The presence of a FLT3 internal tandem duplication in patients with acute myeloid leukemia (AML) adds important prognostic information to cytogenetic risk group and response to the first cycle of chemotherapy: analysis of 854 patients from the United Kingdom Medical Research Council AML 10 and 12 trials

Kottaridis, Panagiotis D.; Gale, Rosemary E.; Frew, Marion E.; Harrison, Gill; Langabeer, Stephen E.; Belton, Andrea A.; Walker, Helen M.; Wheatley, Keith; Bowen, David; Burnett, Alan Kenneth; Goldstone, Anthony H.; Linch, David C.

doi:10.1182/blood.v98.6.1752

Cited by 1,375 publications

(1,222 citation statements)

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“…Many studies indicate that FLT3-ITD confers a poor prognosis in AML patients by increasing relapse risk and reducing survival. [17][18][19][20][21] More recently, increasing evidence suggests that higher FLT3-ITD to wild-type allelic ratios are associated with poor prognosis. 22 In our patients, FLT3 mutation by itself did not impact DFS.…”

Section: Discussionmentioning

confidence: 99%

Concomitant ABCG2 overexpression and FLT3‐ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse

Tiribelli¹,

Geromin²,

Michelutti³

et al. 2010

Cancer

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BACKGROUND: ABCG2 protein overexpression and FLT3 internal tandem duplication (ITD) correlate with higher relapse rate and shorter disease-free survival (DFS) in acute myeloid leukemia (AML), but no data are available on the possible effect of concomitant presence of these 2 factors. METHODS: The authors analyzed the outcome of 166 cases of adult AML patients who were homogeneously treated with a fludarabine-based induction therapy. RESULTS: ABCG2 overexpression and FLT3-ITD were detected in 83 (50%) and 47 (28%) patients, respectively. A significant correlation was found between ABCG2 positivity and FLT3 mutation, with 33 (40%) ITD in 83 ABCG2-positive patients compared with 14 (17%) ITD in 83 ABCG2-negative patients (P ¼ .002). Complete remission (CR) after induction therapy was achieved in 95 (57%) patients. Neither ABCG2 overexpression nor FLT3-ITD had any impact on achievement of CR. Relapse occurred in 42 of 95 (44%) patients at a median time of 28 months. Time to relapse was shortened in patients overexpressing ABCG2 (P ¼ .0004). DFS was not affected by FLT3-ITD alone, but FLT3 mutation significantly worsened long-term outcome of ABCG2-positive patients. DFS at 1 and 3 years in patients with overexpression of both ABCG2 and FLT3-ITD was only 36% and 28%, respectively; in ABCG2-positive/FLT3-negative patients, DFS at 1 and 3 years was 65% and 48%, respectively; and in ABCG2-negative cases (regardless of FLT3 status), DFS at 1 and 3 years was greater than 85% and 75%. CONCLUSIONS: Concomitant overexpression of ABCG2 and FLT3-ITD is relatively frequent and identifies a subgroup of AML patients with a significantly worse prognosis. The possible interactions between these 2 prognostic factors need to be defined. Cancer 2011;117:2156-62.

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Section: Discussionmentioning

confidence: 99%

Concomitant ABCG2 overexpression and FLT3‐ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse

Tiribelli¹,

Geromin²,

Michelutti³

et al. 2010

Cancer

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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).…”

Section: Flt3 As a Prognostic Markermentioning

confidence: 65%

“…[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%

“…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). 32 In vitro evidence suggests that FLT3-ITD may contribute to drug resistance.…”

Section: Flt3 As a Prognostic Markermentioning

confidence: 99%

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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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“…62 These activating mutations of FLT3R, particularly a homozygous activation, confer a worse outcome. 63,64 Inhibitors of such aberrant activation are undergoing clinical evaluation. 65 Early clinical trials have demonstrated activity of FLT3 inhibitors, particularly in patients who harbor FLT3R mutations in their leukemic blasts.…”

Section: Constitutively Active Kinases As Targets Of Therapymentioning

confidence: 99%