Molecular Characterisation of Diffuse Large B Cell Lymphoma in Patients of 80 Years Old or More: Clinical Relevance in a Multicentric Randomized Phase III Study of the Lysa (SENIOR Study)

Introduction The outcome of very elderly patients with newly diagnosed diffuse large B cell lymphoma (DLBCL) remains poorer than that of younger patients, often because of co-morbidities and physiological organ function impairment. However, the biological specificities of DLBCL in very elderly patients are unknown. The LYSA conducted a multicentric, phase III, open-label, randomized trial in newly diagnosed DLBCL > 80y evaluating the efficacy of the combination of lenalidomide with R-miniCHOP (R2-miniCHOP) in comparison to the standard R-miniCHOP (SENIOR trial, NCT02128061). Based on targeted NGS sequencing and gene expression profile (GEP) analysis, the BIOSENIOR project aimed to provide a molecular characterisation of the cohort and detect clinically relevant biomarkers in according to treatment arm. Methods The SENIOR study enrolled patients aged of 80 years or more with non-previously treated CD20+ DLBCL, age-adjusted IPI= 0 to 3, and Ann Arbor stage II to IV. 249 patients were randomized (127 in R-miniCHOP arm and 122 in R2-miniCHOP arm). Median age was 83y (range 80-96. Patients with available tumor DNA /RNA from FFPE biopsies were included in the BIOSENIOR substudy. GEP was performed using Lymph2CX assay (Nanostring®) and a new RTMLPA assay (Bobée et al. J Mol Diagn 2017) able to quantify the expression of 137 relevant genes involved in B-cell biology, microenvironment or therapeutic response (cereblon). Genotyping (QiaSeq ®) was performed using a dedicated 36 genes panel. GEP features were compared to DLBCL patients < 60y enrolled in the LYSA GAINED trial (NCT01659099). Results Tumor DNA/RNA was available for 164/249 patients (66%). GEP was performed in 154 cases by RTMLPA and in 103 cases by Lymph2CX. The concordance to classify GCB/ABC was of 94% between the two technologies. DLBCL were mainly classified in the ABC subtype [77 = ABC (50%); 53 = GCB (34.4%); 17 unclassified (11%)]. Four cases (2.6%) were classified as EBV+ DLBCL and 1 as PMBL. 81 cases (52.5%) were considered as BCL2+, 23 (15%) as MYC+ and 16 (10.4%) as double-expressors (DE) by GEP. Comparison of GEP with younger patients highlighted distinct features and geriatric specificities (figure 1A). Genotypes were obtained in 159 patients. MYD88, PIM1, CREBBP, CD79B and TP53 were the five most frequently mutated genes (Figure 1B). Correlations between biomarkers and outcomes (OS and PFS) were performed in the overall population and according to treatment arms. The GCB/ABC subtyping, as d