title: Alterations of the FLT3 gene in acute promyelocytic leukemia: association with diagnostic characteristics and analysis of clinical outcome in patients treated with the Italian AIDA protocol.
abstract: Alterations in the FLT3 gene, including internal tandem duplications (ITDs) and D835 mutations occur frequently in acute myelogenous leukemia. We investigated the prevalence and clinico-biological correlations of FLT3 ITDs and D835 mutations in 90 patients with acute promyelocytic leukemia (APL) receiving the AIDA protocol. Twenty patients in which both presentation and relapse material was available were analyzed sequentially. Thirty-three patients (37%) harbored the ITD, and seven (7.7%) the D835 mutation in blasts obtained at diagnosis. Presence of ITDs was strongly associated with high WBC count (P = 0.0001), M3 variant (P = 0.0004), and the short (BCR3) PML/RARalpha isoform (P = 0.003). There was no difference in response to induction in the two ITD+ve and ITD-ve groups, while a trend towards inferior outcome was observed for ITD+ve cases when analyzing disease-free survival (DFS) and relapse risk (RR). These differences, however, did not reach statistical significance. Sequential studies showed variable patterns in diagnostic and relapse material, ie ITD (-ve/-ve, +ve/+ve, +ve/-ve, -ve/+ve) and D835 (-ve/-ve, +ve/-ve, -ve/+ve). Our results indicate that FLT3 alterations are associated in APL with more aggressive clinical features and suggest that these lesions may not play a major role in leukemia progression.
authors.affiliation: Department of Cellular Biotechnologies and Hematology, University La Sapienza of Roma, Italy.
authors.forename: N I
authors.initials: NI
authors.lastname: Noguera
authors.forename: M
authors.initials: M
authors.lastname: Breccia
authors.forename: M
authors.initials: M
authors.lastname: Divona
authors.forename: D
authors.initials: D
authors.lastname: Diverio
authors.forename: V
authors.initials: V
authors.lastname: Costa
authors.forename: S
authors.initials: S
authors.lastname: De Santis
authors.forename: G
authors.initials: G
authors.lastname: Avvisati
authors.forename: M B
authors.initials: MB
authors.lastname: Pinazzi
authors.forename: M C
authors.initials: MC
authors.lastname: Petti
authors.forename: F
authors.initials: F
authors.lastname: Mandelli
authors.forename: F
authors.initials: F
authors.lastname: Lo Coco
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017931:DNA Primers / Q000737:chemistry; D004273:DNA, Neoplasm / Q000378:metabolism; D005260:Female; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D015255:Idarubicin / Q000627:therapeutic use*; D015473:Leukemia, Promyelocytic, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D010976:Platelet Count; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012307:Risk Factors; D020080:Tandem Repeat Sequences; D016896:Treatment Outcome; D014212:Tretinoin / Q000627:therapeutic use*; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D017931:DNA Primers; D004273:DNA, Neoplasm; D006454:Hemoglobins; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D015255:Idarubicin