Clinicoprognostic implications of increased serum levels of vascular endothelial growth factor and basic fibroblastic growth factor in early B-cell chronic lymphocytic leukaemia.

S Molica,D Levato,A Ricciotti,G Vitelli,G Digiesi

doi:10.1038/sj.bjc.6600022

Abstract

To assess the relative merit of increased serum levels of vascular endothelial growth factor and basic fibroblastic growth factor in predicting the risk of disease progression of patients with early B-cell chronic lymphocytic leukaemia we analyzed 81 Binet stage A patients whose sera were taken at the time of diagnosis and evaluated for the presence of vascular endothelial growth factor and basic fibroblast growth factor using an enzyme-linked immunosorbent assay. Serum levels of vascular endothelial growth factor positively correlated with Rai sub-stages (P=0.03), peripheral blood lymphocytosis (P=0.03), bone marrow histology (P=0.04) and β2-microglobulin (β2-m) (P=0.006). When dealing with basic fibroblast growth factor only a correlation with Rai sub-stages (P=0.02) could be found. Different cut-offs set on the basis of a stratification in quartiles, failed to demonstrate any correlation between serum levels of basic fibroblast growth factor and disease progression. In contrast, patients with increased serum levels of vascular endothelial growth factor (above median value, 203 pg ml−1) had a three times increased risk of disease progression, although, in multivariate analysis only Rai sub-stages (P=0.0001) and lymphocyte doubling time (P=0.002) retained their prognostic significance. Low levels of vascular endothelial growth factor were indicative of good clinical outcome in the subgroup of patients with either low (P=0.02) or high (P=0.03) β2-m concentration. Finally, the highest prognostic power was obtained when serum vascular endothelial growth factor and β2-m were examined in combination. Median of progression-free survival of patients who had both serum vascular endothelial growth factor and β2-m higher than median value was only 13 months, in contrast median progression-free survival of patients with one marker increased (i.e. above the 50th percentile) was 40 months. Patients with both markers below the median experienced the best clinical outcome (median progression-free survival not reached at 40 months). In conclusion, serum levels of either vascular endothelial growth factor or basic fibroblast growth factor are high in patients with early chronic lymphocytic leukaemia, however, only vascular endothelial growth factor predicts behaviour of disease and helps to refine the prognosis of stage A patients.British Journal of Cancer (2002) 86, 31–35. DOI: 10.1038/sj/bjc/6600022 www.bjcancer.com© 2002 The Cancer Research Campaign

Highlights

Recent studies indicate that angiogenesis may be involved in the pathogenesis of B-cell chronic lymphocytic leukaemia (CLL) (Aguayo et al, 2000; Kini et al, 2000)
Serum levels of VEGF positively correlated with Rai substages
Results of the current study show that serum concentrations of either VEGF or b-FGF are increased in the serum of stage A CLL patients but only serum levels of VEGF reflect clinico-haematological features of tumour mass such as advanced Rai clinical substages, high PB lymphocytosis, increased b2-m and diffuse BM histology

Summary

Introduction

Recent studies indicate that angiogenesis may be involved in the pathogenesis of B-cell chronic lymphocytic leukaemia (CLL) (Aguayo et al, 2000; Kini et al, 2000). Elevated pretreatment levels of b-FGF correlate with a more advanced clinical stage and with resistance to chemotherapy (Menzel et al, 1996; Konig et al, 1997), while low cellular and high serum levels of VEGF are associated with a poor clinical outcome (Molica et al, 1999; Aguayo et al, 2000). These data lend support to the idea that angiogenic cytokines may play a role in the leukaemogenic process of CLL, the relative merit of VEGF and b-FGF in predicting the outcome of disease has not been assessed far. In this subset of patients angiogenic cytokines were investigated as indicator of diseaseprogression (DP), an event which has an important impact on overall survival of CLL patients

Methods

Results

Conclusion