Open AccessS1614 CHROMOSOMAL ABNORMALITIES DETERMINE OUTCOME IN NPM1MUT/FLT3‐ITDNEG/LOW ACUTE MYELOID LEUKEMIA
Author(s) -
Angenendt L.,
Röllig C.,
Montesinos P.,
MartínezCuadrón D.,
Barragan E.,
García R.,
Botella C.,
Martínez P.,
Ravandi F.,
Kadia T.,
Kantarjian H.M.,
Cortes J.,
Juliusson G.,
Lazarevic V.,
Höglund M.,
Lehmann S.,
Recher C.,
Pigneux A.,
Bertoli S.,
Dumas P.Y.,
Dombret H.,
Preudhomme C.,
Micol J.B.,
Terré C.,
Ráčil Z.,
Novák J.,
Žák P.,
Wei A.H.,
Tiong I.S.,
Wall M.,
Estey E.,
Shaw C.,
Exeler R.,
Wagenführ L.,
Stölzel F.,
Thiede C.,
Stelljes M.,
Lenz G.,
Mikesch J.H.,
Serve H.,
Ehninger G.,
Berdel W.E.,
Kramer M.,
Krug U.,
Schliemann C.
Publication year - 2019
Publication title -
hemasphere
Language(s) - Uncategorized
Resource type - Journals
SCImago Journal Rank - 0.677
H-Index - 11
ISSN - 2572-9241
DOI - 10.1097/01.hs9.0000564704.06449.f2
Subject(s) - npm1 , karyotype , myeloid leukemia , medicine , concomitant , adverse effect , cytogenetics , oncology , gastroenterology , biology , genetics , chromosome , gene
Background: Nucleophosmin 1 ( NPM1 ) mutations confer a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms related tyrosine kinase 3 gene ( FLT3 ) with a high allelic ratio is absent ( FLT3 ‐ITD neg/low ). The prognostic impact is considered to be independent of the karyotype, most influentially in the most recent 2017 ELN genetic risk classification. Here we investigate the validity of this assumption. Aims: This study investigates the prognostic impact of concomitant cytogenetic abnormalities in NPM1 mut / FLT3 ‐ITD neg/low AML. Methods: We analyzed the impact of karyotype on outcome in intensively treated patients with NPM1 mut / FLT3 ‐ITD neg/low AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers. NPM1 wt / FLT3 ‐ITD neg/low AML patients with adverse cytogenetic abnormalities from the same cohorts served as comparator for adverse risk. Results: We identified 2426 patients with NPM1 mut / FLT3 ‐ITD neg/low AML. 2000 (82.4%) of these had a normal and 426 (17.6%) had an abnormal karyotype, including 329 (13.6%) patients with karyotype abnormalities of intermediate risk and 83 (3.4%) patients with karyotype abnormalities of adverse risk. In patients with NPM1 mut / FLT3 ‐ITD neg/low AML, adverse cytogenetics were associated with lower complete remission (CR) rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; P < .0001), inferior overall (5‐year OS, 52.4%, 44.8%, 19.5%; P < .0001) and event‐free survival (5‐year EFS, 40.5%, 35.8%, 18.0%; P < .0001), and a higher cumulative incidence of relapse (5‐year CIR, 43.6%, 44.2%, 51.9%; P = .0012). Cytogenetic risk remained independently associated with all endpoints in multivariable mixed‐effects regression analyses adjusted for known clinicopathological risk factors ( P < .0001 for all endpoints). In patients with adverse risk chromosomal aberrations, we found no significant influence of the NPM1 mutational status on outcome. Summary/Conclusion: This international collaborative study reveals that cytogenetic abnormalities are important determinants of outcome in NPM1 mut / FLT3 ‐ITD neg/low AML. Most importantly, NPM1 mutated patients with the FLT3 ‐ITD neg/low genotype and adverse risk cytogenetics share the same unfavorable prognosis as their NPM1 wildtype counterparts and should be classified accordingly.