Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis

Thiede, Christian; Steudel, Christine; Mohr, Brigitte; Schaich, Markus; Schäkel, Ulrike; Platzbecker, Uwe; Wermke, Martin; Bornhäuser, Martin; Ritter, Markus; Neubauer, Andreas; Ehninger, Gerhard; Illmer, Thomas

doi:10.1182/blood.v99.12.4326

Cited by 1,550 publications

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References 44 publications

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“…[1][2][3] FLT3 is one of the most frequently mutated genes in hematological malignancies, present in over 30% of adults with acute myeloid leukemia. [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.…”

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confidence: 99%

“…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. 8,11,12 FLT3-ITD and FLT-D835 cause constitutive activation of FLT3, leading to aberrant activation of multiple downstream pathways, such as phosphatidyl-inositol 3-kinase, mitogen-activated protein kinase, and signal transducer and activator of transcription 5.…”

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confidence: 99%

“…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. 8,11,12 FLT3-ITD and FLT-D835 cause constitutive activation of FLT3, leading to aberrant activation of multiple downstream pathways, such as phosphatidyl-inositol 3-kinase, mitogen-activated protein kinase, and signal transducer and activator of transcription 5. 13 Patients with acute myeloid leukemia associated with FLT3 mutation usually present as de novo disease with high peripheral leukocyte count, high bone marrow blast count, and normal cytogenetics.…”

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confidence: 99%

“…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.…”

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

et al. 2012

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FMS-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in acute myeloid leukemia and is associated with worse clinical outcome. Changes in FLT3 mutation status can occur during the course of disease, but the clinical impact of a change is unclear. We retrospectively reviewed 3555 acute myeloid leukemia patients, who have been assessed for FLT3 mutation at our institution between May 2002 and January 2011. We found that 42 (6.2%) out of 680 patients with FLT3 mutation experienced a change of FLT3 mutation status. In all, 36 patients with wild-type FLT3 at the time of initial diagnosis gained mutation (Negative/Positive) and six initially FLT3-mutated patients became wild type during their following relapses (Positive/Negative). The 5-year survival of these patients was similar to that of patients with persistently wild-type FLT3 (Negative/ Negative; P ¼ 0.464), and significantly better than patients who had stable FLT3 mutation during their disease course (Positive/Positive; Po0.001). However, after mutations became detectable in the Negative/Positive group, the forward survival of these patients tracked that of the Positive/Positive group after relapse (P ¼ 0.761). In addition, we did not find a significant difference in survival between patients with internal tandem duplications and those with point mutations in the tyrosine kinase domain of the FLT3 gene. These results suggest that FLT3 mutations are unstable and that there is potential clinical value in continuously monitoring FLT3 mutation status.

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

et al. 2012

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“…[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).…”

Section: Flt3 As a Prognostic Markermentioning

confidence: 99%

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

2012

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Acute myeloid leukemia (AML) is a highly heterogenous disease with multiple signaling pathways contributing to its pathogenesis. A key driver of AML is the FMS-like tyrosine kinase receptor-3 (FLT3). Activating mutations in FLT3, primarily the FLT3-internal tandem duplication (FLT3-ITD), are associated with decreased progression-free and overall survival. Identification of the importance of FLT3-ITD and the FLT3 pathway in the prognosis of patients with AML has stimulated efforts to develop therapeutic inhibitors of FLT3. Although these inhibitors have shown promising antileukemic activity, they have had limited efficacy to date as single agents and may require use in combination with cytotoxic chemotherapies. Here, we review clinical and preclinical results for the clinically mature FLT3 inhibitors currently in development. We conclude that multitargeted FLT3 inhibitors may have more utility earlier in the course of disease, when in vitro evidence suggests that AML cells are less dependent on FLT3 signaling, perhaps because of upregulation of multiple other signaling pathways. More potent agents may have greater utility in relapsed and heavily pretreated patients, in whom high levels of circulating FLT3 ligand may necessitate use of an agent with a very favorable pharmacokinetic/ pharmacodynamic profile. Novel combination regimens are also discussed.

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Toward Individualized Therapy in Acute Myeloid Leukemia

et al. 2015

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Acute myeloid leukemia (AML) is a heterogeneous disease in its clinical presentation, response to therapy, and overall prognosis. For decades, pretreatment karyotype evaluation has served to identify subgroups for risk-adapted postremission therapy, but the initial treatment approach has been largely unchanged. With continued advances in the genetic and epigenetic characterization of AML, we have discovered even more diversity and are starting to understand the biological underpinnings of these multiple disease entities. Newer therapies are being developed to address the pathophysiology within these individual AML subsets. This review categorizes AML into biologically defined groups based on currently available data and describes the evolving treatment approaches within these groups. Identifying the genetic abnormalities and biological drivers prior to AML treatment will be important as we work to individualize therapy and improve outcomes.

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Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis

Cited by 1,550 publications

References 44 publications

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

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

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

Toward Individualized Therapy in Acute Myeloid Leukemia

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