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

J 2019

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

ANGENENDT, Linus, Christoph ROLLIG, Pau MONTESINOS, David MARTINEZ-CUADRON, Eva BARRAGAN et. al.

Basic information

Original name

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

Authors

ANGENENDT, Linus (276 Germany, guarantor), Christoph ROLLIG (276 Germany), Pau MONTESINOS (724 Spain), David MARTINEZ-CUADRON (724 Spain), Eva BARRAGAN (724 Spain), Raimundo GARCIA (724 Spain), Carmen BOTELLA (724 Spain), Pilar MARTINEZ (724 Spain), Farhad RAVANDI (840 United States of America), Tapan KADIA (840 United States of America), Hagop M. KANTARJIAN (840 United States of America), Jorge CORTES (840 United States of America), Gunnar JULIUSSON (752 Sweden), Vladimir LAZAREVIC (752 Sweden), Martin HOGLUND, Soren LEHMANN (752 Sweden), Christian RECHER (250 France), Arnaud PIGNEUX (250 France), Sarah BERTOLI (250 France), Pierre-Yves DUMAS (250 France), Herve DOMBRET (250 France), Claude PREUDHOMME (250 France), Jean-Baptiste MICOL (250 France), Christine TERRE (250 France), Zdeněk RÁČIL (203 Czech Republic, belonging to the institution), Jan NOVAK (203 Czech Republic), Pavel ZAK (203 Czech Republic), Andrew H. WEI (36 Australia), Ing S. TIONG (36 Australia), Meaghan WALL (36 Australia), Elihu ESTEY (840 United States of America), Carole SHAW (840 United States of America), Rita EXELER (276 Germany), Lisa WAGENFUHR (276 Germany), Friedrich STOLZEL (276 Germany), Christian THIEDE (276 Germany), Matthias STELLJES (276 Germany), Georg LENZ (276 Germany), Jan-Henrik MIKESCH (276 Germany), Hubert SERVE (276 Germany), Gerhard EHNINGER (276 Germany), Wolfgang E. BERDEL (276 Germany), Michael KRAMER (276 Germany), Utz KRUG (276 Germany) and Christoph SCHLIEMANN (276 Germany)

Edition

Journal of clinical oncology, ALEXANDRIA, VA, AMER SOC CLINICAL ONCOLOGY, 2019, 0732-183X

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30204 Oncology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 32.956

RIV identification code

RIV/00216224:14110/19:00112133

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1200/JCO.19.00416

UT WoS

000491485600006

Keywords in English

ACUTE MYELOGENOUS LEUKEMIA; MINIMAL RESIDUAL DISEASE; NPM1 MUTATIONS; FAVORABLE PROGNOSIS; NUCLEOPHOSMIN NPM1; ADULT PATIENTS; AML; IMPACT; TRANSPLANTATION

Abstract

V originále

PURPOSENucleophosmin 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.METHODSWe 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.RESULTSAmong 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.CONCLUSIONKaryotype 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.

Citovat

ANGENENDT, Linus, Christoph ROLLIG, Pau MONTESINOS, David MARTINEZ-CUADRON, Eva BARRAGAN, Raimundo GARCIA, Carmen BOTELLA, Pilar MARTINEZ, Farhad RAVANDI, Tapan KADIA, Hagop M. KANTARJIAN, Jorge CORTES, Gunnar JULIUSSON, Vladimir LAZAREVIC, Martin HOGLUND, Soren LEHMANN, Christian RECHER, Arnaud PIGNEUX, Sarah BERTOLI, Pierre-Yves DUMAS, Herve DOMBRET, Claude PREUDHOMME, Jean-Baptiste MICOL, Christine TERRE, Zdeněk RÁČIL, Jan NOVAK, Pavel ZAK, Andrew H. WEI, Ing S. TIONG, Meaghan WALL, Elihu ESTEY, Carole SHAW, Rita EXELER, Lisa WAGENFUHR, Friedrich STOLZEL, Christian THIEDE, Matthias STELLJES, Georg LENZ, Jan-Henrik MIKESCH, Hubert SERVE, Gerhard EHNINGER, Wolfgang E. BERDEL, Michael KRAMER, Utz KRUG and Christoph SCHLIEMANN. 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. ALEXANDRIA, VA: AMER SOC CLINICAL ONCOLOGY, 2019, vol. 37, No 29, p. 2632-2644. ISSN 0732-183X. Available from: https://dx.doi.org/10.1200/JCO.19.00416.

