title: NUP98/NSD1 and FLT3/ITD coexpression is more prevalent in younger AML patients and leads to induction failure: a COG and SWOG report.
abstract: NUP98/NSD1 has recently been reported in association with poor outcome in acute myeloid leukemia (AML). Previous studies also observed a high overlap between NUP98/NSD1 and FLT3/ITD, raising the question as to whether the reported poor outcome is due to NUP98/NSD1 or caused by the co-occurrence of these 2 genetic lesions. We aimed to determine the prognostic significance of NUP98/NSD1 in the context of FLT3/ITD AML. A total of 1421 patients enrolled in 5 consecutive Children's Oncology Group/Children's Cancer Group and SWOG trials were evaluated. NUP98/NSD1 was found in 15% of FLT3/ITD and 7% of cytogenetically normal (CN)-AML. Those with dual FLT3/ITD and NUP98/NSD1 (82% of NUP98/NSD1 patients) had a complete remission rate of 27% vs 69% in FLT3/ITD without NUP98/NSD1 (P < .001). The corresponding 3-year overall survival was 31% vs 48% (P = .011), respectively. In CN-AML, patients with concomitant NUP98/NSD1 and FLT3/ITD had a worse outcome than those harboring NUP98/NSD1 only. In multivariate analysis, the dual NUP98/NSD1 and FLT3/ITD remained an independent predictor of poor outcome, and NUP98/NSD1 without FLT3/ITD lost its prognostic significance. Our study demonstrates that it is the interaction between NUP98/NSD1 and FLT3/ITD that determines the poor outcome of patients with NUP98/NSD1 disease.
authors.affiliation: Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA; University of Washington, Seattle, WA;
authors.forename: Fabiana
authors.initials: F
authors.lastname: Ostronoff
authors.affiliation: Fred Hutchinson Cancer Research Center, Public Health Sciences Division, Seattle, WA; SWOG Statistical Center, Seattle, WA;
authors.forename: Megan
authors.initials: M
authors.lastname: Othus
authors.affiliation: Children's Oncology Group, Arcadia, CA;
authors.forename: Robert B
authors.initials: RB
authors.lastname: Gerbing
authors.affiliation: Hematologics, Inc., Seattle, WA;
authors.forename: Michael R
authors.initials: MR
authors.lastname: Loken
authors.affiliation: St. Jude Children's Research Hospital, Pathology Division, Memphis, TN;
authors.forename: Susana C
authors.initials: SC
authors.lastname: Raimondi
authors.affiliation: University of Minnesota Medical Center-Fairview, Minneapolis, MN;
authors.forename: Betsy A
authors.initials: BA
authors.lastname: Hirsch
authors.affiliation: Children's Hospital of Philadelphia, Department of Pediatrics, Division of Oncology, Philadelphia, PA;
authors.forename: Beverly J
authors.initials: BJ
authors.lastname: Lange
authors.affiliation: Seattle Genetics, Inc., Seattle, WA;
authors.forename: Stephen
authors.initials: S
authors.lastname: Petersdorf
authors.affiliation: Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA; University of Washington, Seattle, WA;
authors.forename: Jerald
authors.initials: J
authors.lastname: Radich
authors.affiliation: Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA; University of Washington, Seattle, WA;
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Appelbaum
authors.affiliation: Children's Oncology Group, Arcadia, CA; Children's Mercy Hospitals and Clinics, Kansas City, MO; and.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Gamis
authors.affiliation: Children's Oncology Group, Arcadia, CA; University of Southern California, Los Angeles, CA.
authors.forename: Todd A
authors.initials: TA
authors.lastname: Alonzo
authors.affiliation: Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA; Children's Oncology Group, Arcadia, CA;
authors.forename: Soheil
authors.initials: S
authors.lastname: Meshinchi
mesh_terms: D000293:Adolescent; D017677:Age Distribution; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D053208:Kaplan-Meier Estimate; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism* / Q000628:therapy*; D008297:Male; D015999:Multivariate Analysis; D018365:Neoplasm, Residual / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D012044:Regression Analysis; D012074:Remission Induction; D017211:Treatment Failure; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism*
chemical_list: C522276:NUP98-NSD1 protein, human; D015514:Oncogene Proteins, Fusion; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3