Our results suggest that the Bcl-2 inhibitor venetoclax, in combination with the BTK inhibitor ibrutinib, is highly effective in the treatment of a particularly aggressive DLBCL subtype exhibiting BCL2 amplifications on the one hand, and a constitutively active B-cell receptor/Bruton’s tyrosine kinase/NF-κB signaling axis on the other. Here, NFKB1 is linked to diffuse large B-cell lymphoma.