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 a ngiogenesis in the pathophysiology of hematologic malignancies as well. Rec ently, we and others have reported increased angiogenesis in the bone marro w of patients with acute myeloid leukemia (AML) and normalization of bone m arrow 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 form ation of new microvessels. Among these, VEGF (vascular endothelial growth f actor), FGF (fibroblast growth factor) and angiopoietins play a pivotal rol e in the induction of neovascularization in solid tumors. These cytokines s timulate migration and proliferation of endothelial cells and induce angiog enesis in vivo. Recent data suggest an important role for these mediators i n hematologic malignancies as well. Isolated AML blasts overexpress VEGF an d VEGF receptor 2. Thus, the VEGF/VEGFR-2 pathway can promote the growth of leukemic blasts in an autocrine and paracrine manner. Therefore, neovascul arization and angiogenic mediators/receptors may be promising targets for a nti-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 usi ng a combination of thalidomide with hyperfractionated cyclophosphamide and dexamethasone (Hyper-CDT), we observed a partial remission in 12 of 14 eva luable patients (86%). Thus, this combination seems to be very potent. Furt hermore, we evaluated the safety and efficacy of thalidomide in patients wi th AML not qualifying for intensive cytotoxic chemotherapy. 20 patients age d 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 (medi an 6) weeks, dependent on the individual tolerability of the drug. In 4 pat ients we observed a partial response (PR - defined as more than 50% reducti on in leukemic blast infiltration in the bone marrow). This was accompanied by an increase in platelet counts and hemoglobin values. One additional pa tient showed a significant improvement of peripheral blood counts without f ulfilling the criteria of a PR. In parallel, we observed a significant decr ease in microvessel density in these 5 patients during treatment with thali domide. 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 i mportant role in AML. Therefore, receptor tyrosine kinase inhibitors like S U5416 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 secon d relapse of her AML refractory towards chemotherapy by administration of S U5416 (compassionate use), a tyrosine kinase inhibitor of VEGFR-2 and c-kit . Current and future studies will clarify the role of anti-angiogenic treat ment strategies in AML and other hematologic malignancies.