66P High incidence of TP53 and epigenetic modifying oncogene mutations in a large cohort of patients enrolled in phase I clinical trials for R/R DLBCL

Diffuse large B cell lymphoma (DLBCL) is the most common adult non-Hodgkin lymphoma. Despite therapeutic advances, 40% of the patients (pts) will experience a relapse or refractory (R/R) disease. New therapeutic approaches and predictive biomarkers are required for these poor prognosis pts. We aimed to establish whether a molecular characterization could help to better specify the molecular characteristics of relapse and help in therapeutic decision making. Paired target next generation sequencing (NGS) for all consecutive patients (n=89) with R/R DLBCL biopsied at time of enrollment phase I clinical trials (2013-2020), using Ion Torrent technology and an in-house customized panel of 44 genes. At time of inclusion, mean age was 62 (range 23-83) y/o, 50 (56%) were male, median prior lines of therapies was 2 (range 1-9). The sequencing panel was informative in 86 (97%) patients. The most recurrently affected genes were TP53 (n=38 cases mutated; 43%), CREBBP (n=29; 33%), KMT2D (n=24; 27%), PIM1 (n=23; 26%) and BCL2 (n=20; 22%). Mutual exclusivity analysis showed that KMT2D mutations were significantly exclusive from MEF2B (n=11; 12%) mutations. From an unsupervised clustering (based on a distance matrix derived from the presence or absence of variants within the 44 genes), 67/86 patients (78%) could be classified into four distinct genetic groups: namely group K (n=21 patients (24%) enriched in KMT2D, EZH2, and MYC mutations); group S (n=18 patients (20%), enriched in SOCS1, B2M and PIM1 mutations), group B (n=17 patients (19%), enriched in BCL2, GNA13 and TNFSRF14 mutations) and group M (n=11 patients (12%), enriched in MYD88 and CD79B mutations). A molecular characterization of patients with R/R DLBCL identify high incidence of TP53 mutations and epigenetic modifying oncogenes mutations and four molecular distinct genetic clusters that could further serve as the basis of a molecular therapeutic orientation.