Since the recent introduction of targeted therapies (i.e. the B-cell receptor inhibitor ibrutinib and the anti-BCL2 venetoclax), deep changes have occurred in chronic lymphocytic leukemia (CLL) patients'clinical management. Current guidelines recommend that chemoimmunotherapy is limited to patients with mutated variable region of heavy chain immunoglobulin (IGHV) genes and devoid of TP53 gene deletion/mutation, making mandatory the assessment of these biomarkers when patients require treatment. International guidelines for the analysis and reporting of IGHV and TP53 mutations have been established; TP53 mutations are reported if clonal, i.e. identified by Sanger sequencing or with a variant-allele frequency (VAF) above 10% when analyzed by next-generation sequencing (NGS).
From January 2019 to December 2020, a network of 8 Italian certified laboratories, including ours, has been established, with the aim of providing the analysis of TP53 and IGHV gene mutations to all the Italian hematologists managing CLL patients in first disease progression: 678 patients from 45 Italian centers were evaluated.
The present project consists in the retrospective and prospective collection of clinico-biologic data from all the patients analyzed, as well as the re-testing by NGS in our laboratory of those samples resulted TP53 wild-type by Sanger sequencing, in order to address the following unanswered questions: 1) do the Italian hematologists adhere to the current guidelines that have changed the clinical practice in CLL and know on the application of the molecular predictive biomarkers? 2) do the prognostic scores established mostly in the setting of relapsed/refractory patients under novel drugs (i.e. SRSi, 4-factor score) maintain their value in the first-line setting? 3) do clonal and subclonal TP53 mutations impact on the efficacy of first-line targeted therapies? The final aim is the optimization of the personalized approach for CLL patients outside clinical trials.
