Absolute Monocytosis At Diagnosis Is Associated with Poor Survival in Diffuse Large B-Cell Lymphoma -Possibly Related to Increase in Monocytic-Myeloid Derived Suppressor Cells

monocytes and macrophages play a role in promoting angiogenesis and suppression of the anti-tumor immune response. Monocytic-myeloid derived suppressor cells (M-MDSCs) are a subpopulation of immature myeloid cells which have immune-suppressive function and play a role in cancer tolerance. Some patients with malignant lymphoma exhibit peripheral blood monocytosis (PBM) at diagnosis but its exact prevalence is not known.

Recently we encountered PBM in a few patients with DLBCL who had a rapidly progressive fatal course. This observation coupled with emerging data on the role of M-MDSCs is in the tumor microenvironment, led us to undertake a retrospective study to determine prevalence of PBM and its possible prognostic significance in DLBCL. In a proportion of these patients we also quantitated the M-MDSCs pool in the peripheral blood using flow cytometry in an attempt to assess possible changes in this subpopulation of monocytic cells in DLBCL.

Clinical and laboratory data from medical records of 91 newly diagnosed patients with DLBCL seen at our institute during 1996–2010, were evaluated for the presence of absolute PBM> 1000 cells/mm³, at diagnosis and for possible correlations with other prognostic factors including age, stage, gender, B symptoms, extra nodal involvement, serum LDH and CRP levels, bone marrow (BM) involvement and IPI score. A Cox proportional hazards regression model was used to determine significance of the prognostic factors in a multivariate analysis. In the last 23 consecutive patients flow-cytometry analysis peripheral blood cells was also performed using surface staining for CD45+CD14+ HLA DR^−/LOW to define the proportion of M-MDSCs compared to 15 healthy volunteers. Statistical analysis of was done using student T-TEST.

The median age of the entire patient cohort was 66 years (21–87); median follow up was 30 months: (1–332 months) and 57 % were men. All patients received CHOP or R-CHOP. PBM was found in 18.3% at diagnosis. In the multivariate analysis (Cox model), only PBM, bone marrow involvement and IPI score were found to be independent prognostic factors for overall survival (OS) while age and LDH weren't (Table). Blood samples collected at diagnosis from 23 patients showed increased numbers of M- MDSCs compared to healthy volunteers (9.59% range: 5.6–19 % and, 5.44% range 4.8–7.7 % respectively p<0.05).Levels of MDSCs decreased to within normal limits when performed 3 month following chemotherapy in patient in CR (5.76% range: 5.1–7.2 %).

These results show that PBM is an independent factor for predicting poor survival in patients with DLCL and was as significant a risk factor as IPI score. This simple routine laboratory test can be utilized in daily practice as another indicator of poor outcome in DLBCL. The findings provide further support for the functional role of monocytes in the immune response in DLBCL. Furthermore, the consistent finding of significantly increased numbers of M-MDSC in the peripheral blood in these patients suggests that this subpopulation of immunosuppressive monocytes may contribute to the decreased tumor surveillance seen in DLBCL and may help to explain why absolute PBM is associated with poor outcome in these patients. Studies on their biological role as a marker of disease activity in DLBCL are in progress.

View largeDownload slide

View largeDownload slide

Close modal

No relevant conflicts of interest to declare.