Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia

Schlenk, Richard F.; Döhner, Konstanze; Krauter, Jürgen; Fröhling, Stefan; Corbacioglu, Andrea; Bullinger, Lars; Habdank, Marianne; Späth, Daniela; Morgan, Michael; Benner, Axel; Schlegelberger, Brigitte; Heil, Gerhard; Ganser, Arnold; Döhner, Hartmut

doi:10.1056/nejmoa074306

Cited by 1,487 publications

(1,284 citation statements)

References 40 publications

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“…Subsequently, patients suffering from AML develop symptoms attributed to granulocytopenia, anaemia, and thrombocytopenia [2]. Besides age, cytogenetic and molecular features are the main prognostic factors that influence survival [3,4]. Hence, in 2009 the European LeukemiaNet (ELN) proposed a standardized reporting system that risk stratifies patients according to their genetic subgroup.…”

Section: Introductionmentioning

confidence: 99%

“…Hence, in 2009 the European LeukemiaNet (ELN) proposed a standardized reporting system that risk stratifies patients according to their genetic subgroup. As of today, it is well established for early prognostic assessment in AML patients [5,4,6,7,3,[8][9][10]. Thus, patients in this cohort were primarily grouped according to these criteria [5].…”

Section: Introductionmentioning

confidence: 99%

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Flow cytometric maturity score as a novel prognostic parameter in patients with acute myeloid leukemia

et al. 2015

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Abstract:The European LeukemiaNet (ELN) classification is widely accepted for risk stratification of patients with acute myeloid leukemia (AML). In order to establish immunophenotypic features that predict prognosis, the expression of single AML blast cell antigens has been evaluated with partly conflicting results; however, the influence of immunophenotypic blast maturity is largely unknown.In our study, 300 AML patients diagnosed at our institution between 01/2003 and 04/2012 were analyzed. A flow cytometric maturity score was developed in order to distinguish "mature" AML (AML-ma) from "immature" AML (AML-im) by quantitative expression levels of early progenitor cell antigens (CD34, CD117, and TdT).AML-ma showed significantly longer relapse-free survival (RFS) and overall survival (OS) than AML-im (p<0.001). Interestingly, statistically significant differences in RFS and OS were maintained within the Our novel flow cytometric score easily determines AML blast maturity and can predict clinical outcome. It remains to be clarified whether these results simply reflect an accumulation of favorable molecular phenotypes in the AML-ma subgroup or whether they rely on biological differences such as a higher proportion of leukemia stem cells and/or a higher degree of genetic instability within the AML-im subgroup.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Flow cytometric maturity score as a novel prognostic parameter in patients with acute myeloid leukemia

et al. 2015

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“…Mutations in NPM1 are the most commonly observed gene abnormalities in patients with AML, occurring in B50% of patients. 41 Patients with an NPM1 mutation and wild-type FLT3 have the highest likelihood of long-term relapse-free, event-free and OS vs all other patients. 43 However, NPM1 mutations predict better outcomes only in the absence of FLT3-ITD.…”

Section: Flt3 As a Prognostic Markermentioning

confidence: 96%

“…32,39 Mutations in the tyrosine kinase domain of FLT3 frequently occur in patients with prognostically favorable NPM1 mutations, which further complicates analyses of their impact on patient outcomes. 40,41 In fact, a study of 1107 adult patients with AML showed improved survival in patients with FLT3 tyrosine kinase domain mutations vs patients with wild-type FLT3. 42 Frequently, patients with AML have mutations in more than one gene, further complicating prediction of their prognoses.…”

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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“…Patients with FLT3 internal tandem duplication (ITD)-negative and NPM1-mutated AML have a favorable prognosis; those with FLT3-ITD mutations have a poor prognosis [30], essentially among patients with normal karyotype [28]. Patients with AML, diploid karyotype, and bi-allelic CEBPa mutations (2% or less of AML) also have a favorable prognosis [6].…”

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confidence: 99%

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

2015

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Mutations and Treatment Outcome in Cytogenetically Normal Acute Myeloid Leukemia

Abstract: Genotypes defined by the mutational status of NPM1, FLT3, CEBPA, and MLL are associated with the outcome of treatment for patients with cytogenetically normal AML.

Cited by 1,487 publications

References 40 publications

Flow cytometric maturity score as a novel prognostic parameter in patients with acute myeloid leukemia

Flow cytometric maturity score as a novel prognostic parameter in patients with acute myeloid leukemia

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

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

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