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RESEARCH PRODUCT

Impact of NPM1/FLT3-ITD genotypes defined by the 2017 European LeukemiaNet in patients with acute myeloid leukemia

Michael HeuserAndrew H. WeiRebecca B. KlisovicAxel BennerDan JonesRichard F. SchlenkHartmut DöhnerSergio AmadoriArnold GanserBruno C. MedeirosJoseph BrandweinJorge SierraMartin S. TallmanCeline PallaudGerhard EhningerMaria Teresa VosoAgnes GambietzThomas W. PriorRichard A. LarsonTheo De WitteDietger NiederwieserClara D. BloomfieldJürgen KrauterMiguel A. SanzMiguel A. SanzEkaterina PaninaFrederick R. AppelbaumKonstanze DöhnerTiziana OttoneJ. NomdedeuChristian ThiedeRichard StoneJoop H. JansenSumithra J. MandrekarHubert ServeNikolaus JahnGuido MarcucciInsa Gathmann

subject

OncologyPROBABILITIESMalePROGNOSISCancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2]NPM1 MUTATIONBiochemistryEuropean LeukemiaNetchemistry.chemical_compoundALLELIC RATIOAMLRisk FactorsGene Duplicationhemic and lymphatic diseasesMidostaurinFLT3Myeloid NeoplasiaHematopoietic Stem Cell TransplantationMyeloid leukemiaNuclear ProteinsHematologyCHEMOTHERAPYMiddle AgedPrognosisChemotherapy regimenEuropeLeukemia Myeloid Acutemedicine.anatomical_structureTreatment OutcomeTandem Repeat SequencesFemaleNucleophosminmedicine.medical_specialtyNPM1GenotypeImmunologyYOUNGER ADULTSInternal medicineWhite blood cellmedicineNORMAL CYTOGENETICSHumansGenetic Predisposition to DiseaseProportional Hazards ModelsProportional hazards modelbusiness.industryCell BiologyINTERNAL TANDEM DUPLICATIONTransplantationchemistryfms-Like Tyrosine Kinase 3Multivariate AnalysisbusinessSettore MED/15 - Malattie del Sangue

description

Contains fulltext : 218279.pdf (Publisher’s version ) (Open Access) Patients with acute myeloid leukemia (AML) harboring FLT3 internal tandem duplications (ITDs) have poor outcomes, in particular AML with a high (>/=0.5) mutant/wild-type allelic ratio (AR). The 2017 European LeukemiaNet (ELN) recommendations defined 4 distinct FLT3-ITD genotypes based on the ITD AR and the NPM1 mutational status. In this retrospective exploratory study, we investigated the prognostic and predictive impact of the NPM1/FLT3-ITD genotypes categorized according to the 2017 ELN risk groups in patients randomized within the RATIFY trial, which evaluated the addition of midostaurin to standard chemotherapy. The 4 NPM1/FLT3-ITD genotypes differed significantly with regard to clinical and concurrent genetic features. Complete ELN risk categorization could be done in 318 of 549 trial patients with FLT3-ITD AML. Significant factors for response after 1 or 2 induction cycles were ELN risk group and white blood cell (WBC) counts; treatment with midostaurin had no influence. Overall survival (OS) differed significantly among ELN risk groups, with estimated 5-year OS probabilities of 0.63, 0.43, and 0.33 for favorable-, intermediate-, and adverse-risk groups, respectively (P < .001). A multivariate Cox model for OS using allogeneic hematopoietic cell transplantation (HCT) in first complete remission as a time-dependent variable revealed treatment with midostaurin, allogeneic HCT, ELN favorable-risk group, and lower WBC counts as significant favorable factors. In this model, there was a consistent beneficial effect of midostaurin across ELN risk groups.

yearjournalcountryeditionlanguage
2020-01-30
10.1182/blood.2019002697https://hdl.handle.net/2066/218279