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.
OBJECTIVE
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.


METHODS
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 < or =30 at entry into induction (day 0) and < or =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 (DeltaVEGF-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.
Avramis
Ioannis A
IA
Children's Hospital Los Angeles, California 90027, USA.
Panosyan
Eduard H
EH
Dorey
Fred
F
Holcenberg
John S
JS
Avramis
Vassilios I
VI
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D015999:Multivariate Analysis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy*; D011237:Predictive Value of Tests; D011379:Prognosis; D012008:Recurrence; D012074:Remission Induction; D012307:Risk Factors; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000097:blood*
D042461:Vascular Endothelial Growth Factor A