Correlation between High Vascular Endothelial Growth Factor-A Serum Levels and Treatment Outcome in Patients with Standard-Risk Acute Lymphoblastic Leukemia: A Report from Children's Oncology Group Study CCG-1962

Abstract

Purpose: Many molecular pathways, including cell cycle control, angiogenesis, and drug resistance, mediate tumor growth and survival. Vascular endothelial growth factor-A (VEGF-A) serum levels <40 and >100 pg/mL have been associated with good and poor prognoses, respectively. Experimental Design: The hypothesis was that serum VEGF-A levels in standard-risk acute lymphoblastic leukemia pediatric patients at induction are predictive of event-free survival (EFS). One hundred seventeen patients were entered in CCG-1962 study and randomized into the native and polyethylene glycolated asparaginase arms. VEGF-A levels were quantified by an ELISA assay. Results: All patients had a decrease in VEGF-A levels by day 14 of induction, but they later dichotomized; EFS group levels remained low and event group levels increased. A correlation exists between high VEGF-A levels at entry to induction and time to event. Moreover, 6-year EFS patients have lower end of induction VEGF-A levels (28 ± 6 pg/mL) than event patients (>100 pg/mL; P < 0.01). Kaplan-Meier curves using various VEGF-A values were produced; with ≤30 at entry into induction (day 0) and ≤60 pg/mL at the end of induction (day 28), patients with low VEGF-A levels had superior EFS (P < 1e−4). Furthermore, patients who had an increase in VEGF-A during induction (ΔVEGF-positive, days 0-28) were more likely to have an event (P < 1e−4). Bifurcation by asparaginase treatment arm did not alter these results. Conclusions: These observations strongly support that high VEGF-A levels in induction are an asparaginase treatment–independent predictive marker for EFS. Hence, an anti-VEGF-A therapy should be tested in acute lymphoblastic leukemia.

Angiogenic Factors Correlate with T Cell Immune Reconstitution and Clinical Outcomes after Double-Unit Umbilical Cord Blood Transplantation in Adults

“…However, we did not observe significantly worse OS, suggesting that some of the relapsed patients might have responded to salvage therapy. Our findings are consistent with previous observations that elevated VEGF is associated with worse outcomes in patients with hematologic malignancies after chemotherapy [14-16] and that increased pretransplant VEGF levels are associated with higher rate of relapse and worse PFS after allogeneic HSCT from adult donors [17]. …”

“…Consistent with the mandatory role of VEGF-mediated angiogenesis in hematopoiesis, VEGF blockade at the time of transplantation in lethally irradiated mice results in failure of hematopoietic reconstitution and early death [9]. Elevated levels of VEGF and/or its receptors have been reported in patients with hematologic malignancies, where they play a role in an autocrine/paracrine fashion [10-12], and have been shown to be of prognostic significance [13-16]. Levels of VEGF before allogeneic HSCT are associated with increased risk of relapse [17], but reports regarding its role on clinical outcomes such as graft-versus-host disease (GVHD), nonrelapse mortality (NRM), or survival are conflicting [17-20].…”

HMG-CoA reductase inhibitors as adjuvant treatment for hematologic malignancies: what is the current evidence?

“…Zhao et al demonstrated a novel mechanism in which lovastatin inhibits both ligand-induced VEGFR-2 activation through inhibition of receptor internalization and VEGF activation of PI3K/AKT pathway in endothelial cells [72]. Since angiogenesis has a central role in clinically aggressive hematologic malignancies such as nonHodgkin lymphomas [73][74][75], angioimmunoblastic T-cell lymphoma [76,77], ALL [78], AML [79], and multiple myeloma [80], inhibition of the VEGF-mediated intracellular signal via bevacizumab could be further facilitated by blocking the mevalonate pathway.…”

Induction of Vascular Endothelial Growth Factor Secretion by Childhood Acute Lymphoblastic Leukemia Cells via the FLT-3 Signaling Pathway

“…High serum VEGF levels have also been associated with poor prognosis in certain leukemias (5). Accordingly, one study has shown that standard-risk pediatric patients with ALL who have high VEGF levels after induction therapy relapse earlier than those with low levels (6).…”