title: Concomitant ABCG2 overexpression and FLT3-ITD mutation identify a subset of acute myeloid leukemia patients at high risk of relapse.
abstract: 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 = .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 = .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.
authors.affiliation: Division of Hematology and Bone Marrow Transplantation, Department of Medical and Morphological Researches, AOU Udine, Udine, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Tiribelli
authors.forename: Antonella
authors.initials: A
authors.lastname: Geromin
authors.forename: Angela
authors.initials: A
authors.lastname: Michelutti
authors.forename: Margherita
authors.initials: M
authors.lastname: Cavallin
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pianta
authors.forename: Dora
authors.initials: D
authors.lastname: Fabbro
authors.forename: Domenico
authors.initials: D
authors.lastname: Russo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Damante
authors.forename: Renato
authors.initials: R
authors.lastname: Fanin
authors.forename: Daniela
authors.initials: D
authors.lastname: Damiani
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018572:Disease-Free Survival; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D012008:Recurrence; D012074:Remission Induction; D020080:Tandem Repeat Sequences; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D014740:Vidarabine; C024352:fludarabine