Targeting BCL2 in Waldenström Macroglobulinemia: From biology to treatment management

Eleni Kalafati Efstathios Kastritis Tina Bagratuni ^*

• National and Kapodistrian University of Athens, Athens, Greece

Despite recent advances in the treatment of Waldenström macroglobulenimia (WM), including the development of Bruton tyrosine kinase inhibitors (BTKis), the disease remains incurable, highligh+ng the urgent need for new treatments. The overexpression of BCL2 in WM cells promotes cell survival by resis+ng apoptosis and contributes to resistance to chemotherapy and targeted therapies. Meanwhile, Bcl2 proteins that are encoded by oncogenes suppor+ng cell survival, are frequently upregulated in WM, even in the presence of DNA-damaging agents, and hence have emerged as an alterna+ve therapeu+c target.Venetoclax serves as a novel orally administered small agent that targets Bcl-2 protein by ac+ng as a BCL2 homology domain 3 (BH3) mime+c, and has shown promising results in WM pa+ents, including those previously treated with BTKis. Furthermore, venetoclax in combina+on with standard WM regimens has shown enhanced ac+vity, but further studies are required to elucidate the mechanism of its synergis+c ac+on and iden+fy the pa+ents who can benefit from the combined therapy. New BCL2 inhibitors are in advanced stages of clinical development and may offer addi+onal op+ons. The present review will focus on the current knowledge we have on BCL2 inhibitors in WM, the input of these compounds "from bench to bedside", and their u+lity in managing relapsed/refractory WM pa+ents.