@article{1600415,
   author = {Angenendt, Linus and Rollig, Christoph and Montesinos, Pau and MartinezandCuadron, David and Barragan, Eva and Garcia, Raimundo and Botella, Carmen and Martinez, Pilar and Ravandi, Farhad and Kadia, Tapan and Kantarjian, Hagop M. and Cortes, Jorge and Juliusson, Gunnar and Lazarevic, Vladimir and Hoglund, Martin and Lehmann, Soren and Recher, Christian and Pigneux, Arnaud and Bertoli, Sarah and Dumas, PierreandYves and Dombret, Herve and Preudhomme, Claude and Micol, JeanandBaptiste and Terre, Christine and Ráčil, Zdeněk and Novak, Jan and Zak, Pavel and Wei, Andrew H. and Tiong, Ing S. and Wall, Meaghan and Estey, Elihu and Shaw, Carole and Exeler, Rita and Wagenfuhr, Lisa and Stolzel, Friedrich and Thiede, Christian and Stelljes, Matthias and Lenz, Georg and Mikesch, JanandHenrik and Serve, Hubert and Ehninger, Gerhard and Berdel, Wolfgang E. and Kramer, Michael and Krug, Utz and Schliemann, Christoph},
   article_location = {ALEXANDRIA, VA},
   article_number = {29},
   doi = {http://dx.doi.org/10.1200/JCO.19.00416},
   keywords = {ACUTE MYELOGENOUS LEUKEMIA; MINIMAL RESIDUAL DISEASE; NPM1 MUTATIONS; FAVORABLE PROGNOSIS; NUCLEOPHOSMIN NPM1; ADULT PATIENTS; AML; IMPACT; TRANSPLANTATION},
   language = {eng},
   issn = {0732-183X},
   journal = {Journal 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},
   volume = {37},
   year = {2019}
}

TY  - JOUR
ID  - 1600415
AU  - Angenendt, Linus - Rollig, Christoph - Montesinos, Pau - Martinez-Cuadron, David - Barragan, Eva - Garcia, Raimundo - Botella, Carmen - Martinez, Pilar - Ravandi, Farhad - Kadia, Tapan - Kantarjian, Hagop M. - Cortes, Jorge - Juliusson, Gunnar - Lazarevic, Vladimir - Hoglund, Martin - Lehmann, Soren - Recher, Christian - Pigneux, Arnaud - Bertoli, Sarah - Dumas, Pierre-Yves - Dombret, Herve - Preudhomme, Claude - Micol, Jean-Baptiste - Terre, Christine - Ráčil, Zdeněk - Novak, Jan - Zak, Pavel - Wei, Andrew H. - Tiong, Ing S. - Wall, Meaghan - Estey, Elihu - Shaw, Carole - Exeler, Rita - Wagenfuhr, Lisa - Stolzel, Friedrich - Thiede, Christian - Stelljes, Matthias - Lenz, Georg - Mikesch, Jan-Henrik - Serve, Hubert - Ehninger, Gerhard - Berdel, Wolfgang E. - Kramer, Michael - Krug, Utz - Schliemann, Christoph
PY  - 2019
TI  - Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia: A Pooled Analysis of Individual Patient Data From Nine International Cohorts
JF  - Journal of clinical oncology
VL  - 37
IS  - 29
SP  - 2632-2644
EP  - 2632-2644
PB  - AMER SOC CLINICAL ONCOLOGY
SN  - 0732183X
KW  - ACUTE MYELOGENOUS LEUKEMIA
KW  - MINIMAL RESIDUAL DISEASE
KW  - NPM1 MUTATIONS
KW  - FAVORABLE PROGNOSIS
KW  - NUCLEOPHOSMIN NPM1
KW  - ADULT PATIENTS
KW  - AML
KW  - IMPACT
KW  - TRANSPLANTATION
UR  - http://dx.doi.org/10.1200/JCO.19.00416
L2  - http://dx.doi.org/10.1200/JCO.19.00416
N2  - PURPOSENucleophosmin 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.METHODSWe 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.RESULTSAmong 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.CONCLUSIONKaryotype 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.
ER  -

ANGENENDT, Linus, Christoph ROLLIG, Pau MONTESINOS, David MARTINEZ-CUADRON, Eva BARRAGAN, Raimundo GARCIA, Carmen BOTELLA, Pilar MARTINEZ, Farhad RAVANDI, Tapan KADIA, Hagop M. KANTARJIAN, Jorge CORTES, Gunnar JULIUSSON, Vladimir LAZAREVIC, Martin HOGLUND, Soren LEHMANN, Christian RECHER, Arnaud PIGNEUX, Sarah BERTOLI, Pierre-Yves DUMAS, Herve DOMBRET, Claude PREUDHOMME, Jean-Baptiste MICOL, Christine TERRE, Zdeněk RÁČIL, Jan NOVAK, Pavel ZAK, Andrew H. WEI, Ing S. TIONG, Meaghan WALL, Elihu ESTEY, Carole SHAW, Rita EXELER, Lisa WAGENFUHR, Friedrich STOLZEL, Christian THIEDE, Matthias STELLJES, Georg LENZ, Jan-Henrik MIKESCH, Hubert SERVE, Gerhard EHNINGER, Wolfgang E. BERDEL, Michael KRAMER, Utz KRUG and Christoph SCHLIEMANN. Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia: A Pooled Analysis of Individual Patient Data From Nine International Cohorts. \textit{Journal of clinical oncology}. ALEXANDRIA, VA: AMER SOC CLINICAL ONCOLOGY, 2019, vol.~37, No~29, p.~2632-2644. ISSN~0732-183X. Available from: https://dx.doi.org/10.1200/JCO.19.00416.

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