Molecular prediction of long term benefit from ibrutinib in high risk chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is the most common B-cell tumor in adults. A challenging patient subgroup harboring TP53 mutations displays primary refractoriness when treated with chemoimmunotherapy. Ibrutinib, an inhibitor of the Bruton’s tyrosine kinase (BTK), showed significant and unprecedented activity in high-risk CLL harboring TP53 mutations, and currently represents the standard option for TP53 disrupted CLL. However, among TP53 mutated CLL treated with ibrutinib, remission duration is shorter than that expected in patients lacking such genetic abnormality, mainly because of the development of drug resistance mutations. Upon ibrutinib treatment, residual disease persists in the blood for a long period of time. Therefore, drug effectiveness is not fully captured by surrogate markers (i.e. minimal residual disease), and alternative tools are needed to early and dynamically assess ibrutinib activity during treatment. Among residual CLL cells, persistence of TP53 mutated subclones, which have a defective DNA damage response and are genetically instable, can allow the emergence of resistance mutations which, in turns, cause disease progression. On these bases, our first working hypothesis is that clearance of TP53 mutated subclones may represent a predictive biomarker of long term benefit from treatment in high-risk CLL receiving ibrutinib, while they persistence may represent a surrogate biomarker of early disease progression. Peripheral blood circulating CLL are not the ideal population to be interrogated for the early and sensitive monitoring of ibrutinib resistance mutation, since they are not fully representative of the genetics of leukemic cells residing in the tissues. On these bases, our second working hypothesis is that plasma cell free DNA may represent a sensitive tool that can early and dynamically inform on the development of ibrutinib resistant mutations in CLL. In order to address our working hypotheses, we will monitor the clearance of TP53 mutated subclones and the development of ibrutinib resistance mutations in both the cellular tumor fraction of peripheral blood and plasma by using ultra-deep next generation sequencing approaches. The project will take advantage of a prospective longitudinal collection of peripheral blood samples drown from ibrutinib-treated patients harboring TP53 mutations and enrolled into a multicenter observational non-interventional trial. The sample collection will be linked to a prospectively curated clinical database to dynamically correlate clearance of TP53 mutated subclones and development of resistance mutations with progression free survival by using time-dependent statistical approaches. As a result of the accumulating favorable outcome data reported for ibrutinib in high-risk CLL harboring TP53 mutations, there is concern about whether these patients should continue to be offered allogeneic stem cell transplantation (SCT). On these bases, in the setting of ibrutinib treatment, novel biomarkers are required to redefine high-risk CLL candidate for intensive procedures as allogenic-SCT or other toxic cell therapies. The project has the chance of: i) identifying dynamic molecular markers that can help the early and real time prediction of sustained benefit from ibrutinib treatment vs imminent progression; and ii) refine the current approach for treatment tailoring in TP53 mutated patients by allowing the identification of patients who, though being in clinical response under ibrutinib, need immediate switch to alternative options (i.e. other novel agents, allogeneic-SCT or CART).