title: Clinical implications of FLT3 mutations in pediatric AML.
abstract: Activating mutations of the FLT3 gene occur because of an internal tandem duplication of the juxta-membrane domain (FLT3/ITD) or point mutation of the activation loop domain (FLT3/ALM). The presence of FLT3 mutations as well as the allelic ratio of FLT3/ITD (ITD-AR, mutant-wild type ratio) may have prognostic significance. FLT3 mutation status of 630 children with de novo acute myeloid leukemia (AML) treated on CCG-2941 and -2961 was determined, and ITD-AR was calculated for patients with FLT3/ITD. Clinical characteristics and outcomes for patients with FLT3/ALM and FLT3/ITD at varying ITD-ARs was determined and compared with those without FLT3 mutations (FLT3/WT). FLT3/ITD and FLT3/ALM were detected in 77 (12%) and 42 (6.7%) of the patients. Progression-free survival (PFS) was similar in patients with FLT3/ALM and FLT3/WT (51% versus 55%, P = .862). In contrast, PFS at 4 years from study entry for patients with FLT3/ITD was inferior to that of patients with FLT3/WT (31% versus 55%, P < .001). PFS decreased with increasing FLT3/ITD-AR (P < .001), and those with ITD-AR greater than 0.4 had a significantly worse PFS than those with lower ITD-AR (16% versus 72%, P = .001) or with FLT3/WT (55%, P < .001). ITD-AR defines the prognostic significance in FLT3/ITD-positive AML, and ITD-AR greater than 0.4 is a significant and independent prognostic factor for relapse in pediatric AML.
authors.affiliation: Fred Hutchinson Cancer Research Center, Clinical Research Division, D5-380, 1100 Fairview Ave N, Seattle, WA 98103, USA. smeshinc@fhcrc.org
authors.forename: Soheil
authors.initials: S
authors.lastname: Meshinchi
authors.forename: Todd A
authors.initials: TA
authors.lastname: Alonzo
authors.forename: Derek L
authors.initials: DL
authors.lastname: Stirewalt
authors.forename: Michel
authors.initials: M
authors.lastname: Zwaan
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmerman
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.forename: Nyla A
authors.initials: NA
authors.lastname: Heerema
authors.forename: Robert
authors.initials: R
authors.lastname: Gerbing
authors.forename: Beverly J
authors.initials: BJ
authors.lastname: Lange
authors.forename: Jerald P
authors.initials: JP
authors.lastname: Radich
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D042622:DNA Repeat Expansion; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000401:mortality*; D008297:Male; D017354:Point Mutation; D012008:Recurrence; D012307:Risk Factors; D015996:Survival Rate; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
chemical_list: C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3