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

Katherine Tarlock, Todd A. Alonzo, Yi Cheng Wang, Robert B. Gerbing, Rhonda Ries, Michael R. Loken, Laura Pardo, Tiffany Hylkema, Jason Joaquin, Leela Sarukkai, Susana C. Raimondi, Betsy Hirsch, Lillian Sung, Richard Aplenc, Irwin Bernstein, Alan S. Gamis, Soheil Meshinchi, Jessica A. Pollard

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30 Scopus citations


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 KIT mutations 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 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 KIT + CBF AML had overall survival similar to those with 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 gemtuzumab ozogamicin abrogated this negative prognostic impact. E8 mutations lacked significant prognostic effect, and GO failed to significantly improve outcome.

CONCLUSIONS: 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 KIT + patients.

Original languageEnglish (US)
Pages (from-to)5038-5048
Number of pages11
JournalClinical Cancer Research
Issue number16
StatePublished - Aug 15 2019

Bibliographical note

Funding Information:
This research was supported by the following funding: St. Baldrick's Career Development Award (to J.A. Pollard), Hyundai Hope On Wheels (to J.A. Pollard, K. Tarlock), St. Baldrick's Scholar Award (to K. Tarlock), COG Chairs grant U10 CA180886-01 and U10CA98543, NCTN Statistics and Data Center Grant D, NCI R01 CA 114563 (to S. Meshinchi), Andrew McDonough B+ Foundation, and St. Baldrick's Foundation.

Publisher Copyright:
© 2019 American Association for Cancer Research.

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