title: Prognostic implication of FLT3 and Ras gene mutations in patients with acute promyelocytic leukemia (APL): a retrospective study from the European APL Group.
abstract: Internal tandem duplications (ITDs) of the FLT3 gene have been observed in about 35% of APL cases. If FLT3-ITD is associated with a worse outcome in patients with acute myeloid leukemia (AML) in general, its prognostic value in acute promyelocytic leukemia (APL) is still a matter of debate. We investigated incidence, associated clinical features, and prognostic implication of FLT3-ITD, but also FLT3-D835 point mutation and N-Ras or K-Ras mutations in 119 APL patients, all prospectively enrolled in the two consecutive APL-93 and APL-2000 trials. Mutation incidences were 38, 20, and 4%, for FLT3-ITD, FLT3-D835, and Ras, respectively. The presence of FLT3-ITD was associated with high white blood cell count, high Sanz index, M3-variant subtype, and V/S PML-RAR alpha isoforms. Complete remission (CR), induction death, and death in CR rates were not affected by FLT3 or Ras mutations, as well as cumulative incidence of relapse. However, a trend for a shorter overall survival (P=0.09) was observed in FLT3-ITD patients, because of a very poor postrelapse survival (P=0.02). This feature, which has been also reported in patients with AML in general, is suggestive of an underlying genetic instability in FLT3-ITD patients, leading to the acquisition of additional unknown bad-prognosis gene mutations at relapse.
authors.affiliation: Department of Hematology, Hôpital Saint-Louis, Paris, France.
authors.forename: C
authors.initials: C
authors.lastname: Callens
authors.forename: S
authors.initials: S
authors.lastname: Chevret
authors.forename: J-M
authors.initials: JM
authors.lastname: Cayuela
authors.forename: B
authors.initials: B
authors.lastname: Cassinat
authors.forename: E
authors.initials: E
authors.lastname: Raffoux
authors.forename: S
authors.initials: S
authors.lastname: de Botton
authors.forename: X
authors.initials: X
authors.lastname: Thomas
authors.forename: A
authors.initials: A
authors.lastname: Guerci
authors.forename: N
authors.initials: N
authors.lastname: Fegueux
authors.forename: A
authors.initials: A
authors.lastname: Pigneux
authors.forename: A-M
authors.initials: AM
authors.lastname: Stoppa
authors.forename: T
authors.initials: T
authors.lastname: Lamy
authors.forename: F
authors.initials: F
authors.lastname: Rigal-Huguet
authors.forename: A
authors.initials: A
authors.lastname: Vekhoff
authors.forename: S
authors.initials: S
authors.lastname: Meyer-Monard
authors.forename: A
authors.initials: A
authors.lastname: Ferrand
authors.forename: M
authors.initials: M
authors.lastname: Sanz
authors.forename: C
authors.initials: C
authors.lastname: Chomienne
authors.forename: P
authors.initials: P
authors.lastname: Fenaux
authors.forename: H
authors.initials: H
authors.lastname: Dombret
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D002986:Clinical Trials as Topic / Q000706:statistics & numerical data; D005060:Europe; D005260:Female; D020440:Gene Duplication; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011237:Predictive Value of Tests; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D011518:Proto-Oncogene Proteins; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3