Functional properties of KIT mutations are associated with differential clinical outcomes and response to targeted therapeutics in CBF acute myeloid leukemia

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