Serum angiogenin is not elevated in patients with early B-cell chronic lymphocytic leukemia but is prognostic factor for disease progression.

The association between angiogenin and cancer progression and poor outcome in solid tumors has been documented, but its significance in leukemias has not been evaluated. Using an ELISA technique (Quantikine Human Angiogenin Immunoassay; R&D Systems), we measured serum angiogenin levels in 77 previously untreated Binet stage A B-cell chronic lymphocytic leukemia (CLL) patients. No difference in angiogenin serum levels could be found between patients (median: 295 ng/mL; range: 74-1700) and 15 age- and sex-matched healthy controls (median: 264 ng/mL; range: 29-1835) (P = NS; Mann-Whitney test). Increased angiogenin serum level was associated with higher LDH (P = 0.03) and beta2-m (P = 0.007) concentrations. However, angiogenin did not reflect the extent of bone marrow (BM) angiogenesis as evaluated by microvessel area (P = 0.611), circulating levels of vascular endothelial growth factor (VEGF) (P = 0.873) and basic fibroblastic growth factor (FGF-2) (P = 0.421). When the 25 patients with available data were stratified into the four major cytogenetic categories (normal karyotype, 13q as a sole aberration, 12q trisomy, 11q or 17p deletion) and aberrations were compared with angiogenin serum levels, no correlation was found (P = 0.651; Kruskall-Wallis test). A cut-off of angiogenin serum level corresponding to median (i.e. 330 ng/mL) or higher identified later upstaging and longer progression-free survival (PFS). The 5-yr PFS was 51.5% for patients with angiogenin levels lower than median and 85% for patients with higher values [P = 0.03; hazard ratio (HR) = 2.86; 95% CI: 1.08-6.72]. Although in multivariate analysis only Rai substages (P = 0.00001) and peripheral blood lymphocytosis (P = 0.009) retained their prognostic significance, angiogenin could be incorporated into the Rai substages thus leading to the identification of the following risk categories: (i) stage 0 (angionenin >330 ng/mL); (ii) stage 0 (angiogenin <330 ng/mL) + stage I-II (angiogenin >330 ng/mL); and (iii) stage I-II (angiogenin <330 ng/mL). The 40-month PFS were as follows: 85%, 65%, 25% (chi(2) for trend = 6.33; d.f. = 1; P = 0.01). In conclusion, serum angiogenin levels although not increased in comparison with healthy controls, may predict clinical outcome of patients with early CLL and help to refine Rai's stratification.

Angiogenesis in acute and chronic lymphocytic leukemia.

The bone marrow microenvironment plays a crucial role in leukemogenesis. Recent studies suggest that its vascularity changes significantly during this process and that angiogenic factors are of major importance in leukemia. This review summarizes the literature concerning the relationship between angiogenesis and the progression of acute and chronic lymphocytic leukemia. It is becoming increasingly evident that agents which interfere with angiogenesis also block tumor progression and anti-angiogenic management has become a prominent aspect of pre-clinical and clinical assessment. Recent applications of anti-angiogenic agents which interfere with or block leukemia progression are reviewed.

Increased serum levels of matrix metalloproteinase-9 predict clinical outcome of patients with early B-cell chronic lymphocytic leukaemia.

BACKGROUND AND METHODS: Serum levels of matrix metalloproteinase-9 (MMP-9) which agree with progression in solid and haematological tumours were correlated to the risk of disease progression in 62 patients with early (Binet stage A) B-cell chronic lymphocytic leukaemia (CLL). Sera were taken at diagnosis and tested by an enzyme-linked immunosorbent assay. RESULTS: MMP-9 levels positively correlated with haemoglobin levels (P = 0.03) and platelet count (P = 0.03). No association was found with main clinico-haematological features representative of tumour mass, such as peripheral blood lymphocytosis, bone marrow histology, Rai substages and beta-2 microglobulin (beta-2m). A cut-off of MMP-9 levels corresponding to 33rd percentile (203 ng/mL) or higher identified earlier upstaging and shorter progression-free survival. MMP-9 was a significant prognostic marker in multivariate analysis and partially independent of Rai substages, which suggests its inclusion into such a staging system to better stratify prognostically Rai stages I and II patients. CONCLUSIONS: MMP-9 serum levels predict disease behaviour and help to refine the prognosis of stage A CLL patients.

Prognostic value of enhanced bone marrow angiogenesis in early B-cell chronic lymphocytic leukemia.

Because tumor progression is angiogenesis-dependent, angiogenesis density was investigated by immunohistochemistry and computed image analysis in bone marrow (BM) biopsies of 45 newly diagnosed patients with Binet stage A B-cell chronic lymphocytic leukemia (BCLL) and correlated to upstaging and progression-free survival during a 40-month follow-up period. Their microvessel areas and counts were significantly higher than those of patients with anemia due to iron or vitamin B(12) deficiencies. A cutoff value of 0.90 mm(2) x 10(-2) or greater of the microvessel area identified patients with earlier upstaging and shorter progression-free survival. When the cutoff was applied to the Rai subclassification, both Rai 0 and Rai I-II patients who upstaged and shortened the progression-free survival were classified correctly. Information of this type was not given by the microvessel counts. The cutoff did not correlate with other predictors representative of tumor mass or disease progression. The microvessel area correlated with the expression of angiogenic vascular endothelial growth factor (VEGF) by tumor tissue, and serum levels of VEGF were found to be of prognostic value. A causal relationship between risk of progression and BM angiogenesis in BCLL is suggested. A risk stratification inside Rai is proposed. The prognostic usefulness of BM angiogenesis in patients with BCLL is envisaged.