Biomarkers of angiogenesis as prognostic factors in myelodysplastic syndrome patients treated with hypomethylating agents

Angiogenesis occurs in response to tissue ischemia and wound healing, and contributes to the pathogenesis of a variety of diseases, such as benign and malignant neoplasia. Several studies have measured bone marrow microvessel density (MVD) in MDS patients and acute myeloid leukemia (AML) patients transformed from MDS, and MVD was higher in MDS patients than controls, but was lower than in AML patients. Vascular endothelial growth factor (VEGF) is expressed in bone marrow blast cells, and an autocrine VEGF signaling mechanism has been established in MDS. Increased bone marrow angiogenesis and VEGF concentrations are adverse prognostic features in all of these patients. In this study, 69 patients were treated in two groups: hypomethylating agents or supportive care with oxymetholone±pyridoxine. We evaluated the MVD and VEGF expression of paraffin-embedded bone marrow samples from patients. We also investigated the relationship between angiogenesis-related biomarkers including MVD, VEGF expression, and clinical factors. The patient median age was 65 years, and the median follow-up duration was 28 months. MVD assessment among subtypes of WHO MDS classification showed that the MVD of RCUD was significantly lower than in other types (p=0.02). However, there was no significant difference in VEGF expression according to the subtype of MDS. Although MVD and VEGF expression did not differ between risk groups based on the IPSS, the low risk group tended to have lower expression of angiogenesis-related biomarkers. MDS patients receiving hypomethylating agents had significantly lower MVD expression in responders than in non-responders (6.13±3.38 vs. 9.89±2.10, respectively, p=0.039). In a consecutive evaluation at the time of diagnosis and 3 months after the initial treatment, the group with a decrease or no change of MVD had a higher response rate compared to that in the group with an increase of MVD (92.9% vs. 58.8%, respectively, p=0.045). Adverse prognostic factors included older age, MDS type other than RCUD, a higher IPSS risk group, and abnormal cytogenetics. Although angiogenesis-related markers did not demonstrate any significant prognostic association with survival, MVD (≥10n/mm2) and a strong expression of VEGF seemed to be associated with lower survival rate. These data suggested that the MVD value might be helpful in predicting responsiveness to treatment, especially in MDS patients treated with hypomethylating agents. Although angiogenesis-related markers including VEGF did not demonstrate a significant association with survival outcomes, we observed that high MVD and strong VEGF expression seemed to be associated with lower survival rate. Therefore, biologic markers related to angiogenesis might have a potential as prognostic factors for MDS patients.