However, while ibrutinib is generally tolerated, with typically transient adverse effects, the relatively short duration of response—due to the onset of drug resistance and the preponderance of DLBCL cases that are naturally resistant to BTK inhibition, owing to their reliance on BCR-independent mechanisms of NF-κB activation—significantly limits the clinical utility of ibrutinib for managing patients with DLBCL [44,91,93]. This evidence concerns the gene NFKB1 and diffuse large B-cell lymphoma.