title: Resistance prediction in AML: analysis of 4601 patients from MRC/NCRI, HOVON/SAKK, SWOG and MD Anderson Cancer Center.
abstract: Therapeutic resistance remains the principal problem in acute myeloid leukemia (AML). We used area under receiver-operating characteristic curves (AUCs) to quantify our ability to predict therapeutic resistance in individual patients, where AUC=1.0 denotes perfect prediction and AUC=0.5 denotes a coin flip, using data from 4601 patients with newly diagnosed AML given induction therapy with 3+7 or more intense standard regimens in UK Medical Research Council/National Cancer Research Institute, Dutch-Belgian Cooperative Trial Group for Hematology/Oncology/Swiss Group for Clinical Cancer Research, US cooperative group SWOG and MD Anderson Cancer Center studies. Age, performance status, white blood cell count, secondary disease, cytogenetic risk and FLT3-ITD/NPM1 mutation status were each independently associated with failure to achieve complete remission despite no early death ('primary refractoriness'). However, the AUC of a bootstrap-corrected multivariable model predicting this outcome was only 0.78, indicating only fair predictive ability. Removal of FLT3-ITD and NPM1 information only slightly decreased the AUC (0.76). Prediction of resistance, defined as primary refractoriness or short relapse-free survival, was even more difficult. Our limited ability to forecast resistance based on routinely available pretreatment covariates provides a rationale for continued randomization between standard and new therapies and supports further examination of genetic and posttreatment data to optimize resistance prediction in AML.
authors.affiliation: 1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA [2] Division of Hematology, Department of Medicine, University of Washington, Seattle, WA, USA [3] Department of Epidemiology, University of Washington, Seattle, WA, USA.
authors.forename: R B
authors.initials: RB
authors.lastname: Walter
authors.affiliation: SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Othus
authors.affiliation: Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: A K
authors.initials: AK
authors.lastname: Burnett
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: B
authors.initials: B
authors.lastname: Löwenberg
authors.affiliation: Leukemia Department, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: H M
authors.initials: HM
authors.lastname: Kantarjian
authors.affiliation: Division of Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: G J
authors.initials: GJ
authors.lastname: Ossenkoppele
authors.affiliation: Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: R K
authors.initials: RK
authors.lastname: Hills
authors.affiliation: Leukemia Department, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: F
authors.initials: F
authors.lastname: Ravandi
authors.affiliation: Department of Medical Oncology, University Hospital, Bern, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Pabst
authors.affiliation: Department of Haematology, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: A
authors.initials: A
authors.lastname: Evans
authors.affiliation: Leukemia Department, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S R
authors.initials: SR
authors.lastname: Pierce
authors.affiliation: Department of Hematology, Cliniques Universitaires Saint-Luc UCL, Brussels, Belgium.
authors.forename: M-C
authors.initials: MC
authors.lastname: Vekemans
authors.affiliation: 1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA [2] Department of Medicine, Division of Medical Oncology, University of Washington, Seattle, WA, USA.
authors.forename: F R
authors.initials: FR
authors.lastname: Appelbaum
authors.affiliation: 1] Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA [2] Division of Hematology, Department of Medicine, University of Washington, Seattle, WA, USA.
authors.forename: E H
authors.initials: EH
authors.lastname: Estey
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D018365:Neoplasm, Residual; D000090243:Nucleophosmin; D011379:Prognosis; D012044:Regression Analysis; D012074:Remission Induction; D016896:Treatment Outcome; D055815:Young Adult
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