Variable prognostic value of FLT3 internal tandem duplications in patients with de novo AML and a normal karyotype, t(15;17), t(8;21) or inv(16)

Kainz, Birgit; Heintel, Daniel; Marculescu, Rodrig; Schwarzinger, Ilse; Sperr, Wolfgang R.; Le, Trang; Weltermann, Ansgar; Fonatsch, Christa; Haas, Oskar A.; Mannhalter, Christine; Lechner, Klaus; Jaeger, Ulrich

doi:10.1038/sj.thj.6200196

Cited by 71 publications

(58 citation statements)

References 25 publications

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“…36,42,43 The prognostic impact of this mutation in patients with AML in relapse has not been investigated. In the present study, the impact of FLT3/ITD could be analysed in about 50% of the study population.…”

Section: Discussionmentioning

confidence: 99%

“…[32][33][34] To detect the FLT3/ITD mutation, exons 11 and 12 were amplified by single-step PCR from genomic DNA using the primers 11F, 5 0 -GCA ATT TAG GTA TGA AAG CCA GC-3 0 , and 12R, 5 0 -CTT TCA GCA TTT TGA CGG CAA CC-3 0 as described previously. 35,36 PCR was performed using AmpliTaq DNA Polymerase (Perkin-Elmer Cetus, Norwalk, CT, USA) in a Perkin-Elmer GeneAmp PCR System 2400 thermocycler. The PCR mixture contained 500 ng of genomic DNA, 50 mM of MgSO 4 , 75 mM of MgCl 2 , 30 pM of each primer, 9.5 ml of 10 Â buffer, 94 mM of each deoxynucleotide triphosphate and 2 U of Taq polymerase (AmpliTaq, Perkin-Elmer, Norwalk, CT, USA).…”

Section: Pcr Analysesmentioning

confidence: 99%

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Impact of cytogenetics on the prognosis of adults with de novo AML in first relapse

Weltermann

Fonatsch²,

Haas

et al. 2003

Leukemia

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Karyotype is an important prognostic factor in patients with newly diagnosed acute myeloblastic leukaemia (AML). The prognostic value of cytogenetics on the outcome of patients with AML in relapse has not yet been well defined. We analysed the clinical outcome of 152 patients with de novo, chemotherapy-treated AML in first relapse according to the cytogenetic classification of the United Kingdom Medical Research Council. The rate of second complete remission (CR) (88, 64 and 36%) and the probability of survival at 3 years (43, 18 and 0%) were significantly different between the favourable, intermediate and adverse cytogenetic risk groups, respectively. Compared to the favourable group, the relative risk (RR) of death (multivariate analyses) was 2.6 (confidence interval (CI): 1.5-4.4, Po0.001) for the intermediate and 3.7 (CI: 1.7-7.9, P ¼ 0.001) for the adverse group. The prognostic value of the duration of first CR was confirmed (RR of death: 2.0 (CI: 1.0-4.0) for each additional year in first CR), whereas the FLT3 mutation obtained at diagnosis did not markedly influence the outcome of patients with AML in relapse. In conclusion, our results indicate that both karyotype and the duration of first CR are independent prognostic factors for patients with de novo AML in first relapse.

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Section: Discussionmentioning

confidence: 99%

Section: Pcr Analysesmentioning

confidence: 99%

Impact of cytogenetics on the prognosis of adults with de novo AML in first relapse

Weltermann

Fonatsch²,

Haas

et al. 2003

Leukemia

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“…7,27-29 FLT3-ITD-positive patients are more often diagnosed with de novo than secondary AML. 7,8 Both FLT3-ITD and -TKD mutations have been strongly associated with high white blood cell (WBC) count and high bone marrow blast percentages at presentation. 5,7,9,10,30 A positive correlation between MLL (mixed lineage leukemia) intragenic abnormalities (MLL partial tandem duplication (MLL-PTD) or DNA double-strand breakage within the MLL breakpoint cluster region induced by topoisomerase II inhibitors) and FLT3 mutations (ITD and TKD) has been reported.…”

Section: Flt3mentioning

confidence: 99%

“…The most common type is an intern tandem duplication (ITD) in exons 14 and 15 (previously known as exons 11 and 12) that map to the JMD, seen in 25-35% of adult and 12% of childhood AML. [5][6][7][8][9][10][11][12][13][14][15][16] These ITD, and deletion or insertion/deletion mutations affecting the JMD, are sometimes called length mutations (LM) in the literature. Here, we use the term ITD to refer to all JMD mutations.…”

