Zanubrutinib potentiates polatuzumab vedotin efficacy in DLBCL with concurrent CD79b upregulation.

In diffuse large B-cell lymphoma (DLBCL), although most patients are curable, the approximately one-third who experience refractory or relapsed disease face a poor prognosis, underscoring the need for novel therapeutic strategies. Although Bruton's tyrosine kinase inhibitors (BTKis) exhibit anti-lymphoma activity in various B-cell malignancies, they are less effective in patients with the germinal center B-cell-like (GCB) subtype. The anti-CD79b antibody-drug conjugate polatuzumab vedotin has been approved for DLBCL treatment. Previous studies have shown that the combination of the second-generation BTKi zanubrutinib and polatuzumab vedotin, within the R-CHOP regimen, yielded higher response rates in preliminary clinical studies; however, the efficacy of this combination remains unclear. This study aimed to evaluate whether zanubrutinib plus polatuzumab vedotin could represent a novel therapeutic approach. Through assays of drug combination, cell proliferation, cell cycle, and apoptosis, we demonstrated that this combination synergistically inhibited DLBCL cell proliferation both in vitro and in vivo. Moreover, zanubrutinib enhanced polatuzumab vedotin-induced G2/M phase arrest and apoptosis in DLBCL cells, accompanied by increased CD79b expression. Notably, the combination showed superior synergistic efficacy in GCB-subtype cells. In conclusion, these findings provide a novel mechanistic rationale for combining zanubrutinib and polatuzumab vedotin in DLBCL treatment, regardless of cell-of-origin subtype.