Titolo della tesi: NEXT GENERATION SEQUENCING TECHNOLOGIES TO EXPLORE THE LANDSCAPE OF MUTATIONS AND CNVs OF CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH NOVEL TARGET THERAPIES IBRUTINIB AND VENETOCLAX
Chronic lymphocytic leukemia (CLL) is characterized by a heterogeneous clinical course, ranging from extremely indolent cases to rapidly progressive forms requiring prompt treatment intervention. The diverse clinical course at the individual level is determined by the immunogenetic and molecular heterogeneity of the disease. During the past 10 years, innovations in molecular genetic technologies have allowed to understand the biological heterogeneity of CLL, the pathogenesis and clonal evolution of the disease, the mechanisms of resistance to chemotherapy as well as to novel targeted therapies.
We applied Next Generation Sequencing (NGS) technologies to explore the genetic landscape of CLL patients treated with the novel drugs ibrutinib and venetoclax.
In the first project, we investigated the dynamics of major and minor TP53 mutations under ibrutinib treatment performing a longitudinal TP53 monitoring by deep-sequencing, both in treatment naïve and relapse/refractory CLL patients. Ibrutinib, in any line of therapy, decreases the TP53 complexity and it does not exert a positive selective pressure on TP53 mutated clones, unlike chemo-immunotherapy.
In the second project, we analyzed the mutational profile of a cohort of treatment naïve high risk CLL patients candidate to venetoclax treatment using a targeted NGS panel of 25 genes with a prognostic/predictive role in CLL. In addition, we used the same sequencing raw data to infer copy number variations (CNVs) with a novel bioinformatic approach.
Given the crucial role of genomic complexity as predictive marker of response to therapy in CLL, inferring both mutations and CNVs from a single NGS run represents a timely and cost-effective method for a more comprehensive genomic characterization, in order to identify potential predictive genetic markers of venetoclax efficacy.