Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

A Multiparameter Prognostic Risk Score of Chronic GVHD based on CXCL10 and Plasmacytoid DC (pDC) levels in the Peripheral Blood at 3 months after Allogeneic Hematopoietic Stem Cell Transplantion (HSCT).

Abstract

INTRODUCTION: Chronic GVHD (cGVHD) is the major cause of long-term morbidity after allogeneic HSC transplantation. There are no biomarkers that can consistently predict its occurrence. OBJECTIVE: We aimed to evaluate whether peripheral blood (PB) numbers of antigen-presenting cell (APC) subsets or serum chemokine concentrations are biomarkers of cGVHD occurrence. PATIENTS AND METHODS: 101 consecutive patients undergoing transplantation between January 2007 and 2011 were included in the study. Chronic GVHD was diagnosed both by Seattle's modified and NIH criteria. Multicolor flow cytometry was employed to determine the number of PB myeloid DC (mDC) and plasmacytoid DC (pDC), CD16+ DC, and CD16+ and CD16- monocytes, as well as CD4+ and CD8+ T, CD56+ NK and CD19+ B cells. The serum concentration of CXCL8, CXCL10, CCL2, CCL3, CCL4 and CCL5 was measured by cytometry bead array (CBA) assay. RESULTS: After a median of 60 days following enrollment, 37 patients had developed cGVHD. Patients with and without cGVHD had comparable clinical characteristics. However, previous acute GVHD strongly correlated with later cGVHD (57% vs 24%, respectively, p=0.0024). Each potential biomarker was screened for its association with cGVHD using Mann-Whitney test. Biomarkers being significantly different (p<0.05) between patients with and without cGVHD were analyzed by ROC analysis to select the variables predicting cGVHD with AUC>0.5 and p<0.05. A multivariate Fine-Gray model identified the following variables as independently associated with the risk of cGVHD: CXCL10 >= 592.650 pg/ml (HR 2.655, CI 1.298-5.433, p-value: 0.008), pDC >= 2.448 per mcl (HR 0.286, CI 0.142-0.577, p-value<0.001) and previous aGVHD (HR 2.635, CI 1.298-5.347, p-value: 0.007). A risk score was derived based on the weighted coefficients of each variable (2 points each) resulting in the identification of 4 cohorts of patients (score 0, 2, 4 and 6). In a competing risks analysis, the score allowed to stratify patients at different risk of cGVHD: the cumulative incidence of cGVHD was 9,7%, 34,3%, 57,7% and 100%, respectively, in patients with score 0, 2, 4 and 6 (Fig. 3A, p<0,0001). The score could nicely stratify the patients as based on the risk of extensive as well as NIH based global and moderate to severe chronic GVHD. As based on ROC analysis, the score could predict the occurrence of cGVHD with an AUC of 0.791 (95% CI 0.703 - 0.880) (p<0.001). Finally, a cut-off score of >= 4 was identified as the optimal cut-off by Younden J index with a sensitivity of 57.1% and a specificity of 85.0%. CONCLUSION: A multiparameter score including a history of previous acute GVHD, the concentration of CXCL10 and the number of pDC in the PB at 3 months after transplant may stratify patients at different risk of cGVHD. However, the score will need to be validated in a much larger, independent and possibly multicenter cohort of patients, transplanted from different donor types and with distinct GVHD prophylaxis regimens.