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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2632-2642
Number of pages11
JournalJournal of Clinical Oncology
Volume37
Issue number29
DOIs
StatePublished - Oct 10 2019
Externally publishedYes

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Acute Myeloid Leukemia
Chromosome Aberrations
Karyotype
Cytogenetics
Abnormal Karyotype
nucleophosmin
Protein-Tyrosine Kinases
Disease-Free Survival
Registries
Regression Analysis
Databases
Guidelines
Recurrence
Mutation
Incidence
Genes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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

In: Journal of Clinical Oncology, Vol. 37, No. 29, 10.10.2019, p. 2632-2642.

Research output: Contribution to journalArticle

Angenendt, L, Röllig, C, Montesinos, P, Martínez-Cuadrón, D, Barragan, E, García, R, Botella, C, Martínez, P, Ravandi, F, Kadia, T, Kantarjian, HM, Cortes, J, Juliusson, G, Lazarevic, V, Höglund, M, Lehmann, S, Recher, C, Pigneux, A, Bertoli, S, Dumas, PY, Dombret, H, Preudhomme, C, Micol, JB, Terré, C, Ráčil, Z, Novák, J, Žák, P, Wei, AH, Tiong, IS, Wall, M, Estey, E, Shaw, C, Exeler, R, Wagenführ, L, Stölzel, F, Thiede, C, Stelljes, M, Lenz, G, Mikesch, JH, Serve, H, Ehninger, G, Berdel, WE, Kramer, M, Krug, U & Schliemann, C 2019, 'Chromosomal abnormalities and prognosis in NPM1-mutated acute myeloid leukemia: A pooled analysis of individual patient data from nine international cohorts', Journal of Clinical Oncology, vol. 37, no. 29, pp. 2632-2642. https://doi.org/10.1200/JCO.19.00416
Angenendt, Linus ; Röllig, Christoph ; Montesinos, Pau ; Martínez-Cuadrón, David ; Barragan, Eva ; García, Raimundo ; Botella, Carmen ; Martínez, Pilar ; Ravandi, Farhad ; Kadia, Tapan ; Kantarjian, Hagop M. ; Cortes, Jorge ; Juliusson, Gunnar ; Lazarevic, Vladimir ; Höglund, Martin ; Lehmann, Sören ; Recher, Christian ; Pigneux, Arnaud ; Bertoli, Sarah ; Dumas, Pierre Yves ; Dombret, Hervé ; Preudhomme, Claude ; Micol, Jean Baptiste ; Terré, Christine ; Ráčil, Zdeněk ; Novák, Jan ; Žák, Pavel ; Wei, Andrew H. ; Tiong, Ing S. ; Wall, Meaghan ; Estey, Elihu ; Shaw, Carole ; Exeler, Rita ; Wagenführ, Lisa ; Stölzel, Friedrich ; Thiede, Christian ; Stelljes, Matthias ; Lenz, Georg ; Mikesch, Jan Henrik ; Serve, Hubert ; Ehninger, Gerhard ; Berdel, Wolfgang E. ; Kramer, Michael ; Krug, Utz ; Schliemann, Christoph. / Chromosomal abnormalities and prognosis in NPM1-mutated acute myeloid leukemia : A pooled analysis of individual patient data from nine international cohorts. In: Journal of Clinical Oncology. 2019 ; Vol. 37, No. 29. pp. 2632-2642.
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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 Martin H{\"o}glund and S{\"o}ren Lehmann 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",
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TY - JOUR

T1 - Chromosomal abnormalities and prognosis in NPM1-mutated acute myeloid leukemia

T2 - A pooled analysis of individual patient data from nine international cohorts

AU - Angenendt, Linus

AU - Röllig, Christoph

AU - Montesinos, Pau

AU - Martínez-Cuadrón, David

AU - Barragan, Eva

AU - García, Raimundo

AU - Botella, Carmen

AU - Martínez, Pilar

AU - Ravandi, Farhad

AU - Kadia, Tapan

AU - Kantarjian, Hagop M.

AU - Cortes, Jorge

AU - Juliusson, Gunnar

AU - Lazarevic, Vladimir

AU - Höglund, Martin

AU - Lehmann, Sören

AU - Recher, Christian

AU - Pigneux, Arnaud

AU - Bertoli, Sarah

AU - Dumas, Pierre Yves

AU - Dombret, Hervé

AU - Preudhomme, Claude

AU - Micol, Jean Baptiste

AU - Terré, Christine

AU - Ráčil, Zdeněk

AU - Novák, Jan

AU - Žák, Pavel

AU - Wei, Andrew H.

AU - Tiong, Ing S.

AU - Wall, Meaghan

AU - Estey, Elihu

AU - Shaw, Carole

AU - Exeler, Rita

AU - Wagenführ, Lisa

AU - Stölzel, Friedrich

AU - Thiede, Christian

AU - Stelljes, Matthias

AU - Lenz, Georg

AU - Mikesch, Jan Henrik

AU - Serve, Hubert

AU - Ehninger, Gerhard

AU - Berdel, Wolfgang E.

AU - Kramer, Michael

AU - Krug, Utz

AU - Schliemann, Christoph

PY - 2019/10/10

Y1 - 2019/10/10

N2 - 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.

AB - 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.

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