EHA Library - The official digital education library of European Hematology Association (EHA)

NPM1 MUTATED AML: IMPACT OF CO-MUTATIONAL PATTERNS - RESULTS OF THE EUROPEAN HARMONY ALLIANCE
Author(s): ,
Alberto Hernández-Sánchez
Affiliations:
Hospital Universitario de Salamanca,Salamanca,Espagne;Hospital Universitario de Salamanca,Salamanca,Spanien;Hospital Universitario de Salamanca,Salamanca,Spagna;Hospital Universitario de Salamanca,Salamanca,Spain;Hospital Universitario de Salamanca,Salamanca,España;Hospital Universitario de Salamanca,Salamanca,Spanje;Hospital Universitario de Salamanca,Salamanca,Espanha;Hospital Universitario de S
,
Ángela Villaverde-Ramiro
Affiliations:
Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,Espagne;Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,Spanien;Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,Spagna;Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,Spain;Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,España;Instituto de Investigaci
,
Javier Martínez Elicegui
Affiliations:
Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,Espagne;Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,Spanien;Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,Spagna;Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,Spain;Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,España;Instituto de Investigaci
,
Teresa González
Affiliations:
Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,Espagne;Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,Spanien;Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,Spagna;Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,Spain;Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,España;Instituto de Investigaci
,
Axel Benner
Affiliations:
German Cancer Research Center (DKFZ),Heidelberg,Allemagne;German Cancer Research Center (DKFZ),Heidelberg,Deutschland;German Cancer Research Center (DKFZ),Heidelberg,Germania;German Cancer Research Center (DKFZ),Heidelberg,Germany;German Cancer Research Center (DKFZ),Heidelberg,Alemania;German Cancer Research Center (DKFZ),Heidelberg,Duitsland;German Cancer Research Center (DKFZ),Heidelberg,Aleman
,
Eric Sträng
Affiliations:
Charité Universitätsmedizin Berlin,Berlin,Allemagne;Charité Universitätsmedizin Berlin,Berlin,Deutschland;Charité Universitätsmedizin Berlin,Berlin,Germania;Charité Universitätsmedizin Berlin,Berlin,Germany;Charité Universitätsmedizin Berlin,Berlin,Alemania;Charité Universitätsmedizin Berlin,Berlin,Duitsland;Charité Universitätsmedizin Berlin,Berlin,Alemanha;Charité Universitätsmedizin Berlin,Berl
,
Gastone Castellani
Affiliations:
University of Bologna,Bologna,Italie;University of Bologna,Bologna,Italien;University of Bologna,Bologna,Italia;University of Bologna,Bologna,Italy;University of Bologna,Bologna,Italia;University of Bologna,Bologna,Italië;University of Bologna,Bologna,Itália;University of Bologna,Bologna,Италия;University of Bologna,Bologna,Italien
,
Caroline A. Heckman
Affiliations:
University of Helsinki,Helsinki,Finlande;University of Helsinki,Helsinki,Finnland;University of Helsinki,Helsinki,Finlandia;University of Helsinki,Helsinki,芬兰;University of Helsinki,Helsinki,Finlandia;University of Helsinki,Helsinki,Finland;University of Helsinki,Helsinki,Finlandia;University of Helsinki,Helsinki,Финляндия;University of Helsinki,Helsinki,Finland;Institute for Molecular Medicine Fi
,
Jurjen Versluis
Affiliations:
Erasmus University Medical Center Cancer Institute,Rotterdam,Pays-bas;Erasmus University Medical Center Cancer Institute,Rotterdam,Niederlande;Erasmus University Medical Center Cancer Institute,Rotterdam,Paesi Bassi;Erasmus University Medical Center Cancer Institute,Rotterdam,Netherland;Erasmus University Medical Center Cancer Institute,Rotterdam,Países Bajos;Erasmus University Medical Center Canc