Section: Flt3mentioning

confidence: 99%

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

et al. 2008

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Acute myeloid leukemia (AML) is a heterogeneous group of neoplastic disorders with great variability in clinical course and response to therapy, as well as in the genetic and molecular basis of the pathology. Major advances in the understanding of leukemogenesis have been made by the characterization and the study of acquired cytogenetic abnormalities, particularly reciprocal translocations observed in AML. Besides these major cytogenetic abnormalities, gene mutations also constitute key events in AML pathogenesis. In this review, we describe the contribution of known gene mutations to the understanding of AML pathogenesis and their clinical significance. To gain more insight in this understanding, we clustered these alterations in three groups: (1) mutations affecting genes that contribute to cell proliferation (FLT3, c-KIT, RAS, protein tyrosine standard phosphatase nonreceptor 11); (2) mutations affecting genes involved in myeloid differentiation (AML1 and CEBPA) and (3) mutations affecting genes implicated in cell cycle regulation or apoptosis (P53, NPM1). This nonexhaustive review aims to show how gene mutations interact with each other, how they contribute to refine prognosis and how they can be useful for risk-adapted therapeutic management of AML patients.

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“…FLT3 mutations are regarded as one of the most significant prognostic factors in normal karyotype AML. [11][12][13][14][15][24][25][26] Several previous studies have suggested that the presence of FLT3/ITDs is associated with poor prognosis in younger adult patients with AML. However, these data were obtained in patient populations that were highly heterogeneous with regard to patients' age, karyotype, and treatment regimens.…”

Section: Discussionmentioning

confidence: 99%

FLT3 mutations in normal karyotype acute myeloid leukemia in first complete remission treated with autologous peripheral blood stem cell transplantation

Yoshimoto

Nagafuji

Miyamoto

et al. 2005

Bone Marrow Transplant

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Summary:We retrospectively analysed the significance of FLT3 mutations in patients with acute myeloid leukemia (AML) having a normal karyotype, who were treated with highdose chemotherapy and autologous peripheral blood stem cell transplantation (auto-PBSCT). In all, 34 patients with normal karyotype AML in first complete remission receiving high-dose chemotherapy and auto-PBSCT were analysed based on the presence or absence of FLT3/ITDs and FLT3/D835. They were 16 males and 18 females and with a median age of 41.5 years. FLT3/ITDs were detected in eight of 34 patients (23.5 %), and FLT3 D835 mutations in two of 34 patients (5.9%). White blood cell count (P ¼ 0.0087), serum concentration of lactate dehydrogenase (P ¼ 0.005), and percentages of peripheral blood (P ¼ 0.0131) and bone marrow (BM) blasts (P ¼ 0.0312) were significantly higher in patients showing the FLT3 mutations. Overall survival (OS) and diseasefree survival (DFS) were similar between patients with or without FLT3 mutations (5 year DFS, 67.5 vs 68.55%, P ¼ 0.819; 5 year OS, 64.81 vs 78.88%, P ¼ 0.4457, by the log-rank test). FLT3 mutations demonstrate no further prognostic impact in patients with normal karyotype AML in first CR treated with high-dose chemotherapy and auto-PBSCT. Myeloablative chemotherapy supported by auto-PBSCT may overcome any poor prognostic implications of FLT3 mutations. Bone Marrow Transplantation (2005) 36, 977-983.

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Variable prognostic value of FLT3 internal tandem duplications in patients with de novo AML and a normal karyotype, t(15;17), t(8;21) or inv(16)

Abstract: These data suggest a high prognostic value of FLT3/ITD in patients with normal cytogenetics. However, we find no evidence that FLT3/ITD is a predictive marker for patients with t(15;17).

Cited by 71 publications

References 25 publications

Impact of cytogenetics on the prognosis of adults with de novo AML in first relapse

Impact of cytogenetics on the prognosis of adults with de novo AML in first relapse

Cooperating gene mutations in acute myeloid leukemia: a review of the literature

FLT3 mutations in normal karyotype acute myeloid leukemia in first complete remission treated with autologous peripheral blood stem cell transplantation

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