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**Pomalidomide + orelabrutinib + rituximab (POR regimen)** is an investigational chemotherapy-free combination therapy primarily evaluated for relapsed/refractory and newly diagnosed B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL) in elderly frail patients and primary central nervous system lymphoma (PCNSL). Pomalidomide, a third-generation immunomodulatory drug (IMiD), promotes cereblon-mediated ubiquitination and degradation of transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), enhancing T-cell and NK-cell activation while inhibiting malignant B-cell proliferation. Orelabrutinib is a selective small-molecule Bruton's tyrosine kinase (BTK) inhibitor that blocks B-cell receptor signaling pathways critical for B-cell lymphoma survival. Rituximab, a chimeric monoclonal antibody, targets CD20 on B-cells, inducing antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct apoptosis. Preclinical synergy between pomalidomide and orelabrutinib supports their combination, with clinical data showing high overall response rates (ORR) and good tolerability as induction therapy prior to consolidation regimens.
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