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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 and Kadia, Tapan , et al. (2019) In Journal of clinical oncology : official journal of the American Society of Clinical Oncology 37(29). p.2632-2642
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... (More)

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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Journal of clinical oncology : official journal of the American Society of Clinical Oncology
volume
37
issue
29
pages
2632 - 2642
publisher
American Society of Clinical Oncology
external identifiers
  • scopus:85072994068
  • pmid:31430225
ISSN
1527-7755
DOI
10.1200/JCO.19.00416
language
English
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yes
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b6adf402-6bf6-45fd-a4a9-5adc6d5c71c9
date added to LUP
2019-10-15 09:04:02
date last changed
2020-02-19 05:40:44
@article{b6adf402-6bf6-45fd-a4a9-5adc6d5c71c9,
  abstract     = {<p>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 &lt; .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; P &lt; .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; P &lt; .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 &lt; .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.</p>},
  author       = {Angenendt, Linus and Röllig, Christoph and Montesinos, Pau and Martínez-Cuadrón, David and Barragan, Eva and García, Raimundo and Botella, Carmen and Martínez, Pilar and Ravandi, Farhad and Kadia, Tapan and Kantarjian, Hagop M. and Cortes, Jorge and Juliusson, Gunnar and Lazarevic, Vladimir and Recher, Christian and Pigneux, Arnaud and Bertoli, Sarah and Dumas, Pierre Yves and Dombret, Hervé and Preudhomme, Claude and Micol, Jean Baptiste and Terré, Christine and Ráčil, Zdeněk and Novák, Jan and Žák, Pavel and Wei, Andrew H. and Tiong, Ing S. and Wall, Meaghan and Estey, Elihu and Shaw, Carole and Exeler, Rita and Wagenführ, Lisa and Stölzel, Friedrich and Thiede, Christian and Stelljes, Matthias and Lenz, Georg and Mikesch, Jan Henrik and Serve, Hubert and Ehninger, Gerhard and Berdel, Wolfgang E. and Kramer, Michael and Krug, Utz and Schliemann, Christoph},
  issn         = {1527-7755},
  language     = {eng},
  month        = {10},
  number       = {29},
  pages        = {2632--2642},
  publisher    = {American Society of Clinical Oncology},
  series       = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology},
  title        = {Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia : A Pooled Analysis of Individual Patient Data From Nine International Cohorts},
  url          = {http://dx.doi.org/10.1200/JCO.19.00416},
  doi          = {10.1200/JCO.19.00416},
  volume       = {37},
  year         = {2019},
}