The Dual PI3K-δ/γ Inhibitor Duvelisib in Combination with the Bcl-2 Inhibitor Venetoclax Shows Promising Responses in Richter Syndrome-PDX Models

Richtersyndrome (RS) is defined as the transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, typically a diffuse large B cell lymphoma (DLBCL) with poor prognosis and without effective therapies. Chemotherapy, as well as novel inhibitory agents, show only partial and temporary responses, highlighting the need for alternative therapies that can overcome drug resistance. Duvelisib (DUV) is an oral phosphatidylinositol 3-kinase (PI3K)-δ and γ dual inhibitor showing efficacy in patients with refractory CLL. Venetoclax (VEN) is a Bcl-2 selective inhibitor, able to induce apoptosis in CLL cells. The lack of RS cell lines and murine models has limited understanding of the molecular mechanisms contributing to the pathogenesis of this disease, impacting also on the development of effective therapies. In our lab, 4 different RS patient-derived xenografts (PDXs) were established, representing useful tools to study the biology of the disease and to test novel therapeutic strategies.