Bevacizumab Reduces VEGF Expression in Patients with Relapsed and/or Refractory Acute Myeloid Leukaemia (AML) without Clinical Antileukemic Activity.

Abstract

Angiogenesis is required for tumor growth and metastasis and is an attractive target for cancer therapy. Because of its pivotal role in tumorassociated angiogenesis across a wide range of malignancies, vascular endothelial growth factor-A (VEGF-A) has emerged as a central therapeutic target in cancer.Neoangiogenesis has been shown to play an important role in the pathogenesis of AML (Padro et al., Blood 2000) and antiangiogenic therapy could constitute a novel strategy for its treatment (Mesters et al., Blood 2001). Autocrine and paracrine secretion of vascular endothelial growth factor (VEGF) in the bone marrow may promote proliferation and survival of leukemic blasts (Fiedler et al., Blood 1997). This concept represented the rationale for the therapeutic application of bevacizumab (BV), a recombinant humanised monoclonal antibody against VEGF, in patients with advanced AML after failure of standard treatment. Nine patients (median age 63 years; range 46–81 years) with relapsed and/or refractory AML not judged medically fit for further intensive chemotherapy were enrolled in this study. All patients received at least one cycle of BV (10 mg/kg body weight), 5 patients received 2 cycles (days 1 and 14) and 2 patients a 3rd cycle (day 35). Treatment was well tolerated, without treatment-related side effects. Two patients had to be withdrawn from drug administration after cycle one due to progressive disease. After treatment with BV none of the patients fulfilled the criteria of a partial response, defined as the clearance of at least 50 % marrow blasts accompanied by increases in platelet counts and haemoglobin values. The level of VEGF expression in the bone marrow determined by immunohistochemistry significantly decreased during treatment with BV (before BV treatment: median of 3.78 arbitrary units (AU) [range 1.5–5.8 AU]; after BV treatment: median of 2.57 AU [range 1.3–5.0 AU]; Wilcoxon test, P<0.05). In contrast, VEGFR-2 expression by leukemic blasts and bone marrow microvessel density did not change significantly. In conclusion, single agent BV has no significant antileukemic activity in relapsed and/or refractory AML.