Publication details

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

Authors	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
Year of publication	2019
Type	Article in Periodical
Magazine / Source	Journal of clinical oncology
MU Faculty or unit	Faculty of Medicine
Citation
Web	http://dx.doi.org/10.1200/JCO.19.00416
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
Description	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.