Outcome of patients with FLT3-mutated acute myeloid leukemia in first relapse

Ravandi, Farhad; Kantarjian, Hagop M.; Faderl, Stefan; Garcia‐Manero, Guillermo; O’Brien, Susan; Koller, Charles; Pierce, Sherry; Brandt, Mark; Kennedy, Deborah D.; Cortes, Jorge; Beran, Miloslav

doi:10.1016/j.leukres.2009.10.001

Cited by 113 publications

(85 citation statements)

References 29 publications

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“…The median survival of these patients after acquiring a FLT3 mutation was very similar to that of patients in the Positive/Positive group after first relapse, often less than 5 months post first relapse. 34,36 Based on these results, we suggest that all acute myeloid leukemia patients be tested repeatedly for FLT3 mutation over their disease course to monitor the mutation status.…”

Section: Discussionmentioning

confidence: 96%

“…24,27,29,33 These patients also seem not to benefit from intensifying chemotherapy. [34][35][36] The number of patients in these studies, however, are truly small. We present the first study focused on a large group of such patients, thereby making it possible to statistically analyze clinical characteristics and the prognostic impact of a change in FLT3 status.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

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

et al. 2012

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“…[20][21][22] Prognostic factors for the achievement of a second complete remission were age of the patient, the duration of first complete remission and -as the only molecular marker -the presence of an FLT3-ITD at initial diagnosis. Similar results were reported by Ravandi et al 21 and Boissel et al 23 However, in both studies molecular aberrations apart from FLT3-ITD were not taken into account and the analysis by Boissel et al also included patients with other karyotypes. The significantly inferior second complete remission rate of FLT3-ITD-positive patients is of interest since in several large studies the presence of an FLT3-ITD was not associated with an inferior complete remission rate after first-line induction therapy.…”

Section: Discussionmentioning

confidence: 99%

FLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with normal karyotype

Wagner¹,

Damm²,

Thol³

et al. 2011

Haematologica

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Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany. Phone: international +49.511.5323691. Fax: international +49.511.5323611. E-mail: wagner.katharina@mh-hannover.de Background Several genetic aberrations with prognostic impact in first-line therapy have been described in patients with acute myeloid leukemia and normal karyotype. However, little is known about the influence of these aberrations on outcome after relapse. This study aimed to identify clinical and molecular risk factors for patients with relapsed acute myeloid leukemia with normal karyotype. Design and MethodsWe analyzed 94 patients with acute myeloid leukemia and normal karyotype after first relapse for clinical and molecular risk factors for survival. All patients had received first-line treatment and follow-up within two prospective, multicenter trials. Leukemic blasts were analyzed at diagnosis for genetic aberrations in the FLT3, NPM1, CEBPA, WT1, IDH1 and IDH2 genes by polymerase chain reaction and/or direct sequencing. ResultsA second complete remission was achieved in 52% of patients who received re-induction therapy. The presence of an FLT3-internal tandem duplication, duration of first complete remission less than 6 months and age above the median of 47 years were associated with a significantly lower rate of second complete remission. The median survival after relapse was 11 months and the 6-year survival rate was 28%. In multivariate analysis, FLT3-internal tandem duplication and age above the median were the only independent negative prognostic factors for survival. The 6-year survival rate of patients with none of these factors was 56%, whereas it was significantly inferior in patients with one or both of these factors (15% and 6%, respectively). This was also true for patients who underwent allogeneic stem cell transplantation after relapse. ConclusionsFLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with a normal karyotype. Patients with at least one of these risk factors have a dismal outcome and might be considered for investigational treatment approaches after relapse. (ClinicalTrials.gov Identifier: NCT00209833) Key words: prognostic factors, FLT3-ITD, CN-AML, second complete remission.Citation: Wagner K, Damm F, Thol F, Göhring G, Görlich K, Heuser M, Schäfer I, Schlegelberger B, Heil G, Ganser A, and

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“…31 These findings were subsequently confirmed in numerous other trials. [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.…”

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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Outcome of patients with FLT3-mutated acute myeloid leukemia in first relapse

Cited by 113 publications

References 29 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

FLT3-internal tandem duplication and age are the major prognostic factors in patients with relapsed acute myeloid leukemia with normal karyotype

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

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