Chromosomal abnormalities and prognosis in NPM1-mutated acute myeloid leukemia: A pooled analysis of individual patient data from nine international cohorts

Linus Angenendt, Christoph Röllig, Pau Montesinos, David Martínez-Cuadrón, Eva Barragan, Raimundo García, Carmen Botella, Pilar Martínez, Farhad Ravandi, Tapan Kadia, Hagop M. Kantarjian, Jorge Cortes, Gunnar Juliusson, Vladimir Lazarevic, Martin Höglund, Sören Lehmann, Christian Recher, Arnaud Pigneux, Sarah Bertoli, Pierre Yves DumasHervé Dombret, Claude Preudhomme, Jean Baptiste Micol, Christine Terré, Zdeněk Ráčil, Jan Novák, Pavel Žák, Andrew H. Wei, Ing S. Tiong, Meaghan Wall, Elihu Estey, Carole Shaw, Rita Exeler, Lisa Wagenführ, Friedrich Stölzel, Christian Thiede, Matthias Stelljes, Georg Lenz, Jan Henrik Mikesch, Hubert Serve, Gerhard Ehninger, Wolfgang E. Berdel, Michael Kramer, Utz Krug, Christoph Schliemann

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55 Scopus citations


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 NPM1mut/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 NPM1mut/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 NPM1mut/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 NPM1mut/FLT3-ITDneg/low AML. When adverse-risk cytogenetics are present, patients with NPM1mut 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 NPM1mut/FLT3-ITDneg/low AML.

Original languageEnglish (US)
Pages (from-to)2632-2642
Number of pages11
JournalJournal of Clinical Oncology
Issue number29
StatePublished - Oct 10 2019
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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