,
María Abáigar
Affiliations:
Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,Espagne;Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,Spanien;Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,Spagna;Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,Spain;Instituto de Investigación Biomédica de Salamanca (IBSAL),Salamanca,España;Instituto de Investigaci
,
Marta Sobas
Affiliations:
Wroclaw Medical University,Wroclaw,Pologne;Wroclaw Medical University,Wroclaw,Polen;Wroclaw Medical University,Wroclaw,Polonia;Wroclaw Medical University,Wroclaw,Poland;Wroclaw Medical University,Wroclaw,Polonia;Wroclaw Medical University,Wroclaw,Polen;Wroclaw Medical University,Wroclaw,Polonia;Wroclaw Medical University,Wroclaw,Польша;Wroclaw Medical University,Wroclaw,Polen
,
Raúl Azibeiro
Affiliations:
Hospital Universitario de Salamanca,Salamanca,Espagne;Hospital Universitario de Salamanca,Salamanca,Spanien;Hospital Universitario de Salamanca,Salamanca,Spagna;Hospital Universitario de Salamanca,Salamanca,Spain;Hospital Universitario de Salamanca,Salamanca,España;Hospital Universitario de Salamanca,Salamanca,Spanje;Hospital Universitario de Salamanca,Salamanca,Espanha;Hospital Universitario de S
,
Laura Tur
Affiliations:
GMV Innovating Solutions,Valencia,Espagne;GMV Innovating Solutions,Valencia,Spanien;GMV Innovating Solutions,Valencia,Spagna;GMV Innovating Solutions,Valencia,Spain;GMV Innovating Solutions,Valencia,España;GMV Innovating Solutions,Valencia,Spanje;GMV Innovating Solutions,Valencia,Espanha;GMV Innovating Solutions,Valencia,Испания;GMV Innovating Solutions,Valencia,Spanien
,
Peter JM Valk
Affiliations:
Erasmus University Medical Center Cancer Institute,Rotterdam,Pays-bas;Erasmus University Medical Center Cancer Institute,Rotterdam,Niederlande;Erasmus University Medical Center Cancer Institute,Rotterdam,Paesi Bassi;Erasmus University Medical Center Cancer Institute,Rotterdam,Netherland;Erasmus University Medical Center Cancer Institute,Rotterdam,Países Bajos;Erasmus University Medical Center Canc
,
Klaus H Metzeler
Affiliations:
University of Munich,Munich,Allemagne;University of Munich,Munich,Deutschland;University of Munich,Munich,Germania;University of Munich,Munich,Germany;University of Munich,Munich,Alemania;University of Munich,Munich,Duitsland;University of Munich,Munich,Alemanha;University of Munich,Munich,Германия;University of Munich,Munich,Tyskland
,
Rosa Ayala
Affiliations:
Hospital Universitario 12 de Octubre,Madrid,Espagne;Hospital Universitario 12 de Octubre,Madrid,Spanien;Hospital Universitario 12 de Octubre,Madrid,Spagna;Hospital Universitario 12 de Octubre,Madrid,Spain;Hospital Universitario 12 de Octubre,Madrid,España;Hospital Universitario 12 de Octubre,Madrid,Spanje;Hospital Universitario 12 de Octubre,Madrid,Espanha;Hospital Universitario 12 de Octubre,Madr
,
Daniele Dall'Olio
Affiliations:
University of Bologna,Bologna,Italie;University of Bologna,Bologna,Italien;University of Bologna,Bologna,Italia;University of Bologna,Bologna,Italy;University of Bologna,Bologna,Italia;University of Bologna,Bologna,Italië;University of Bologna,Bologna,Itália;University of Bologna,Bologna,Италия;University of Bologna,Bologna,Italien
,
Jesse Tettero
Affiliations:
Amsterdam University Medical Center,Amsterdam,Pays-bas;Amsterdam University Medical Center,Amsterdam,Niederlande;Amsterdam University Medical Center,Amsterdam,Paesi Bassi;Amsterdam University Medical Center,Amsterdam,Netherland;Amsterdam University Medical Center,Amsterdam,Países Bajos;Amsterdam University Medical Center,Amsterdam,Nederland;Amsterdam University Medical Center,Amsterdam,Holanda;Ams
