title: FLT3 internal tandem duplication in 234 children with acute myeloid leukemia: prognostic significance and relation to cellular drug resistance.
abstract: FLT3 is a receptor tyrosine kinase involved in the proliferation and differentiation of hematopoietic stem cells. FLT3 internal tandem duplications (FLT3/ITDs) are reported in acute myeloid leukemia (AML) and predict poor clinical outcome. We found FLT3/ITDs in 11.5% of 234 children with de novo AML. FLT3/ITD-positive patients were significantly older and had higher percentages of normal cytogenetic findings or French-American-British (FAB) classification M1/M2 and lower percentages of 11q23 abnormalities or FAB M5. FLT3/ITD-positive patients had lower remission induction rates (70% vs 88%; P =.01) and lower 5-year probability rates of event-free survival (pEF) (29% vs 46%; P =.0046) and overall survival (32% vs 58%; P =.037). Patients with high ratios (higher than the median) between mutant and wild-type FLT3 had significantly worse 2-year EFS rates than FLT3/ITD-negative patients (pEFS 20% vs 61%; P =.037), whereas patients with ratios lower than the median did not (pEFS 44% vs 61%; P =.26). FLT3/ITD was the strongest independent predictor for pEFS, with an increase in relative risk for an event of 1.92 (P =.01). Using an MTT (methyl-thiazol-tetrazolium)-based assay, we studied cellular drug resistance on 15 FLT3/ITD-positive and 125 FLT3/ITD-negative AML samples, but we found no differences in cellular drug resistance that could explain the poor outcomes in FLT3/ITD-positive patients. We conclude that FLT3/ITD is less common in pediatric than in adult AML. FLT3/ITD is a strong and independent adverse prognostic factor, and high ratios between mutant and WT-FLT3 further compromise prognosis. However, poor outcomes in FLT3/ITD-positive patients could not be attributed to increased in vitro cellular drug resistance.
authors.affiliation: Department of Pediatric Hematology/Oncology, VU University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands. cm.zwaan@vumc.nl
authors.forename: Christian M
authors.initials: CM
authors.lastname: Zwaan
authors.forename: Soheil
authors.initials: S
authors.lastname: Meshinchi
authors.forename: Jerald P
authors.initials: JP
authors.lastname: Radich
authors.forename: Anjo J P
authors.initials: AJ
authors.lastname: Veerman
authors.forename: Dieuwke R
authors.initials: DR
authors.lastname: Huismans
authors.forename: Leonhard
authors.initials: L
authors.lastname: Munske
authors.forename: Martina
authors.initials: M
authors.lastname: Podleschny
authors.forename: Karel
authors.initials: K
authors.lastname: Hählen
authors.forename: Rob
authors.initials: R
authors.lastname: Pieters
authors.forename: Martin
authors.initials: M
authors.lastname: Zimmermann
authors.forename: Dirk
authors.initials: D
authors.lastname: Reinhardt
authors.forename: Jochen
authors.initials: J
authors.lastname: Harbott
authors.forename: Ursula
authors.initials: U
authors.lastname: Creutzig
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.forename: Frank
authors.initials: F
authors.lastname: Griesinger
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D003630:Daunorubicin / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D015255:Idarubicin / Q000627:therapeutic use; D007223:Infant; D007231:Infant, Newborn; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D012307:Risk Factors; D020080:Tandem Repeat Sequences; D051941:fms-Like Tyrosine Kinase 3
chemical_list: D000903:Antibiotics, Antineoplastic; D011518:Proto-Oncogene Proteins; C497970:FLT3 protein, human; D020794:Receptor Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D015255:Idarubicin; D003630:Daunorubicin