Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in the AMLCG study and usefulness as a marker for the detection of minimal residual disease

Abstract

FLT3 length mutation (FLT3-LM) is a molecular marker potentially useful for the characterization of acute myeloid leukemia (AML). To evaluate the distribution of FLT3-LM within biologic subgroups, we screened 1003 patients with AML at diagnosis for this mutation. FLT3-LM was found in 234 (23.5%) of all patients and thus is the most frequent mutation in AML described so far. Of all positive patients, 165 (70.5%) revealed a normal karyotype. Of the 69 patients with chromosome aberrations, 24 (34.8%) had a t(15;17). The mutation was rare in AML with t(8;21), inv(16) 11q23 rearrangements, and complex karyotypes. FLT3-LM was not distributed equally within different FrenchAmerican-British (FAB) subtypes and was correlated with a high peripheral blood count in FAB M1, M2, and M4 (P < .0001). In addition, the median age of patients with the mutation was lower (54.9 vs 57.6 years; P ‫؍‬ .043), and, at a ratio of 1.36:1 (P ‫؍‬ .023), the mutation was more frequent in females than in males. Within the AMLCG study, FLT3-LM was of intermediate prognostic significance. The complete remission rate of 70.3% in patients with FLT3-LM was similar to that (

Clinical impact of change of FLT3 mutation status in acute myeloid leukemia patients

“…Several studies have observed FLT3 mutation status changes in small subsets of acute myeloid leukemia patients and have implied the prognostic importance. 10,16,[21][22][23][24][25][26][27][28][29] In aggregate, these data suggest that gain of FLT3 mutations may be associated with worse prognosis. 24,27,29,33 These patients also seem not to benefit from intensifying chemotherapy.…”

“…[4][5][6][7][8] The most common type of FLT3 mutation is internal tandem duplications (FLT3-ITDs) in the juxtamembrane domain of the receptor, which have been found in 15-35% of adult acute myeloid leukemia patients. 4,5,9,10 Point mutations in the heavily converted areas of the intracellular tyrosine kinase domain (TKD), most commonly the nucleotide substitution of aspirate 835 (FLT3-D835), occur in 5-10% of adult acute myeloid leukemia patients. 3,7,8,11 Although most patients have only one type of the FLT3 mutation, 1-3% of acute myeloid leukemia patients have both FLT3-ITD and FLT-D835.…”

“…14 FLT3-ITD is an independent predictor of poor prognosis and is associated with increased relapse risk after chemotherapy, and decreased disease-free survival and overall survival. 6,8,10,15,16 The clinical significance of FLT3-D835 is still unclear. Some studies have shown that FLT3-D835 is associated with shorter disease-free and overall survival.…”

“…10,16,[21][22][23][24][25][26][27][28][29] However, owing to a lack of a sufficient number of patients, no study has been able to provide statistical significant correlations between FLT3 status changes and disease progression. The goal of this study is to examine the clinical features and outcome of a large cohort of acute myeloid leukemia patients in whom FLT3 mutation status changed.…”

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

“…[33][34][35][36][37] In general, patients with FLT3-ITD AML achieve complete remission rates comparable to those of patients with wild-type disease, but have significantly higher rates of relapse and shorter durations of disease-free and overall survival (OS). 31,[33][34][35] In the Medical Research Council studies, patients with FLT3-ITD AML had a 74% relapse rate vs 48% for patients with FLT3-wild-type AML. 31 The 5-year OS rate was 32% for patients with FLT3-ITD AML vs 44% for patients with FLT3-wildtype AML; 31 event-free survival was 20 vs 41 weeks, respectively (Po0.00001).…”