,
Joaquín Martínez-López
Affiliations:
Hospital Universitario 12 de Octubre,Madrid,Espagne;Hospital Universitario 12 de Octubre,Madrid,Spanien;Hospital Universitario 12 de Octubre,Madrid,Spagna;Hospital Universitario 12 de Octubre,Madrid,Spain;Hospital Universitario 12 de Octubre,Madrid,España;Hospital Universitario 12 de Octubre,Madrid,Spanje;Hospital Universitario 12 de Octubre,Madrid,Espanha;Hospital Universitario 12 de Octubre,Madr
,
Hervé Dombret
Affiliations:
EA3518 Leukemia Translational Laboratory,Paris,France;EA3518 Leukemia Translational Laboratory,Paris,Frankreich;EA3518 Leukemia Translational Laboratory,Paris,Francia;EA3518 Leukemia Translational Laboratory,Paris,France;EA3518 Leukemia Translational Laboratory,Paris,Francia;EA3518 Leukemia Translational Laboratory,Paris,Frankrijk;EA3518 Leukemia Translational Laboratory,Paris,França;EA3518 Leukem
,
Marta Pratcorona
Affiliations:
Hospital de la Santa Creu i Sant Pau,Barcelona,Espagne;Hospital de la Santa Creu i Sant Pau,Barcelona,Spanien;Hospital de la Santa Creu i Sant Pau,Barcelona,Spagna;Hospital de la Santa Creu i Sant Pau,Barcelona,Spain;Hospital de la Santa Creu i Sant Pau,Barcelona,España;Hospital de la Santa Creu i Sant Pau,Barcelona,Spanje;Hospital de la Santa Creu i Sant Pau,Barcelona,Espanha;Hospital de la Santa
,
Frederik Damm
Affiliations:
Charité Universitätsmedizin Berlin,Berlin,Allemagne;Charité Universitätsmedizin Berlin,Berlin,Deutschland;Charité Universitätsmedizin Berlin,Berlin,Germania;Charité Universitätsmedizin Berlin,Berlin,Germany;Charité Universitätsmedizin Berlin,Berlin,Alemania;Charité Universitätsmedizin Berlin,Berlin,Duitsland;Charité Universitätsmedizin Berlin,Berlin,Alemanha;Charité Universitätsmedizin Berlin,Berl
,
Ken I Mills
Affiliations:
Queens University Belfast,Belfast,Royaume-uni;Queens University Belfast,Belfast,Vereinigtes Königreich;Queens University Belfast,Belfast,Regno Unito;Queens University Belfast,Belfast,United Kingdom;Queens University Belfast,Belfast,Reino Unido;Queens University Belfast,Belfast,Verenigd Koninkrijk;Queens University Belfast,Belfast,Reino Unido;Queens University Belfast,Belfast,Соединённое Королевств
,
Jiří Mayer
Affiliations:
University Hospital Brnoand Masaryk University,Brno,Tchèque, République;University Hospital Brnoand Masaryk University,Brno,Tschechische Republik;University Hospital Brnoand Masaryk University,Brno,Rep. Ceca;University Hospital Brnoand Masaryk University,Brno,Czech;University Hospital Brnoand Masaryk University,Brno,República Checa;University Hospital Brnoand Masaryk University,Brno,Tsjechische Re
,
Christian Thiede
Affiliations:
University of Technics Dresden Medical Dept.,Dresden,Allemagne;University of Technics Dresden Medical Dept.,Dresden,Deutschland;University of Technics Dresden Medical Dept.,Dresden,Germania;University of Technics Dresden Medical Dept.,Dresden,Germany;University of Technics Dresden Medical Dept.,Dresden,Alemania;University of Technics Dresden Medical Dept.,Dresden,Duitsland;University of Technics D
,
Maria Teresa Voso
Affiliations:
University of Rome 'Cattolica S. Cuore',Rome,Italie;University of Rome 'Cattolica S. Cuore',Rome,Italien;University of Rome 'Cattolica S. Cuore',Rome,Italia;University of Rome 'Cattolica S. Cuore',Rome,Italy;University of Rome 'Cattolica S. Cuore',Rome,Italia;University of Rome 'Cattolica S. Cuore',Rome,Italië;University of Rome 'Cattolica S. Cuore',Rome,Itália;University of Rome 'Cattolica S. Cuo
,
Guillermo F Sanz
Affiliations:
