Among the earliest changes following the start of ibrutinib therapy, we observed a decrease of NF-κB binding signatures in CLL cells, which was followed by a rapid reduction in the regulatory activity of transcription factors involved in B cell development and function (such as EBF1, FOXM1, IRF4, PAX5, and PU.1). This evidence concerns the gene IRF4 and B-cell chronic lymphocytic leukemia.