Functional Properties of KIT Mutations are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia

Clinical Cancer Research Online First Ar.. by Tarlock, K., Alonzo, T. A., Wang, Y.. - 2h ago Preview

 
 
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Purpose:KIT mutations (KIT+) are common in core binding factor (CBF) AML and have been associated with varying prognostic significance. We sought to define the functional and clinical significance of distinct KITmutations in CBF pediatric AML. Experimental Design: Following transfection of exon 17 (E17) and exon 8 (E8) mutations into HEK293 and Ba/F3 cells, KIT phosphorylation, cytokine independent growth, and response to tyrosine kinase inhibitors (TKI) were evaluated. Clinical outcomes of patients treated on COG AAML0531 (NCT01407757), a phase III study of gemtuzumab ozogamicin (GO), were analyzed according to mutation status (KIT+ vs wild type KIT (KIT-)) and mutation location (E8 vs. E17). Results: KIT mutations were detected in 63/205(31%) patients; 22 (35%) involved only E8, 32(51%) only E17, 6(10%) both exons, and 3(5%) alternative exons. Functional studies demonstrated that E17, but not E8, mutations result in aberrant KIT phosphorylation and growth. TKI exposure significantly impacted growth of E17, but not E8, transfected cells. KIT+ CBF AML patients had comparable overall survival (OS) to that of KIT- (78%, vs. 81%, p=0.905) but higher relapse rates (RR 43% vs. 21%, p=0.005). E17 KIT+ outcomes were inferior to KIT- patients [disease free survival (DFS) 51% vs. 73%, p=0.027; RR 21% vs. 46%, p=0.007)] although GO abrogated this negative prognostic impact. E8 mutations lacked significant prognostic impact and GO failed to significantly improve outcome. Conclusions: E17 mutations impact prognosis in CBF AML, as well as response to GO and TKIs, thus clinical trials utilizing both agents should be considered for KIT+ patients.