AML beyond the boundaries of daunomycin and cytarabine

Since the introduction of the anthracyclins and cytarabine some decades ago, there has been little progress in remission induction therapy of acute myeloid leukemia (AML). Genetic lesions in AML uncovered by molecular analysis provide opportunities for therapeutic targeting. AML cells express growth factor receptors that contain kinases or activate kinases downstream within the cell. These kinases offer potential targets for intervention as well. VEGFR-2 (vascular endothelial growth receptor type 2) and the hematopoietic growth factor receptors KIT (for stem cell factor) and FLT3 (FMS-like tyrosine kinase 3) are prototypes of receptors with intrinsic kinase activity expressed on AML blasts. These receptors have been implicated in autocrine and paracrine pathogenetic mechanisms of growth of AML. Activating mutations in the FLT3 and KIT receptors may be acquired during the evolution of AML. FLT3 and KIT mutations constitutively induce growth signals (in the absence of growth factor) and therefore define additional conditions suitable for therapeutic targeting. The most common form of FLT3 mutations (FLT3 internal tandem duplications) occurs in 20%-30% of cases and defines an aggressive form of AML that has a high rate of recurrence (see, eg, Gilliland et al, Rev Curr Opin Hematol. 2002;9:274-281). Similarly, mutations in KIT confer negative prognostic impact in subsets of AML (Care et al, Br J Haematol. 2003;121:775-777).

SU5416 is an indoline compound that may abrogate the signaling of activated kinase receptors and lead the leukemic cells into apoptosis (see, eg, Levis et al, Blood. 2002;99:3885-3891; Yee et al, Blood. 2002; 100:2941-2949). SU5416 blocks not only kinase activity of VEGF-R2 but also KIT and FLT3 receptors, wild-type as well as mutant. In this issue, Giles and colleagues (page 795) report on a phase 2 study of SU5416. The investigators present the toxicity and pharmacokinetic profiles and report 4 responses among 56 patients with refractory and relapsed AML and MDS. Whether these responses classify SU5416 as a candidate of sufficient interest for further development is presently unclear. The investigators noted no complete responses, but their series comprised highly unfavorable AMLs, with several patients not completing the treatment plan. Further, in order to understand the efficacy of the inhibitor, one would like to correlate the clinical responses with the level of abrogated signaling and induced cell kill of the patients' primary cells by SU5416 in vitro. Also, one would like to know about the presence of genetic abnormalities (eg, FLT3 mutations) in this series. This correlative documentation is not given. The study is exemplary of the laboratory and clinical orchestrated development of various kinase inhibitors that is currently in full swing at several research sites. One hopes these intense investigational activities will advance AML therapeutics toward new boundaries.