title: Characterization of children with FLT3-ITD acute myeloid leukemia: a report from the AIEOP AML-2002 study group.
abstract: Recurrent molecular markers have been routinely used in acute myeloid leukemia (AML) for risk assessment at diagnosis, whereas their post-induction monitoring still represents a debated issue. We evaluated the prognostic value and biological impact of minimal residual disease (MRD) and of the allelic ratio (AR) of FLT3-internal-tandem duplication (ITD) in childhood AML. We retrospectively screened 494 children with de novo AML for FLT3-ITD mutation, identifying 54 harboring the mutation; 51% of them presented high ITD-AR at diagnosis and had worse event-free survival (EFS, 19.2 versus 63.5% for low ITD-AR, <0.05). Forty-one percent of children with high levels of MRD after the 1st induction course, measured by a patient-specific real-time-PCR, had worse EFS (22.2 versus 59.4% in low-MRD patients, P<0.05). Next, we correlated these parameters with gene expression, showing that patients with high ITD-AR or persistent MRD had characteristic expression profiles with deregulated genes involved in methylation and acetylation. Moreover, patients with high CyclinA1 expression presented an unfavorable EFS (20.3 versus 51.2% in low CyclinA1 group, P<0.01). Our results suggest that ITD-AR levels and molecular MRD should be considered in planning clinical management of FLT3-ITD patients. Different transcriptional activation of epigenetic and oncogenic profiles may explain variability in outcome among these patients, for whom novel therapeutic approaches are desirable.
authors.affiliation: Istituto di Ricerca Pediatrica - Città della Speranza, Padova, Italy.
authors.forename: E
authors.identifier: 0000-0002-1176-3359
authors.initials: E
authors.lastname: Manara
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Clinica di Oncoematologia Pediatrica, Università di Padova, Padova, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Basso
authors.affiliation: Istituto di Ricerca Pediatrica - Città della Speranza, Padova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Zampini
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Clinica di Oncoematologia Pediatrica, Università di Padova, Padova, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Buldini
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Clinica di Oncoematologia Pediatrica, Università di Padova, Padova, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Tregnago
authors.affiliation: Clinica Pediatrica, Università di Bologna, Ospedale 'S. Orsola', Bologna, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Rondelli
authors.affiliation: Clinica Pediatrica, Università di Bologna, Ospedale 'S. Orsola', Bologna, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Masetti
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Clinica di Oncoematologia Pediatrica, Università di Padova, Padova, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Bisio
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Clinica di Oncoematologia Pediatrica, Università di Padova, Padova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Frison
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Clinica di Oncoematologia Pediatrica, Università di Padova, Padova, Italy.
authors.forename: K
authors.initials: K
authors.lastname: Polato
authors.affiliation: Clinica Pediatrica, Centro Ricerca Tettamanti, Università di Milano-Bicocca, Monza, Italia.
authors.forename: G
authors.initials: G
authors.lastname: Cazzaniga
authors.affiliation: Department of Paediatric Haemato-Oncology, Santobono-Pausilipon Hospital, Napoli, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Menna
authors.affiliation: Paediatric Onco-Haematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children's Hospital, Torino, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Fagioli
authors.affiliation: IRCCS Bambino Gesù Children's Hospital Rome, Università di Pavia, Rome, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Merli
authors.affiliation: Clinica Pediatrica, Centro Ricerca Tettamanti, Università di Milano-Bicocca, Monza, Italia.
authors.forename: A
authors.initials: A
authors.lastname: Biondi
authors.affiliation: Clinica Pediatrica, Università di Bologna, Ospedale 'S. Orsola', Bologna, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Pession
authors.affiliation: IRCCS Bambino Gesù Children's Hospital Rome, Università di Pavia, Rome, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Locatelli
authors.affiliation: Dipartimento di Salute della Donna e del Bambino, Clinica di Oncoematologia Pediatrica, Università di Padova, Padova, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Pigazzi
mesh_terms: D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D044127:Epigenesis, Genetic / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000235:genetics*; D018365:Neoplasm, Residual / Q000235:genetics; D011379:Prognosis; D012189:Retrospective Studies; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: D051941:fms-Like Tyrosine Kinase 3