Molecular characterization contributes to diagnosis and predicts outcome in primary mediastinal large b‐cell lymphomas: a lysa study

Introduction: Primary mediastinal large B-cell lymphoma (PMBL) is a unique entity with an unusually good prognosis, except for ∼15% of refractory patients. Routine diagnosis relies on a clinicopathological confrontation. Tools to detect earlier refractory patients are lacking. Methods: We implemented a biological characterization of a multicenter retrospective LYSA cohort that previously reported clinical outcomes of 313 adult PMBL patients treated with first-line ACVBP or CHOP plus anti-CD20 between 2007 and 2017. We centrally reviewed 211 cases with available tumor material at diagnosis and then excluded 17 cases (misclassifications/inadequate material). Next, we applied Gene Expression Profiling (GEP) with a 137-genes RT-MLPA assay (LymphoSign signature) and Next-Generation Sequencing (NGS) with a 45-genes panel. Primary endpoints were progression-free survival (PFS) and overall survival (OS) according to molecular data. Results: We obtained GEP and NGS data for 139 (72%) and 131 (67.5%) cases, respectively. We observed a dominant expression of the PMBL-related driver genes IL4I1, B2M, PDL2, CD23, CD30, MAL, PDL1, and STAT6. Commonly mutated genes were SOCS1 (85.5%), B2M (61.1%), STAT6 (51.9%), IGLL5 (51.1%) and TNFAIP3 (51.1%). After integration of morphologic and available molecular data, 131/194 cases (67.5%) were considered as PMBL bona fide (with typical morphology and molecular profile). Within the PMBL bona fide group, we identified a cluster of 43 cases with overexpression of PDL1/2 genes (PDL1+/PDL2+, cutoff ≥median expression of each gene). As compared with others, PDL1+/PDL2+ cases were as follows: median [range] age of 34 [18–67] years (vs. 33.5 [19–64] years, p = 0.621), male sex: 53% (vs. 35%, p = 0.05), elevated LDH: 95% (vs. 76.3%, p = 0.008), PS 0–1: 79% (vs. 89.6%, p = 0.12), stage III–IV: 55.8% (vs. 39%, p = 0.08), IPI ≥ 3: 37.2% (vs. 18.4%, p = 0.027), extra-nodal involvements: 60% (vs. 45.5%, p = 0.12), metabolic tumor volume (MTV) ≥ 360 cm3: 53% (vs. 25.4%, p = 0.007). Treatments in the PDL1+/PDL2+ group did not differ from other patients: R-ACVBP: 69.8% (vs. 66.2%), R-CHOP14: 18.6% (vs. 20.8%) and R-CHOP21: 11.6% (vs. 14.3%) (p = 0.411). PDL1+/PDL2+ status was associated with poorer PFS (HR = 7, p < 0.001) and OS (HR = 15, p < 0.001, Figure 1). B2M mutations were inactivating and associated with lower PFS (p = 0.006). In a multivariate model including IPI ≥ 3, PDL1/2 status, MTV ≥ 360 and B2M mutations, only PDL1+/PDL2+ status was an independent prognostic factor of adverse PFS (HR = 7.1, 95% CI [1.5;33.1], p = 0.013). The research was funded by: This work was supported by grants from the Ligue Contre le Cancer (Comité de Seine-Maritime, AO_2020), the GIP Cancéropôle Nord-Ouest (N°2021/01 and N°2021/13), Force Hémato (N°02-2020) and CALYM (ANR-2020). Keywords: diagnostic and prognostic biomarkers, extranodal non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.