Ultra-deep NGS have shed light on the molecular mechanisms of the acquisition of resistance to a given treatment in CLL, as shown for TP53 mutations under chemoimmunotherapy (71–73), BTK and PLCγ2 mutations under ibrutinib (74–78) and BCL2 mutations under venetoclax (79, 80). Here, TP53 is linked to B-cell chronic lymphocytic leukemia.