Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412

Abstract

Leukemic cells from 30% of patients with acute myeloid leukemia (AML) have an activating mutation in the FLT3 (fms-like tyrosine kinase) gene, which represents a target for drug therapy. We treated 20 patients, each with mutant FLT3 relapsed/ refractory AML or high-grade myelodysplastic syndrome and not believed to be candidates for chemotherapy, with an FLT3 tyrosine kinase inhibitor, PKC412 (N-benzoylstaurosporine), at a dose of 75 mg 3 times daily by mouth. The drug was generally well tolerated, although 2 patients developed fatal pulmonary events of unclear etiology. The peripheral blast count decreased by 50% in 14 patients (70%). Seven patients (35%) experienced a greater than 2-log reduction in peripheral blast count for at least 4 weeks (median response duration, 13 weeks; range, 9-47 weeks); PKC412 reduced bone marrow blast counts by 50% in 6 patients (2 of these to < 5%).

The multikinase inhibitor midostaurin (PKC412A) lacks activity in metastatic melanoma: a phase IIA clinical and biologic study

“…Our results are in contrast to those obtained with midostaurin in AML where inhibition of autophosphorylation of mutated Flt-3 was documented in leukaemic blasts isolated from patients receiving midostaurin (Stone et al, 2005). In 70% of AML patients, there was a 50% reduction of peripheral blood blast cells, and in 25% of patients a 50% reduction in bone marrow blast cells.…”

“…After the start of this trial, the final report of a Phase I study (Propper et al, 2001) suggested 75 mg bid (150 mg day À1 ) as more tolerable midostaurin dosing for longterm administration. However, a recent Phase II trial of midostaurin to inhibit activated Flt3 kinase in acute myeloid leukaemia (AML) found 225 mg day À1 well-tolerated and had promising activity (Stone et al, 2005).…”

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth

“…The non-linear pharmacokinetics of CGP62221 follows the same pattern as that of midostaurin, whereas the second metabolite, CGP52421, rises over time until reaching steady-state concentrations after one month of daily treatment (33)(34)(35)(36)(37). Our data show that CGP52421 is less effective in producing growth inhibition and apoptosis in neoplastic MC when compared to midostaurin.…”

“…A remarkable phenomenon is that even in patients who have resistant disease or relapse, mediator-related symptoms improve or disappear during therapy (30). treatment, followed by a significant decrease, before reaching a stable plateau after 3-4 weeks (33)(34)(35)(36)(37). The drug has two active metabolites (Supplementary Figure S1), which result from cytochrome CYP3A4-mediated oxidation of the parent-drug (36,37).…”

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

“…[107][108][109][110] PKC412 showed potential in phase-I/II trials of adult AML. 111 An international pediatric relapsed AML phase-II trial with PKC412 is currently ongoing.…”