Neoangiogenesis has been shown to play an important role in the pathogenesis of acute myeloid leukemia (AML). Autocrine and paracrine secretion of angiogenic and hematopoietic growth factors such as vascular endothelial growth factor (VEGF) and stem cell factor (SCF) in the bone marrow microenvironment may promote proliferation and survival of leukemic blasts. This concept represented the rationale for the initiation of a multicenter phase 2 trial of SU5416, a small molecule inhibitor of phosphorylation of VEGF receptors 1 and 2, c-kit, the SCF receptor, and fms-like tyrosine kinase-3 (FLT3) in patients with advanced AML. Entered into the study were 43 patients with refractory AML or elderly patients not judged medically fit for intensive induction chemotherapy; 42 patients received at least one dose of study drug. Treatment was generally well tolerated, with nausea, headache, and bone pain the most frequent treatment-related side effects. One patient had a morphologic remission (French-American-British [FAB] criteria of complete response without normalization of blood neutrophil and platelet counts) lasting for 2 months. There were 7 patients who achieved a partial response (reduction of blasts by at least 50% in bone marrow and peripheral blood) lasting 1 to 5 months. Patients with AML blasts expressing high levels of VEGF mRNA by quantitative polymerase chain reaction (PCR) had a significantly higher response rate and reduction of bone marrow microvessel density than patients with low VEGF expression consistent with the antiangiogenic effects of SU5416.
In two multicenter trials, a total of 576 patients with acute myeloid leukemia (AML) were treated and found to be evaluable. Two hundred forty-two patients were in a 1978 pilot study and 334 patients were in a 1982 randomized study. Ages were between 15 and 78 years (median, 48). The uniform remission induction therapy in both studies consisted of one to two courses of a 9-day combination of 6-thioguanine (TG) with cytosine arabinoside (ARA-C) and daunorubicin (DNR) [TAD9]. The timing and sequencing of TAD9 was designed according to cell kinetic effects of ARA-C. A complete remission (CR) was achieved in 65% (70% and 61%, respectively) of patients within a median of 33 days, and in 68% of responders after only one course. The CR rate in patients 60 to 78 years of age was 51% (66% and 39%, respectively). In the 1978 pilot study, different protocols of post-remission treatment were applied at the different centers: monthly 5-day maintenance, TAD9 consolidation, both consolidation and maintenance, or no further therapy. The group receiving treatment during CR showed 24% probability of remissions at 4 years v 0% probability of remissions in the untreated group. Between the different post-remission protocols, no significant differences were observed. Remission duration was not influenced by age, WBC, or morphologic cell type, but was longer in patients achieving CR within 30 days (P = .017). In the subsequent 1982 study, 145 patients in CR were randomized for TAD9 consolidation with or without monthly maintenance. The updated life-table analysis revealed a predicted rate of continuous remission at 2 1/2 years of 30% for the maintenance and 17% for the nonmaintenance arm (P = .003). These results of response and remission duration in adult patients of all ages support the validity of intensified induction therapy and of consequent myelosuppressive treatment in remission.
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