title: Differential impact of allelic ratio and insertion site in FLT3-ITD-positive AML with respect to allogeneic transplantation.
abstract: The objective was to evaluate the prognostic and predictive impact of allelic ratio and insertion site (IS) of internal tandem duplications (ITDs), as well as concurrent gene mutations, with regard to postremission therapy in 323 patients with FLT3-ITD-positive acute myeloid leukemia (AML). Increasing FLT3-ITD allelic ratio (P = .004) and IS in the tyrosine kinase domain 1 (TKD1, P = .06) were associated with low complete remission (CR) rates. After postremission therapy including intensive chemotherapy (n = 121) or autologous hematopoietic stem cell transplantation (HSCT, n = 17), an allelic ratio ≥ 0.51 was associated with an unfavorable relapse-free (RFS, P = .0008) and overall survival (OS, P = .004); after allogeneic HSCT (n = 93), outcome was significantly improved in patients with a high allelic ratio (RFS, P = .02; OS, P = .03), whereas no benefit was seen in patients with a low allelic ratio (RFS, P = .38; OS, P = .64). Multivariable analyses revealed a high allelic ratio as a predictive factor for the beneficial effect of allogeneic HSCT; ITD IS in TKD1 remained an unfavorable factor, whereas no prognostic impact of concurrent gene mutations was observed. The clinical trials described herein were previously published or are registered as follows: AMLHD93 and AMLHD98A, previously published; AML SG 07-04, ClinicalTrials.gov identifier #NCT00151242.
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany;
authors.forename: Richard F
authors.initials: RF
authors.lastname: Schlenk
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany;
authors.forename: Sabine
authors.initials: S
authors.lastname: Kayser
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany;
authors.forename: Lars
authors.initials: L
authors.lastname: Bullinger
authors.affiliation: Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany;
authors.forename: Guido
authors.initials: G
authors.lastname: Kobbe
authors.affiliation: Department of Oncology and Hematology, Klinikum Oldenburg, Oldenburg, Germany;
authors.forename: Jochen
authors.initials: J
authors.lastname: Casper
authors.affiliation: Department of Internal Medicine III, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany;
authors.forename: Mark
authors.initials: M
authors.lastname: Ringhoffer
authors.affiliation: Department of Internal Medicine I, University Hospital of Saarland, Homburg, Germany;
authors.forename: Gerhard
authors.initials: G
authors.lastname: Held
authors.affiliation: Department of Internal Medicine III, University Hospital of Bonn, Bonn, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Brossart
authors.affiliation: Department of Hematology and Oncology, University Hospital of Freiburg, Freiburg, Germany;
authors.forename: Michael
authors.initials: M
authors.lastname: Lübbert
authors.affiliation: Department of Hematology and Oncology, Eberhard-Karls University, Tübingen, Germany;
authors.forename: Helmut R
authors.initials: HR
authors.lastname: Salih
authors.affiliation: Department of Medicine III, Johannes Gutenberg-University Mainz, Mainz, Germany;
authors.forename: Thomas
authors.initials: T
authors.lastname: Kindler
authors.affiliation: Department of Internal Medicine II, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany;
authors.forename: Heinz A
authors.initials: HA
authors.lastname: Horst
authors.affiliation: Department of Hematology and Oncology, University Hospital of Göttingen, Göttingen, Germany;
authors.forename: Gerald
authors.initials: G
authors.lastname: Wulf
authors.affiliation: Department of Internal Medicine V, University Hospital Innsbruck, Innsbruck, Austria;
authors.forename: David
authors.initials: D
authors.lastname: Nachbaur
authors.affiliation: Department of Internal Medicine III, Technical University of Munich, Munich, Germany;
authors.forename: Katharina
authors.initials: K
authors.lastname: Götze
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany;
authors.forename: Alexander
authors.initials: A
authors.lastname: Lamparter
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany;
authors.forename: Peter
authors.initials: P
authors.lastname: Paschka
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany;
authors.forename: Verena I
authors.initials: VI
authors.lastname: Gaidzik
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany;
authors.forename: Veronica
authors.initials: V
authors.lastname: Teleanu
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany;
authors.forename: Daniela
authors.initials: D
authors.lastname: Späth
authors.affiliation: Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany; and.
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Krauter
authors.affiliation: Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany;
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.affiliation: Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany;
authors.forename: Konstanze
authors.initials: K
authors.lastname: Döhner
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D004252:DNA Mutational Analysis; D020440:Gene Duplication; D005787:Gene Frequency; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods / Q000706:statistics & numerical data; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D008875:Middle Aged; D016254:Mutagenesis, Insertional / Q000235:genetics*; D017434:Protein Structure, Tertiary / Q000235:genetics; D020080:Tandem Repeat Sequences / Q000235:genetics; D014184:Transplantation, Homologous; D016896:Treatment Outcome; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000737:chemistry / Q000235:genetics*
chemical_list: C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3