[Angiogenesis in patients with hematologic malignancies]

Abstract

Angiogenesis in Patients with Hematologic Malignancies The importance of angiogenesis for the progressive growth and viability of solid tumors is well established. Emerging data suggest an involvement of angiogenesis in the pathophysiology of hematologic malignancies as well. Recently, we and others have reported increased angiogenesis in the bone marrow of patients with acute myeloid leukemia (AML) and normalization of bone marrow microvessel density when patients achieved a complete remission (CR) after induction chemotherapy. Tumor angiogenesis depends on the expression of specific mediators that initiate a cascade of events leading to the formation of new microvessels. Among these, VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor) and angiopoietins play a pivotal role in the induction of neovascularization in solid tumors. These cytokines stimulate migration and proliferation of endothelial cells and induce angiogenesis in vivo. Recent data suggest an important role for these mediators in hematologic malignancies as well. Isolated AML blasts overexpress VEGF and VEGF receptor 2. Thus, the VEGF/VEGFR-2 pathway can promote the growth of leukemic blasts in an autocrine and paracrine manner. Therefore, neovascularization and angiogenic mediators/receptors may be promising targets for anti-angiogenic and anti-leukemic treatment strategies. The immunomodulatory drug thalidomide inhibits angiogenesis in animal models. Moreover, it has significant activity in refractory multiple myeloma. In a current phase II study for patients with primary refractory or relapsed multiple myeloma using a combination of thalidomide with hyperfractionated cyclophosphamide and dexamethasone (Hyper-CDT), we observed a partial remission in 12 of 14 evaluable patients (86%). Thus, this combination seems to be very potent. Furthermore, we evaluated the safety and efficacy of thalidomide in patients with AML not qualifying for intensive cytotoxic chemotherapy. 20 patients aged 58-85 (median 69) years were recruited to this phase I/II study and were treated with a dose of 200-400 mg per os daily for a duration of 1-40 (median 6) weeks, dependent on the individual tolerability of the drug. In 4 patients we observed a partial response (PR - defined as more than 50% reduction in leukemic blast infiltration in the bone marrow). This was accompanied by an increase in platelet counts and hemoglobin values. One additional patient showed a significant improvement of peripheral blood counts without fulfilling the criteria of a PR. In parallel, we observed a significant decrease in microvessel density in these 5 patients during treatment with thalidomide. In conclusion, thalidomide seems to have anti-angiogenic as well as anti-leukemic activity in AML. The VEGF/VEGFR-2 pathway seems to play an important role in AML. Therefore, receptor tyrosine kinase inhibitors like SU5416 or SU6668 are currently evaluated in the context of phase II studies in AML. We could recently induce a stable remission in a patient with second relapse of her AML refractory towards chemotherapy by administration of SU5416 (compassionate use), a tyrosine kinase inhibitor of VEGFR-2 and ckit. Current and future studies will clarify the role of anti-angiogenic treatment strategies in AML and other hematologic malignancies.