FLT3 target practice

Comment on Levis et al, page 1145, and on Li et al, page 1137

Preclinical data are reported that provide novel approaches to targeting the transmembrane FMS-like tyrosine kinase 3 (FLT3) in acute myeloid leukemia (AML) by combining a small molecule inhibitor of FLT3 (CEP-701) with chemotherapy in a carefully derived schedule and by use of anti-FLT3 antibody.

The mutated FLT3 tyrosine kinase is a well-validated target in AML. Activating mutations (either a 3– to greater-than-40–amino acid repeat in the juxtamembrane region [internal tandem duplication or ITD] or an activating loop mutation, typically D835Y) confer growth factor independence in leukemic cell lines and can cause a fatal myeloproliferative syndrome in a murine bone marrow transplant model. These mutations occur in about 30% of patients with AML and are associated with an inferior prognosis (reviewed in Gilliland and Griffin¹  and Levis and Small² ).

Several orally bioavailable small molecules (ie, PKC412,³  MLN 578,⁴  and CEP-701⁵ ) that inhibit activated FLT3 are being evaluated for safety and clinical efficacy in patients with AML whose blasts contain such a FLT3 mutation. Early results suggest that each of these agents has biologic activity in mutant FLT3 AML. In some patients the peripheral blast count decreases, and in a small number the degree of marrow leukemia infiltration declines. Of the first 20 patients with mutant FLT3 AML who received PKC-412, 7 had at least 2-log reduction in the peripheral blast count (1 of whom essentially achieved complete remission [CR]).³  Of 14 similar patients receiving an adequate dose of CEP-701, 5 experienced a reduction in the blast count, albeit for less than 3 months.⁵  In both trials, ancillary studies documented target inhibition insofar as FLT3 autophosphorylation was decreased. However, since each FLT3 inhibitor also affects other kinases, it is not possible to conclusively link response to FLT3 inhibition, allowing for the possibility that inhibition of other targets could be important.FIG1 

While the initial results are exciting because of the bench-to-bedside flow of the effort, it is definitely time to go back to the bench to determine novel methods to increase the magnitude and duration of the response with the oral FLT3 inhibitors. There are 2 studies published in this issue of Blood that represent preclinical efforts that will lead to additional FLT3-targeted clinical trials in AML.

Investigators at Johns Hopkins (Levis and colleagues) have taken the appropriate step of combining their novel FLT3 inhibitor, CEP-701, with other agents known to be useful in AML, namely daunorubicin, cytarabine, mitoxantrone, and etoposide. As was hoped, their in vitro studies with FLT3/ITD-expressing cell lines and with primary mutant FLT3 AML blasts demonstrated that the chemotherapeutic agents and CEP-701 act synergistically. However, it was important that the FLT3 inhibitor was administered after chemotherapy began. Pretreatment with CEP-701 was antagonistic, presumably by causing cell cycle arrest, thereby preventing the cell-cycle active drugs from being effective. These results have obvious implications for clinical trials now ongoing or planned that combine a FLT3 inhibitor with antileukemic chemotherapy.

Signaling via FLT3 is probably important in maintaining the leukemogeneic state in the one-third of AMLs that harbor a FLT3 mutation and could be relevant even in the remainder of cases, most of which at least express this molecule. Interruption of such signaling either by small molecules or with a neutralizing antibody, as accomplished by investigators at Im-Clone Systems (Li and colleagues), may be a therapeutic avenue. The human IMC-EB10 antibody binds to FLT3 and prevents FLT3 ligand–mediated signaling in wild-type cells and autonomous FLT3-mediated signaling in mutant FLT3 leukemia cells. This effect was translated into antileukemia efficacy and a survival benefit in both FLT3-dependent and -independent murine leukemias. It remains unclear why this agent would suppress leukemias that do not clearly depend on FLT3 activation for growth. Nonetheless, taken together these studies provide hope that targeting FLT3 in AML could yield a bountiful harvest of therapeutic success.