Vascular endothelial growth factor (VEGF-A) serum levels in standard risk ALL pediatric patients (CCG-1962 study)

Abstract

9026 Background: Many molecular pathways including cell-cycle control, angiogenesis & drug resistance mediate tumor growth and survival. Activation of Akt, PI3K and Ras can be induced by the activation of receptor tyrosine kinases, such as the VEGF-R and related growth factor receptors. VEGF-A serum levels <40 and >100 pg/ml have been associated with good and poor prognoses, respectively. The higher the VEGF-A levels the greater the chance of MRD blasts surviving chemotherapy. ALL blasts secrete VEGF-A and express VEGF-R. The hypothesis was that serum VEGF-A levels in SR ALL pediatric patients at entry of Induction (IND) are predictive of Event-Free Survival (EFS). Methods: 117 patients were entered in CCG-1962 study and were randomized into the Native & PEG-ASNase arms. VEGF-A serum levels in Induction were quantified by an ELISA assay. Results: . All patients had a decrease in VEGF-A levels by Day 14 of IND, but they later dichotomized; with EFS group levels remained low and Event group increasing. The VEGF-A levels at the end of IND remained unchanged in all patients in the DI1 and DI2 treatment phases. A linear relationship exists between high VEGF-A levels at entry to IND and time to Event. Moreover, 7 yr EFS patients have lower VEGF-A average levels of 28±2 pg/ml than Event patients, >100 pg/ml (P<0.01). VEGF-A levels were analyzed by STATA-9 to yield Kaplan-Meier curves. Various cut-off values of VEGF-A were used, with the 30 and 60 pg/ml being the most significant. Low VEGF-A levels at entry or at the end of IND had superior EFS (P<0.0001). In addition, these patients were examined for Δ-VEGF-A positive or not positive. These analyses produced a significant difference, in that patients who had an increase in serum levels of VEGF-A from IND to a later treatment phase had an Event and the patients who had a decrease or no change were EFS (P<1E-6). Bifurcation by Native or PEG-ASNase arm did not alter these results. Conclusions: These results taken together with the results from other studies, strongly support that high VEGF-A serum concentrations in IND and no increase in Δ-VEGF-A are treatment-independent surrogate markers for EFS. Since many studies have demonstrated the same fact, an anti-VEGF-A modality may be useful to enhance the outcome of the ALL patients. No significant financial relationships to disclose.