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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

Authors' Affiliations: ¹ Childrens Hospital Los Angeles, Los Angeles, California; ² Children's Oncology Group, Arcadia, California; and ³ Seattle Children's Hospital, Seattle, Washington

Requests for reprints: Vassilios I. Avramis, Division of Hematology/Oncology, Childrens Hospital Los Angeles, MS #57, 4650 Sunset Boulevard, Los Angeles, CA 90027. Phone: 323-669-2288; Fax: 323-661-5058; E-mail: vavramis{at}chla.usc.edu.

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 (VEGF-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.