(2) Targeted therapies to prevent the activation of bypassing signaling pathways, including PI3K inhibitors [334], BCL-2 inhibitors [146, 341], SYK and LYN inhibitors [342], HSP90 inhibitors [343], etc. In a multicenter phase 2 clinical study, venetoclax induced durable clinical response and prolonged survival in CLL patients who progressed after ibrutinib treatment [341]. This evidence concerns the gene BCL2 and B-cell chronic lymphocytic leukemia.