Preliminary clinical activity of TP- 0903 in relapsed or refractory acute myeloid leukemia with FLT3-ITD mutations
Acute myeloid leukemia (AML) patients with FMS-like tyrosine kinase 3 internaltandem duplication (FLT3-ITD) experience shorter disease-free survival and highrelapse rates even with FLT3 inhibitor therapy. One of the main mechanisms forloss of response is the acquisition of molecular mutations that confer drugresistance to FLT3 inhibitors. TP-0903 is an oral multi-kinase inhibitor withactivity against FLT3 and several other kinases known to mediate drugresistance. Three heavily treated relapsed/refractory AML patients with FLT3-ITD were treated with TP-0903 50 mg daily, on a phase 1b/2 clinical trial, for aslong as disease response or clinical benefit was observed. The dose for one Q6patient was reduced to 37 mg daily mid-cycle after developing grade 3 nauseathat improved to grade 2 within 24 h of discontinuing the drug. All patientsachieved stable disease; however, a significant reduction in bone marrow blastpercentage after one to two cycles of treatment was observed in two patients,which correlated with a decrease in FLT3-ITD allelic ratio and variant allelefrequency of co-occurring mutations (e.g., NPM1 and DNMT3A). TP-0903 wasfeasible with no unusual toxicity signals. Additional preclinical and clinical studiesare needed in order to determine the role of TP-0903 in AML.