Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML)

Abstract

In core binding factors (CBF) acute myeloid leukemia (AML), the disruption of CBFa/b genes impairs normal hematopoietic differentiation and is supposed to cooperate with additional mutations promoting proliferation. The incidence and the prognosis of receptor tyrosine kinase (RTK) c-Kit and FLT3 mutations and Ras mutations were evaluated in 103 pediatric and adult patients with CBF-AML. c-Kit mutations were present in 17% patients. c-Kit exon 8 mutations were more frequent in inv(16) than in t(8;21) subset (20 versus 6%). Only one patient had FLT3-ITD but FLT3-D835 was as frequent as reported in AML population (7%). Ras mutations were significantly more frequent in inv(16) than in t(8;21) subset (36 versus 8%, P ¼ 0.001). RTK mutations were associated with a higher white blood cell count (WBC) (36 versus 21 G/L, P ¼ 0.05). FLT3 mutations were significantly associated with a shorter EFS and survival (Po0.0001 and P ¼ 0.0002) owing to an excess of early events. c-Kit mutations were associated with a shorter EFS and RFS (P ¼ 0.002 and P ¼ 0.003) in t(8;21) but not inv(16) patients. As previously observed, Ras mutations did not affect prognosis. Screening for RTK mutations may help to identify patients with a more adverse outcome and thus susceptible to benefit from intensified protocols or RTK inhibitors. Leukemia (2006) 20, 965-970.

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

“…Anyway, it has to be noted that in the CALGB study the KIT-mutated patients were significantly older (median age: 38 vs. 49 years; P < 0.001) and were more frequently male (P < 0.05) compared with nonmutated patients. Moreover, in the reviewed literature, all the focused studies on the prognostic significance of KIT mutations in the CBFb-MYH11 adult patients have been unable to demonstrate any role of such mutations on survival; furthermore, to our knowledge, all studies but one [26] do not show any influence of KIT mutations on relapse [27,[30][31][32].…”

“…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].…”

Comparable outcomes between autologous and allogeneic transplant for adult acute myeloid leukemia in first CR

“…54 As previously mentioned, (16). 27,33,35,72 In a recent analysis from the German-Austrian AML Study Group, the frequency and prognostic impact of secondary genetic lesions were evaluated in patients with CBF AML who were treated in prospective trials (n=176). 73 Secondary chromosomal abnormalities were found in 39% of patients, with the most common abnormalities being trisomy 22 (18%), trisomy 8 (16%), and 7q deletion (5%).…”

Induction of Vascular Endothelial Growth Factor Secretion by Childhood Acute Lymphoblastic Leukemia Cells via the FLT-3 Signaling Pathway

“…In addition to regulating the expansion of normal hematopoietic progenitors, FLT-3 is also highly expressed in several hematologic malignancies, including AML and ALL (8). In addition, FLT-3 mutation in AML is associated with poor prognosis (9).…”