D816 mutation of the KIT gene in core binding factor acute myeloid leukemia is associated with poorer prognosis than other KIT gene mutations

Abstract

The clinical impact of KIT mutations in core binding factor acute myeloid leukemia (CBF-AML) is still unclear. In the present study, we analyzed the prognostic significance of each KIT mutation (D816, N822K, and other mutations) in Japanese patients with CBF-AML. We retrospectively analyzed 136 cases of CBF-AML that had gone into complete remission (CR). KIT mutations were found in 61 (45%) of the patients with CBF-AML. D816, N822K, D816 and N822K, and other mutations of the KIT gene were detected in 29 cases (21%), 20 cases (15%), 7 cases (5%), and 5 cases (4%), respectively. The rate of relapse-free survival (RFS) and overall survival (OS) in patients with D816 and with both D816 and N822K mutations was significantly lower than in patients with other or with no KIT mutations (RFS: p < 0.001, OS: p < 0.001). Moreover, stratified analysis of the chromosomal abnormalities t(8;21)(q22;q22) and inv(16)(p13.1q22), t(16;16)(p13.1;q22) showed that D816 mutation was associated with a significantly worse prognosis. In a further multivariate analysis of RFS and OS, D816 mutation was found to be an independent risk factor for significantly poorer prognosis. In the present study, we were able to establish that, of all KIT mutations, D816 mutation alone is an unfavorable prognostic factor.

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

“…We also provide biologic rationale for the discrepancies in clinical outcomes observed, demonstrating the functional significance of activating E17 abnormalities. The recent study by Yui and colleagues supports our findings demonstrating in adult CBF AML, that only E17 mutations conferred inferior prognosis, with the D816 mutation demonstrating the strongest impact on prognosis (25). Kim and colleagues also reported on the adverse prognostic impact of D816 mutations, which were most pronounced in t(8;21) AML (39).…”

“…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).…”

Usefulness of BCOR gene mutation as a prognostic factor in acute myeloid leukemia with intermediate cytogenetic prognosis

“…The fact that our subjects were exclusively Japanese means that caution is required in the interpretation of the results. In the KIT gene, the N822 mutation has been reported to occur at high frequency in Japanese subjects . We suggest that BCOR mutations may similarly have a high rate of incidence in the Japanese population.…”

Heterogeneous prognosis among KIT mutation types in adult acute myeloid leukemia patients with t(8;21)

“…A reflection is that the existence of the KIT mutation brings t(8;21) AML from low to intermediate risk regardless of mutation type in the National Comprehensive Cancer Network guidelines 8 , whereas European LeukemiaNet has provided no further recommendation for those with a KIT mutation 9 . Recently, Yui et al 10 showed that the D816 mutation had a poorer prognosis than other mutations. Thus, it is urgent to perform large-scale studies under modern treatment modes to comprehensively evaluate the prognoses of the individual KIT mutation types.…”