High PDL1/PDL2 gene expression correlates with worse outcome in primary mediastinal large B-cell lymphoma

Abstract

Primary mediastinal B-cell lymphoma (PMBL) is an uncommon entity of aggressive large B-cell lymphoma with an unusually good prognosis, except for 10-15% of chemorefractory cases with poor outcomes. To identify patients at high risk of chemorefractoriness, we performed molecular characterization of a retrospective multicenter cohort of PMBL patients treated with first-line immunochemotherapy. The traits of the patients with gene-expression profiling (GEP) data (n=120) were as follows: median [range] age of 34 [18-67] years, female sex 58.3%, elevated LDH 82.5%, ECOG 0-1 85.7%, Ann Arbor stage I-II 55%, IPI 1-2 64.4%, and median metabolic tumor volume 290.4 [15.7-1147.5] cm3. Among all 137 markers tested for correlation with survival data, only PDL1 and PDL2 expression showed a prognostic impact. Overall, both PDL1 and PDL2 genes were highly expressed in 37 (30.8%) patients (PDL1high/PDL2high; cutoff: median expression of each gene: PDL1 = 0.402, PDL2 = 9.147). The baseline clinical characteristics of PDL1high/PDL2high patients were similar to those of other patients. In univariate analysis, PDL1high/PDL2high status was associated with poor PFS (HR=4.292, 95% CI [1.447-12.817]) and OS (HR=8.24 [1.71-39.7]). In multivariate analysis, PDL1high/PDL2high status was an independent prognostic factor of adverse outcomes (PFS: HR= 5.22 [1.352-20.168], OS: HR= 10.368 [1.204-89.267]). We validated these results in an independent cohort of 40 patients and confirmed the significant association between PDL1high/PDL2high status and inferior PFS (HR=6.11 [1.61-23.2]). High PDL1/PDL2 gene expression defines a population with strong immune privilege and poor outcomes from standard chemotherapy who might benefit from first-line anti-PD1 immunotherapy.