Sequence analyses of relapsed or refractory diffuse large B‐cell lymphomas unravel three genetic subgroups of patients and the GNA13 mutant as poor prognostic biomarker, results of LNH‐EP1 study

Abstract Advances in molecular profiling of newly diagnosed diffuse large B‐cell lymphoma (DLBCL) have recently refine genetic subgroups. Genetic subgroups remain undetermined at the time of relapse or refractory (RR) disease. This study aims to decipher genetic subgroups and search for prognostic molecular biomarkers in patients with RR‐DLBCL. From 2015 to 2021, targeted next‐generation sequencing analyses of germline‐matched tumor samples and fresh tissue from RR‐DLBCL patients were performed. Unsupervised clustering of somatic mutations was performed and correlations with patient outcome were sought. A number of 120 patients with RR‐DLBCL were included in LNH‐EP1 study and a molecular tumor landscape was successfully analyzed in 87% of patients (104/120 tumor samples). The median age was 67.5 years (range 27.4–87.4), median number of previous treatments was 2 (range 1–9). The most frequently mutated genes were TP53 ( n = 53 mutations; 42% of samples), CREBBP ( n = 39; 32%), BCL2 ( n = 86; 31%), KMT2D ( n = 39; 28%) and PIM1 ( n = 54; 22%). Unsupervised clustering separated three genetic subgroups entitled BST (enriched in BCL2 , SOCS1 , and TNFRSF14 mutations); TKS (enriched in TP53 , KMT2D , and STAT6 mutations); and PCM (enriched in PIM1, CD79B , and MYD88 mutations). Median overall survival (OS) was 11.0 (95% confidence interval [CI]: 8.1–12.6) months. OS was not significantly different between the three genetic subgroups. GNA13 mutant was significantly associated with an increased risk of death (hazard ratio: 6.6 [95% CI: 2.1–20.6]; p = .0011) and shorter OS ( p = .0340). At the time of relapse or refractory disease, three genetic subgroups of DLBCL patients were delineated, which could help advance precision molecular medicine programs.