Phase 2 AVT triplet: tafasitamab (CD19 mAb) + acalabrutinib (BTK inhibitor) + venetoclax (BCL-2 inhibitor)

This Phase 2, open-label study at City of Hope tests whether adding tafasitamab (a CD19-directed monoclonal antibody marketed as Monjuvi by Incyte and MorphoSys/Novartis) to the acalabrutinib + venetoclax backbone can deepen responses in previously untreated, treatment-naïve CLL/SLL with active disease. Acalabrutinib (Calquence; AstraZeneca) inhibits Bruton tyrosine kinase to disrupt B-cell receptor signaling, while venetoclax (Venclexta; AbbVie and Genentech/Roche) blocks BCL-2 to trigger apoptosis in CLL cells. The regimen is designed to explore high-quality remissions (often aiming for undetectable minimal residual disease) using complementary mechanisms: targeted pathway blockade plus immune-mediated killing of CD19-positive B cells (CD19 is broadly present across CLL/SLL). The scientific angle is whether an anti-CD19 antibody can improve depth/duration over today’s common first-line approaches, which typically include a covalent BTK inhibitor (acalabrutinib or zanubrutinib) given continuously, or time-limited venetoclax plus an anti-CD20 antibody (e.g., obinutuzumab), selected based on patient risk and tolerability.