Functional Properties of <i>KIT</i> Mutations Are Associated with Differential Clinical Outcomes and Response to Targeted Therapeutics in CBF Acute Myeloid Leukemia.

Abstract

<i>KIT</i> mutations (<i>KIT</i> ⁺) 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 <i>KIT</i> mutations in CBF pediatric AML. 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 [<i>KIT</i> ⁺ vs. wild-type <i>KIT</i> (<i>KIT</i> ^-)] and mutation location (E8 vs. E17). <i>KIT</i> mutations were detected in 63 of 205 patients (31%); 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 affected growth of E17, but not E8, transfected cells. Patients with <i>KIT</i> ⁺ CBF AML had overall survival similar to those with <i>KIT</i> ^- (78% vs. 81%, <i>P</i> = 0.905) but higher relapse rates (RR = 43% vs. 21%; <i>P</i> = 0.005). E17 <i>KIT</i> ⁺ outcomes were inferior to <i>KIT</i> ^- patients [disease-free survival (DFS), 51% vs. 73%, <i>P</i> = 0.027; RR = 21% vs. 46%, <i>P</i> = 0.007)], although gemtuzumab ozogamicin abrogated this negative prognostic impact. E8 mutations lacked significant prognostic effect, and GO failed to significantly improve outcome. E17 mutations affect prognosis in CBF AML, as well as response to GO and TKIs; thus, clinical trials using both agents should be considered for <i>KIT</i> ⁺ patients.