venetoclax + orelabrutinib

**Venetoclax + orelabrutinib** is an investigational **oral combination therapy** consisting of two small molecule inhibitors: **venetoclax** (a selective BCL-2 inhibitor) and **orelabrutinib** (a selective Bruton’s tyrosine kinase [BTK] inhibitor). This dual regimen is being explored primarily for the treatment of aggressive B-cell malignancies, including **double-hit lymphoma (DHL)** and other mature B-cell lymphomas. The combination has been shown to synergistically induce cell death, arrest cell cycle progression, and promote apoptosis via the mitochondrial pathway in preclinical DHL models and primary lymphoma cells. Mechanistically, orelabrutinib disrupts BCR signaling, while venetoclax restores apoptosis in BCL-2 dependent cancer cells. Together, they downregulate pro-survival proteins (such as Mcl-1), interfere with PI3K/AKT and MAPK signaling, and increase susceptibility to programmed cell death, offering potential new therapy options for patients with poor prognosis whose lymphomas are resistant to existing treatments[1][5].