Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia: A Pooled Analysis of Individual Patient Data From Nine International Cohorts

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title = "Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia: A Pooled Analysis of Individual Patient Data From Nine International Cohorts",
abstract = "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.",
author = "Linus Angenendt and Christoph R{\"o}llig and Pau Montesinos and David Mart{\'i}nez-Cuadr{\'o}n and Eva Barragan and Raimundo Garc{\'i}a and Carmen Botella and Pilar Mart{\'i}nez and Farhad Ravandi and Tapan Kadia and Kantarjian, {Hagop M.} and Jorge Cortes and Gunnar Juliusson and Vladimir Lazarevic and Christian Recher and Arnaud Pigneux and Sarah Bertoli and Dumas, {Pierre Yves} and Herv{\'e} Dombret and Claude Preudhomme and Micol, {Jean Baptiste} and Christine Terr{\'e} and Zdeněk R{\'a}čil and Jan Nov{\'a}k and Pavel Ž{\'a}k and Wei, {Andrew H.} and Tiong, {Ing S.} and Meaghan Wall and Elihu Estey and Carole Shaw and Rita Exeler and Lisa Wagenf{\"u}hr and Friedrich St{\"o}lzel and Christian Thiede and Matthias Stelljes and Georg Lenz and Mikesch, {Jan Henrik} and Hubert Serve and Gerhard Ehninger and Berdel, {Wolfgang E.} and Michael Kramer and Utz Krug and Christoph Schliemann",
year = "2019",
month = "10",
day = "10",
doi = "10.1200/JCO.19.00416",
language = "English",
volume = "37",
pages = "2632--2642",
journal = "Journal of Clinical Oncology",
issn = "0732-183X",
publisher = "American Society of Clinical Oncology",
number = "29",