In the chemoimmunotherapy era, TP53 mutations defined a subgroup of high risk chronic lymphocytic leukemia (CLL) patients in whom allogeneic stem cell transplantation had to be strongly considered. As a result of the accumulating favorable outcome data reported for new biological drugs, including ibrutinib, in high risk CLL harboring TP53 mutations, there is concern about whether these patients should continue to be offered allogeneic stem cell transplantation. Despite their improved outcome, a proportion of high risk CLL harboring TP53 mutations is going to develop ibrutinib resistance, which in turns translate in a very poor survival. On these bases, in the setting of ibrutinib treatment, novel biomarkers are required to re-define high risk CLL patients candidate for consolidation strategies including allogeneic stem cell transplantation. Our working hypotheses are that: i) clearance of high risk TP53 mutated clones upon treatment with ibrutinib may associate with long progression free survival (PFS), while conversely, the persistence or increase of high risk TP53 mutated subclones under ibrutinib may associate with acquisition of resistance and disease progression; and ii) plasma cell free DNA represents an accessible source of tumor DNA for the early and sensitive identification of mutations causing resistance to ibrutinib. By using highly sensitive ultra-deep next generation sequencing strategies to monitor molecular biomarkers potentially relevant for ibrutinib in DNA coming from both cellular and the plasma fractions of peripheral blood, the project has the chance of identifying new dynamic molecular markers that can help the early and real time prediction of sustained benefit from ibrutinib treatment vs imminent progression in TP53 mutated CLL patients. In the end, the results of this study will provide the bases to refine the current approach for treatment tailoring in TP53 mutated patients by allowing the identification of cases who, though being in clinical response under ibrutinib, will conceivably benefit from immediate switch to alternative options (i.e. novel drugs, allogeneic stem cell transplantation, or CART).