Hospital Universitario y Politécnico La Fe,Valencia,Espagne;Hospital Universitario y Politécnico La Fe,Valencia,Spanien;Hospital Universitario y Politécnico La Fe,Valencia,Spagna;Hospital Universitario y Politécnico La Fe,Valencia,Spain;Hospital Universitario y Politécnico La Fe,Valencia,España;Hospital Universitario y Politécnico La Fe,Valencia,Spanje;Hospital Universitario y Politécnico La Fe,Va
,
Frederico Calado
Affiliations:
Novartis, Oncology Region Europe,Basel,Suisse;Novartis, Oncology Region Europe,Basel,Schweiz;Novartis, Oncology Region Europe,Basel,Svizzera;Novartis, Oncology Region Europe,Basel,Switzerland;Novartis, Oncology Region Europe,Basel,Suiza;Novartis, Oncology Region Europe,Basel,Zwitserland;Novartis, Oncology Region Europe,Basel,Suíça;Novartis, Oncology Region Europe,Basel,Швейцария ;Novartis, Oncolog
,
Konstanze Döhner
Affiliations:
University Hospital of Ulm,Ulm,Allemagne;University Hospital of Ulm,Ulm,Deutschland;University Hospital of Ulm,Ulm,Germania;University Hospital of Ulm,Ulm,Germany;University Hospital of Ulm,Ulm,Alemania;University Hospital of Ulm,Ulm,Duitsland;University Hospital of Ulm,Ulm,Alemanha;University Hospital of Ulm,Ulm,Германия;University Hospital of Ulm,Ulm,Tyskland
,
Verena I Gaidzik
Affiliations:
Ulm University Hospital,Ulm,Allemagne;Ulm University Hospital,Ulm,Deutschland;Ulm University Hospital,Ulm,Germania;Ulm University Hospital,Ulm,Germany;Ulm University Hospital,Ulm,Alemania;Ulm University Hospital,Ulm,Duitsland;Ulm University Hospital,Ulm,Alemanha;Ulm University Hospital,Ulm,Германия;Ulm University Hospital,Ulm,Tyskland
,
Michael Heuser
Affiliations:
Hannover Medical School,Hannover,Allemagne;Hannover Medical School,Hannover,Deutschland;Hannover Medical School,Hannover,Germania;Hannover Medical School,Hannover,Germany;Hannover Medical School,Hannover,Alemania;Hannover Medical School,Hannover,Duitsland;Hannover Medical School,Hannover,Alemanha;Hannover Medical School,Hannover,Германия;Hannover Medical School,Hannover,Tyskland
,
Torsten Haferlach
Affiliations:
MLL Munich Leukemia Laboratory,Munich,Allemagne;MLL Munich Leukemia Laboratory,Munich,Deutschland;MLL Munich Leukemia Laboratory,Munich,Germania;MLL Munich Leukemia Laboratory,Munich,Germany;MLL Munich Leukemia Laboratory,Munich,Alemania;MLL Munich Leukemia Laboratory,Munich,Duitsland;MLL Munich Leukemia Laboratory,Munich,Alemanha;MLL Munich Leukemia Laboratory,Munich,Германия;MLL Munich Leukemia
,
Amin T Turki
Affiliations:
Essen University Hospital,Essen,Allemagne;Essen University Hospital,Essen,Deutschland;Essen University Hospital,Essen,Germania;Essen University Hospital,Essen,Germany;Essen University Hospital,Essen,Alemania;Essen University Hospital,Essen,Duitsland;Essen University Hospital,Essen,Alemanha;Essen University Hospital,Essen,Германия;Essen University Hospital,Essen,Tyskland;West-German Cancer Center,E
,
Dirk Reinhardt
Affiliations:
Essen University Hospital,Essen,Allemagne;Essen University Hospital,Essen,Deutschland;Essen University Hospital,Essen,Germania;Essen University Hospital,Essen,Germany;Essen University Hospital,Essen,Alemania;Essen University Hospital,Essen,Duitsland;Essen University Hospital,Essen,Alemanha;Essen University Hospital,Essen,Германия;Essen University Hospital,Essen,Tyskland
,
Rubén Villoria Medina
Affiliations:
GMV Innovating Solutions,Valencia,Espagne;GMV Innovating Solutions,Valencia,Spanien;GMV Innovating Solutions,Valencia,Spagna;GMV Innovating Solutions,Valencia,Spain;GMV Innovating Solutions,Valencia,España;GMV Innovating Solutions,Valencia,Spanje;GMV Innovating Solutions,Valencia,Espanha;GMV Innovating Solutions,Valencia,Испания;GMV Innovating Solutions,Valencia,Spanien
,
Michel van Speybroeck
Affiliations:
Janssen Pharmaceutica N.V.,Beerse,Belgique;Janssen Pharmaceutica N.V.,Beerse,Belgien;Janssen Pharmaceutica N.V.,Beerse,Belgio;Janssen Pharmaceutica N.V.,Beerse,Belgium;Janssen Pharmaceutica N.V.,Beerse,Bélgica;Janssen Pharmaceutica N.V.,Beerse,België;Janssen Pharmaceutica N.V.,Beerse,Bélgica;Janssen Pharmaceutica N.V.,Beerse,Belgium;Janssen Pharmaceutica N.V.,Beerse,Belgien
,
Renate Schulze-Rath
Affiliations:
Bayer Pharma AG,Berlin,Allemagne;Bayer Pharma AG,Berlin,Deutschland;Bayer Pharma AG,Berlin,Germania;Bayer Pharma AG,Berlin,Germany;Bayer Pharma AG,Berlin,Alemania;Bayer Pharma AG,Berlin,Duitsland;Bayer Pharma AG,Berlin,Alemanha;Bayer Pharma AG,Berlin,Германия;Bayer Pharma AG,Berlin,Tyskland
,
Martje Barbus
Affiliations:
AbbVie Germany GmbH & Co. KG,Wiesbaden,Allemagne;AbbVie Germany GmbH & Co. KG,Wiesbaden,Deutschland;AbbVie Germany GmbH & Co. KG,Wiesbaden,Germania;AbbVie Germany GmbH & Co. KG,Wiesbaden,Germany;AbbVie Germany GmbH & Co. KG,Wiesbaden,Alemania;AbbVie Germany GmbH & Co. KG,Wiesbaden,Duitsland;AbbVie Germany GmbH & Co. KG,Wiesbaden,Alemanha;AbbV
,
John E Butler
Affiliations:
Bayer AG,Berlin,Allemagne;Bayer AG,Berlin,Deutschland;Bayer AG,Berlin,Germania;Bayer AG,Berlin,Germany;Bayer AG,Berlin,Alemania;Bayer AG,Berlin,Duitsland;Bayer AG,Berlin,Alemanha;Bayer AG,Berlin,Германия;Bayer AG,Berlin,Tyskland
,
Jesús M Hernández Rivas
Affiliations:
Hospital Universitario de Salamanca,Salamanca,Espagne;Hospital Universitario de Salamanca,Salamanca,Spanien;Hospital Universitario de Salamanca,Salamanca,Spagna;Hospital Universitario de Salamanca,Salamanca,Spain;Hospital Universitario de Salamanca,Salamanca,España;Hospital Universitario de Salamanca,Salamanca,Spanje;Hospital Universitario de Salamanca,Salamanca,Espanha;Hospital Universitario de S
,
Brian JP Huntly
Affiliations:
Wellcome - MRC Cambridge Stem Cell Institute,Cambridge,Royaume-uni;Wellcome - MRC Cambridge Stem Cell Institute,Cambridge,Vereinigtes Königreich;Wellcome - MRC Cambridge Stem Cell Institute,Cambridge,Regno Unito;Wellcome - MRC Cambridge Stem Cell Institute,Cambridge,United Kingdom;Wellcome - MRC Cambridge Stem Cell Institute,Cambridge,Reino Unido;Wellcome - MRC Cambridge Stem Cell Institute,Cambri
,
Gert J Ossenkoppele
Affiliations:
Amsterdam University Medical Center,Amsterdam,Pays-bas;Amsterdam University Medical Center,Amsterdam,Niederlande;Amsterdam University Medical Center,Amsterdam,Paesi Bassi;Amsterdam University Medical Center,Amsterdam,Netherland;Amsterdam University Medical Center,Amsterdam,Países Bajos;Amsterdam University Medical Center,Amsterdam,Nederland;Amsterdam University Medical Center,Amsterdam,Holanda;Ams
,
Hartmut Döhner
Affiliations:
University Hospital of Ulm,Ulm,Allemagne;University Hospital of Ulm,Ulm,Deutschland;University Hospital of Ulm,Ulm,Germania;University Hospital of Ulm,Ulm,Germany;University Hospital of Ulm,Ulm,Alemania;University Hospital of Ulm,Ulm,Duitsland;University Hospital of Ulm,Ulm,Alemanha;University Hospital of Ulm,Ulm,Германия;University Hospital of Ulm,Ulm,Tyskland
Lars Bullinger
Affiliations:
Charité Universitätsmedizin Berlin,Berlin,Allemagne;Charité Universitätsmedizin Berlin,Berlin,Deutschland;Charité Universitätsmedizin Berlin,Berlin,Germania;Charité Universitätsmedizin Berlin,Berlin,Germany;Charité Universitätsmedizin Berlin,Berlin,Alemania;Charité Universitätsmedizin Berlin,Berlin,Duitsland;Charité Universitätsmedizin Berlin,Berlin,Alemanha;Charité Universitätsmedizin Berlin,Berl
(Abstract release date: 05/12/22) EHA Library. Hernández-Sánchez A. 06/10/22; 356994; S130
Alberto Hernández-Sánchez
Alberto Hernández-Sánchez
Contributions
Abstract
Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S130

