Low lymphocyte-to-monocyte ratio predicts poor outcome in high-risk aggressive large B-cell lymphoma.

Low lymphocyte-to-monocyte-ratio (LMR) has been associated with unfavorable survival in patients with diffuse large B-cell lymphoma (DLBCL). To date, however, the impact of LMR on survival has not been examined in a uniformly treated cohort of patients with high-risk aggressive large B-cell lymphoma. We collected peripheral blood absolute lymphocyte counts (ALCs) and absolute monocyte counts (AMC) prior to treatment and calculated LMR from 112 adult patients, who were less than 65 years of age, had age-adjusted International Prognostic Index 2-3, or site-specific risk factors for central nervous system (CNS) recurrence, and were treated in a Nordic Lymphoma Group LBC-05 trial with dose-dense immunochemotherapy and early systemic CNS prophylaxis (www.ClinicalTrials.gov, number NCT01325194). Median pretreatment ALC was 1.40 × 109/l (range, 0.20-4.95), AMC 0.68 × 109/l (range, 0.10-2.62), and LMR 2.08 (range, 0.10-12.00). ALC did not correlate with tumor-infiltrating lymphocytes, AMC did not correlate with tumor-associated macrophages, and neither ALC nor AMC correlated with survival. However, low LMR (<1.72) translated to unfavourable progression-free survival (PFS) (5-year PFS 70% vs. 92%, p = 0.002) and overall survival (OS) (5-year OS, 77% vs. 92%, p = 0.020). In the patients with low LMR, relative risk of progression was 4.4-fold (95% confidence interval [CI] 1.60-12.14, p = 0.004), and relative risk of death was 3.3-fold (95% CI 1.18-9.50, p = 0.024) in comparison to the patients with high LMR. We conclude that low LMR is an adverse prognostic factor in uniformly treated young patients with high-risk aggressive large B-cell lymphoma.

Soluble PD-1 but Not PD-L1 Levels Predict Poor Outcome in Patients with High-Risk Diffuse Large B-Cell Lymphoma.

Interaction of checkpoint receptor programmed death 1 (PD-1) with its ligand 1 (PD-L1) downregulates T cell effector functions and thereby leads to tumor immune escape. Here, we aimed to determine the clinical significance of soluble PD-1 (sPD-1) and soluble PD-L1 (sPD-L1) in patients with diffuse large B-cell lymphoma (DLBCL). We included 121 high-risk DLBCL patients treated in the Nordic NLG-LBC-05 trial with dose-dense immunochemotherapy. sPD-1 and sPD-L1 levels were measured from serum samples collected prior to treatment, after three immunochemotherapy courses, and at the end of therapy. sPD-1 and sPD-L1 levels were the highest in pretreatment samples, declining after three courses, and remaining low post-treatment. Pretreatment sPD-1 levels correlated with the quantities of PD1+ T cells in tumor tissue and translated to inferior survival, while no correlation was observed between sPD-L1 levels and outcome. The relative risk of death was 2.9-fold (95% CI 1.12-7.75, p = 0.028) and the risk of progression was 2.8-fold (95% CI 1.16-6.56, p = 0.021) in patients with high pretreatment sPD-1 levels compared to those with low levels. In conclusion, pretreatment sPD-1 level is a predictor of poor outcome after dose-dense immunochemotherapy and may be helpful in further improving molecular risk profiles in DLBCL.

Prognostic influence of macrophages in patients with diffuse large B-cell lymphoma: a correlative study from a Nordic phase II trial.

The prognostic impact of the tumor microenvironment in diffuse large B-cell lymphoma has not been systematically assessed. We analyzed mRNA and antigen expression of monocytes, macrophages, lymphocytes, dendritic and natural killer cells in pretreatment tumor samples of patients with high-risk diffuse large B-cell lymphoma using gene expression microarray and immunohistochemistry. The patients were treated in a Nordic phase II study with dose-dense chemoimmunotherapy and central nervous system prophylaxis. Of the studied markers for non-malignant inflammatory cells, CD68 expression and CD68(+) macrophage counts correlated with favorable outcome. Five-year progression-free survival rates were 83% and 43% for the patients with high and low CD68 mRNA levels, respectively (P=0.007), while overall survival rates were 83% and 64%, respectively (P=ns). The patients with high CD68(+) macrophage counts had better 5-year progression-free survival (74% versus 40%; P=0.003) and overall survival (90% versus 60%; P=0.009) than the patients with low macrophage counts. Low CD68(+) macrophage count retained its prognostic impact on overall survival with age-adjusted International Prognostic Index [RR=5.0 (95% CI 1.024-19.088); P=0.017]. The findings were validated in three independent cohorts of patients treated with chemoimmunotherapy. In contrast, in patients treated with chemotherapy, high CD68(+) macrophage count was associated with poor progression-free survival (40% versus 72%; P=0.021) and overall survival (39% versus 72%; P=0.015). Together, the data suggest that macrophages exhibit a dual, treatment-specific role in diffuse large B-cell lymphoma. For the patients treated with chemoimmunotherapy, high pretreatment CD68 mRNA levels and CD68(+) macrophage numbers predict a favorable outcome.