Adverse Prognostic Significance of KIT Mutations in Adult Acute Myeloid Leukemia With inv(16) and t(8;21): A Cancer and Leukemia Group B Study

Abstract

We report for the first time that mutKIT, and particularly mutKIT17, confer higher relapse risk, and both mutKIT17 and mutKIT8 appear to adversely affect OS in AML with inv(16). We also confirm the adverse impact of mutKIT on relapse risk in t(8;21) AML. We suggest that patients with core-binding factor AML should be screened for mutKIT at diagnosis for both prognostic and therapeutic purposes, given that activated KIT potentially can be targeted with novel tyrosine kinase inhibitors.

Old and new prognostic factors in acute myeloid leukemia with deranged core‐binding factor beta

“…Similarly, regarding the impact on outcome, this research article study showed that KIT mutations did not reach a significative value as independent prognostic factor for relapse and survival neither in the multivariate nor in the Kaplan-Meier analysis, in contrast to those reported in adult patients with t(8;21) (Figs. 1B-2B; Tables III and IV) [24,[26][27][28][30][31][32].…”

“…Retrospective studies have demonstrated that the presence of KIT mutations in exon 17 have been associated with a poor outcome in CBF-AML and, for that reason, KIT mutation testing has been recently incorporated into National Cancer Guidelines to better stratify such patients in different prognostic subgroups [25]. However, while several studies showed that activating KIT mutations confer a significantly lower survival in AML with t(8;21)(q22;q22), the negative prognostic impact of KIT mutations in CBFb-AML remains controversial [24,[26][27][28][29][30][31][32][33].…”

Acute myeloid leukemia—Major progress over four decades and glimpses into the future

“…Some studies suggested that KIT or multiple mutations may confer adverse prognosis in CBF AML [40,70]. This has not been our experience with the FLAG-Ida/GO, where the efficacy of the regimen may have overcome the adverse impact of the mutations.…”

“…Mutations of epigenetically related molecular events (DNMT3A, IDH1/2, TET2, ASXL1, and MLL) may suggest the possible benefit of epigenetictargeted therapy. In CBF AML, mutations in c-KIT have been reported to be associated with an adverse prognosis in some series [39][40][41]. The addition of a c-KIT inhibitor (dasatinib) to chemotherapy may have therapeutic benefits in c-KIT-mutated CBF AML [42].…”

Targeted next generation sequencing of clinically significant gene mutations and translocations in leukemia

“…Although mutations in commonly tested genes involving AML prognosis such as FLT3 and NPM1 tend to have a limited spectrum of mutations, making them amenable to PCR-based testing, the broader range of mutations in genes such as CEPBA, DNMT3A, and KIT necessitates the use of direct sequencing, adding to the expense and turn-around time of testing. 5,[10][11][12] The detection of recurrent, balanced chromosomal translocations is critical to leukemia prognosis and is generally done by FISH and G-banded cytogenetics, relying on direct visualization of DNA. Although FISH offers increased sensitivity over conventional cytogenetics, the identification of novel translocation partners, such as those involving the MLL locus, or variant breakpoints requires the use of multiple probes, again increasing the cost and complexity of testing.…”