KITmutations correlate with adverse survival in children with core-binding factor acute myeloid leukemia

Abstract

The prevalence and clinical relevance of KIT mutations in childhood core-binding factor (CBF) acute myeloid leukemia (AML) have not been well characterized. In this study, a total of 212 children with de novo AML were enrolled from a Chinese population and 50 (23.5%) of the patients were deemed CBF-AML. KIT mutations were identified in 30% of the CBF-AML cohort. The KIT mutations were clustered in exon 17 and exon 8, and KIT mutations in exons 8 and 17 were correlated with a shorter overall survival (OS) (5-year OS: 30.0 ± 14.5% vs. 73.0 ± 8.5%, p = .007) and event-free survival (EFS) (5-year EFS: 30.0 ± 14.5% vs. 73.0 ± 8.5%, p = .003). Multivariate analysis revealed KIT mutations as an independent risk factor in CBF-AML. Our results suggest that KIT mutations are a molecular marker for an inferior prognosis in pediatric CBF-AML.

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

“…Unlike the study by Klein and colleagues and our previous study cohort, the uniform conventional chemotherapy backbone used in this study cohort may have facilitated our ability to detect differences in outcome for KIT þ disease. Similar to the 4 other pediatric studies in which prognostic significance was noted (17,22,27,45), our study Association of E17 mutations with outcomes in CBF AML. A, DFS in CBF patients for KIT E17 þ compared with KIT À patients.…”

“…A second recent meta-analysis by Chen and colleagues found that outcomes were inferior in KIT þ CBF AML overall, and specifically in KIT þ t(8;21) (15). Four additional pediatric studies found that KIT mutations adversely affected OS, DFS, and RR in pediatric t(8;21) AML (17,22,27,45). Conversely, a more recent series of t(8;21) pediatric patients with CBF AML enrolled on multiple cooperative group clinical trials failed to demonstrate prognostic significance of KIT þ disease (2).…”

“…Data regarding the prognostic significance of KIT þ CBF AML is conflicting, particularly in children. While some pediatric and dual adult/pediatric studies have failed to show a prognostic impact (2,20,21,23,24), other pediatric series and meta-analyses dispute such findings, suggesting prognostic impact may differ in the context of certain KIT mutations or cytogenetic subgroups (15,17,22,(25)(26)(27).…”

KIT is required for fetal liver erythropoiesis but dispensable for angiogenesis

“…In agreement with our observation that KIT promotes erythroid at the expense of myeloid cell fate, gain-of-function mutations in the Kit coding sequence have been described to trigger clonal expansion of malignant pro-erythroblasts in murine erythroleukemia (Kosmider et al, 2005). Moreover, gain-of-function mutations have been associated with human adult and pediatric core binding factor acute myeloid leukemia (CBF-AML), for which KIT mutations are poor prognostic factors (Cairoli et al, 2006;Chen et al, 2018;Krauth et al, 2014). It should therefore be investigated whether KIT mutations also contribute to human erythroleukemia.…”

Core‐binding factor acute myeloid leukemia with t(8;21): Risk factors and a novel scoring system (I‐CBFit)

“…KIT D816V mutations were reported in 4%‐28% and strongly associated with poorer DFS (6%‐48%) . In pediatric populations, KIT mutations clustered in exon 17 and exon 8 were identified in 20‐30% of the CBF‐AML patients, yet its effect on prognosis is not agreed upon . A meta‐analysis indicated KIT mutation increased relapse risk (RR at 2 years 1.76 [95% CI: 1.45‐2.12]) and decreased OS 1.35 (95% CI: 1.09‐1.66) …”