Of note, at the molecular level, the in vitro treatment with Ibrutinib down-regulated: i) the pro-survival NOTCH1 pathway, which represents a major molecular target of GSI [31] and plays a relevant role in B-CLL leukemogenesis [32]; ii) the c-MYC expression, which is constitutively activated in situ in the lymph nodes of B-CLL patients [33], and has been proposed to confer resistance to Ibrutinib in B-NHL [27]; iii) CXCR4 expression, which plays a key role in the retention of B-CLL into the microenvironmental niches [34], coupled to reduction of migratory response of B-CLL cells to SDF-1α. This evidence concerns the gene NOTCH1 and B-cell chronic lymphocytic leukemia.