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AZD5153 + acalabrutinib is a combination therapy investigated for **relapsed/refractory aggressive Non-Hodgkin's lymphoma**, including diffuse large B-cell lymphoma (DLBCL)[1][3][5]. **AZD5153** is a small molecule, bivalent and reversible inhibitor of **BRD4**, a protein in the bromodomain and extraterminal (BET) family, which targets transcriptional regulators involved in proliferation and survival of cancer cells[1][2][5]. **Acalabrutinib** is a selective, covalent inhibitor of **Bruton tyrosine kinase (BTK)**, disrupting B-cell receptor signaling critical for the survival of various B-cell malignancies[1][4][5]. Preclinical and early clinical data suggest that the combination augments anti-tumor activity by interfering with **PAX5/BCR signaling**, and impacts downstream **NF-κB**, **toll-like receptor**, and **interferon** pathways in DLBCL, especially ABC-DLBCL (activated B-cell subtype)[1].
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