In the present study, by taking advantage of three different cohorts of in vivo ibrutinib-treated CLL and of a series of ibrutinib-naive primary CLL samples, we demonstrate that (1) the VLA-4 integrin can also be activated upon BCR triggering in ibrutinib-exposed CLL cells, (2) CLL cases expressing CD49d usually fail to display the canonical ibrutinib-induced lymphocytosis and experience a lower nodal response, and (3) CD49d expression is consistently associated with shorter PFS in the context of ibrutinib-treated CLL. The gene discussed is BCR; the disease is B-cell chronic lymphocytic leukemia.