Whereas mechanism-based treatment with novel agents proved very efficacious in unfavorable genetic subsets of CLL (i.e. U-IGHV, TP53 disruption, 11q-) [79–81] several studies showed that the CK may have a negative prognostic role in R/R CLL receiving kinase targeted treatment or the BCL2 inhibitor venetoclax, as summarized in Table 2 [14, 61, 79, 82–83]. The gene discussed is BCL2; the disease is B-cell chronic lymphocytic leukemia.