A high LDH to absolute lymphocyte count ratio in patients with DLBCL predicts for a poor intratumoral immune response and inferior survival

Purpose: To test the utility of the circulating Lactate Dehydrogenase (LDH) to absolute lymphocyte count (ALC) ratio (LAR) to predict outcome to conventional first-line chemo-immunotherapy in Diffuse Large B-cell Lymphoma (DLBCL), and investigate its correlation to the tumour immune microenvironment (TME). Experimental Design: A population based cohort of 210 patients (median age: 64, range 18-90 years) with median follow up 3.8 years was analysed. All patients were treated with R-CHOP, and no immunosuppression related cases were included. Tissue for nanoString gene expression was available in 141. Results: High (i.e. adverse) LAR was associated with inferior progression free and overall survival (PFS 45% vs. 78%; OS 56% vs 86%, both p < 0.001) at 5-years. Patients with a high LAR had a strikingly different TME compared to patients with a low ratio. Low LAR was associated with a good-risk TME immune gene signature (p < 0.0001), including high CD8 and lower M2 macrophage infiltration. COO classification was not significantly different between high and low LAR patients. LAR was predictive of outcome independent of cell of origin and the international prognostic index (IPI). In particular, LAR discriminated patients with high IPI (3- 5), showing 5-year PFS and OS of 32% vs. 74% (p=0.0006), and 43% vs. 81% (p=0.0003). A combined nanoString based immune score and the LAR allowed better prediction of outcome than either prognosticator alone (p < 0.0001). Conclusions: The LAR reflects the TME within DLBCL, and is a strong predictor of outcome in DLBCL treated with conventional first-line therapy that is independent of and additive to the IPI. Further studies are required to determine if this easily applicable blood assay can determine patients that might benefit from immune checkpoint blockade.