In the era of chemotherapy-free CLL targeted treatments (such as Bruton’s tyrosine kinase, BTK, and B-cell lymphoma 2 protein, BCL2, inhibitors), patients assessment is important to start a novel agent at the correct timing, in order to obtain a deep response [6,7,8] such as complete remission (CR) of disease [9], a better progression-free survival (PFS) [9,10], and possibly to obtain a state of minimal residual disease negativity [9]. The gene discussed is BTK; the disease is B-cell chronic lymphocytic leukemia.