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Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia: A Pooled Analysis of Individual Patient Data From Nine International Cohorts
Univ Hosp Munster, Munster, Germany.
Tech Univ Dresden, Univ Hosp, Dresden, Germany.
Hosp Univ & Politec La Fe, Valencia, Spain;Ctr Invest Biomed Red Canc, Madrid, Spain.
Hosp Univ & Politec La Fe, Valencia, Spain;Ctr Invest Biomed Red Canc, Madrid, Spain.
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2019 (English)In: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 37, no 29, p. 2632-2642Article in journal (Refereed) Published
Abstract [en]

PURPOSE: Nucleophosmin 1 (NPM1) mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene (FLT3) is absent (FLT3-ITDneg) or present with a low allelic ratio (FLT3-ITDlow). The 2017 European LeukemiaNet guidelines assume this is true regardless of accompanying cytogenetic abnormalities. We investigated the validity of this assumption.

METHODS: We analyzed associations between karyotype and outcome in intensively treated patients with NPM1(mut)/FLT3-ITDneg/low AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers.

RESULTS: Among 2,426 patients with NPM1(mut)/FLT3-ITDneg/low AML, 2,000 (82.4%) had a normal and 426 (17.6%) had an abnormal karyotype, including 329 patients (13.6%) with intermediate and 83 patients (3.4%) with adverse-risk chromosomal abnormalities. In patients with NPM1(mut)/FLT3-ITDneg/low AML, adverse cytogenetics were associated with lower complete remission rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; P < .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; P < .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; P < .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.2%, 51.9%, respectively; P = .0012). These associations remained in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors (P < .001 for all end points). In patients with adverse-risk chromosomal aberrations, we found no significant influence of the NPM1 mutational status on outcome.

CONCLUSION: Karyotype abnormalities are significantly associated with outcome in NPM1(mut)/FLT3-ITDneg/low AML. When adverse-risk cytogenetics are present, patients with NPM1(mut) share the same unfavorable prognosis as patients with NPM1 wild type and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in NPM1(mut)/FLT3-ITDneg/low AML.

Place, publisher, year, edition, pages
AMER SOC CLINICAL ONCOLOGY , 2019. Vol. 37, no 29, p. 2632-2642
National Category
Cancer and Oncology Hematology
Identifiers
URN: urn:nbn:se:uu:diva-396959DOI: 10.1200/JCO.19.00416ISI: 000491485600006PubMedID: 31430225OAI: oai:DiVA.org:uu-396959DiVA, id: diva2:1369993
Funder
German Research Foundation (DFG), DFG EXC 1003Available from: 2019-11-13 Created: 2019-11-13 Last updated: 2019-11-13Bibliographically approved

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Höglund, MartinLehmann, Sören

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