Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study

Abstract

Distinct forms of tyrosine kinase domain (TKD), juxtamembrane domain, exon 8, and internal tandem duplication (ITD) mutations of c-KIT, were observed in about 46% of core binding factor leukemia (CBFL) patients. To evaluate their prognostic significance, 67 adult patients with CBFL were analyzed to ascertain the c-KIT mutation status. In acute myeloid leukemia (AML) with t(8;21), the presence of c-KIT TKD mutation at codon 816 (TKD 816 ) was associated with a high white blood cell count at diagnosis (median, 29.60 ؋ 10 9 /L) and a higher incidence (33%) of extramedullary leukemia (EML) during the course of the disease. Data also showed that the TKD 816 mutated patients (n ‫؍‬ 12) had a significantly higher incidence of relapse and a lower overall survival (OS) at 24 months, compared with the 17 c-KIT unmutated (c-KIT ؊ ) patients (90% vs 35.3%, P ‫؍‬ .002; 25% vs 76.5%, P ‫؍‬ .006, respectively). No difference in relapse incidence (P ‫؍‬ .126) and OS (P ‫؍‬ .474) was observed between the c-KIT mutated other than TKD 816 (n ‫؍‬ 7) and the c-KIT ؊ patients. These findings indicate that c-KIT TKD 816 mutation has a negative impact on the outcome of AML with

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

“…Authors suggested that the different gene profiling may lead to an enhancement of proliferation in the KITmutated cases, which may be reflected in the higher blast counts of those patients [43]. The clinical observations that affected patients with t(8;21) appear to have a higher WBC count and WBC-index at presentation and a higher frequency of EML might support this hypotheses [30,39,45].…”

“…Patients were enrolled in intensive chemotherapy protocols, as previously described [30]. In brief, they received a standard induction therapy with an anthracycline-containing regimen, most commonly the "713" regimen with cytarabine in 7-day continuous intravenous infusion and three doses of anthracycline (idarubicin 12 mg/m 2 /day or daunorubicin 60 mg/m 2 /day) or the "ICE" schedule, including etoposide 100 mg/m 2 /day on days 1-5.…”

“…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 harboring t(8;21)(q22;q22): a heterogeneous disease with poor outcome in a subset of patients unrelated to secondary cytogenetic aberrations

“…Molecular genetic investigation also revealed that receptor tyrosine kinase (RTK) gene mutations may impact outcome in patients with AML with t(8;21). [21][22][23][24] To further investigate the role of previously identified prognostic indicators in AML with t(8;21), particularly cytogenetic findings, in light of the advances in the past decade, we examined 56 cases of AML with t(8;21) diagnosed and treated in our hospital from May 1995 to July 2005. We reviewed the cytogenetic data of each case in the context of the overall clinicopathologic presentation and correlated the results with overall survival.…”

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

“…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].…”