated the efficacy of oral BEN administered alone or in combination with the oral BCL-2 in-hibitor Venetoclax (VEN) and/or the oral BTKi acalabrutinib (ACAL), against two human MCL cell lines (Jeko-1 and Z-138) representative of the R/R disease subtype. We performed in vitro analyses using MTS viability and Annexin V/PI apoptosis assays. BEN induced significant cyto-toxicity in both cell lines at low, clinically relevant concentrations. In contrast, VEN demonstrat-ed limited efficacy as monotherapy, with Z-138 showing sensitivity only at high doses. However, combining BEN with VEN with or without ACAL, enhanced apoptosis and cytotoxicity, with more pronounced effects in Z-138. In vivo, oral BEN significantly reduced tumor growth and prolonged survival in both xenograft models. In the Z-138 model, the addition of VEN ± ACAL further improved survival outcomes. Overall, our findings support the efficacy of oral BEN as both a monotherapy and as part of an all-oral treatment regimen for MCL. These results warrant further investigation into the clinical potential of oral BEN, particularly in combination with targeted agents.