Clinical Impact of Different Levels of VEGF-C on Leukemic Blasts in the Bone Marrow and Peripheral Blood of Acute Myeloid Leukemia

Background: Vascular endothelial growth factor-C (VEGF-C) is a lymph-angiogenic growth factor and in general, transmits intracellular signals, resulting in cell proliferation and survival. Previous studies have reported that VEGF-C is important for cancer progression based on the autocrine VEGF-C loop promoting the invasion and metastasis of cancer cells as well as the spread of cancer cells by active recruitment of new lymphatics by tumor-derived VEGF-C. Acute myeloid leukemia (AML) blasts express VEGF-C and its receptors. A few studies demonstrated that high VEGF-C mRNA expression of AML blasts were related to increased in vitro and in vivo drug resistance and could predict adverse long-term outcomes. However, whether the expression of VEGF-C in the bone marrow (BM) and peripheral blood (PB) has a similar role in the pathophysiology of AML remains unclear.

Methods: In this study, we analyzed plasma levels of VEGF-C in both BM and PB samples of AML patients. The levels of VEGF-C were measured using a commercially available ELISA in the newly diagnosed AML patients (58 in BM, 26 in PB), patients in complete remission (CR) (26 in BM, 20 in PB), and refractory/relapsed AML (15 in BM, 10 in PB). In addition, response after 1^st induction chemotherapy was assessed in 67 evaluable patients and to create the predictive model for an achievement of CR, logistic regression was used after log transformation of VEGF-C levels.

Results: In the BM of patients with newly diagnosed AML, the level of VEGF-C was 47.87 ± 12.4 pg/ml which was significantly lower than that of refractory/relapsed AML [518.3 ± 320.0 pg/ml (P=0.005)] but there was no difference, compared to that of patients in CR [44.57 ± 8.44 pg/ml (P = 0.865)]. In contrast no trend was observed in the PB samples. Next, to create the predictive model for an achievement of CR, sixty-seven evaluable patients who received standard induction chemotherapy were analyzed. Thirty-seven men and 30 women were included. With a median age of 49 years (range, 20-78), the distribution of favorable, intermediate-I, intermediate-II, and adverse cytogenetic risk (ELN) were 25%, 31%, 21%, and 22%, respectively. The patients with continuous values of Log₁₀VEGF-C were divided into 2 groups (low vs. high levels) by a ROC curve analysis. Univariate analysis showed that high levels in BM samples were associated with achievement of CR after 1^st induction chemotherapy. Ultimately, multivariate analyses revealed that low levels of Log₁₀VEGF-C showed a trend for failure to achieve a response of CR (RR of 0.24, P = 0.065) and intermediate II/adverse cytogenetic risk was associated with a failure of CR, compared to favorable/intermediate I (RR of 0.21, P = 0.036). In contrast, in the PB samples, a low value of Log₁₀VEGF-C was an independent factor for achievement of CR (RR of 28.7, P = 0.043).

Conclusion: Our data demonstrate that the high VEGF-C level in the BM samples at diagnosis was associated with a trend toward higher CR rate and high VEGF-C level in the PB samples was significantly related to a failure of CR, suggesting discrepancy of the role of VEGF-C level in the BM and PB. Further studies on the different mechanism of the VEGF-C/VEGF-receptor pathway in the BM and PB are warranted.