Type: Oral Presentation

Session title: Novel treatment options and prognostic markers in AML

Background

Acute myeloid leukemia (AML) is a heterogeneous disease in terms of clinical features, outcomes and genetics. While mutations of NPM1 are usually considered as a favorable prognostic marker, the vast majority of the patients carry several co-mutations that might influence the prognosis. Therefore, a better understanding of the NPM1mut AML mutational landscape is warranted. The large cohort of AML patients collected within the European HARMONY Alliance provides an excellent basis for this purpose.

Aims

To identify clinically significant co-mutational patterns in NPM1mut AML in order to establish a revised risk stratification model.

Methods

From the HARMONY Alliance AML database, a total of 1001 NPM1mut intensively treated patients were selected. Clinically significant co-mutations were evaluated using graphical patterns created with the Gephi tool and confirmed by detailed survival analysis using Kaplan-Meier and Cox regression models. Finally, a novel multi-state risk stratification model for NPM1mut AML was established.

Results

The study population of 1001 NPM1mut AML patients included 57% females and median age was 53 years. Regarding ELN2017 classification, 68% of patients were classified into the favorable, 29% intermediate and 3% adverse risk groups. The most frequent co-mutations were DNMT3A (54%), followed by FLT3-ITD (38%). In total, 24% of patients presented with a high allelic mutant-to-wildtype ratio ≥0.5 (FLT3-ITDhigh) while 14% had low allelic ratio <0.5 (FLT3-ITDlow). Other frequent co-mutations were NRAS (21%), TET2 (20%) and PTPN11 (15%).

The triple mutation pattern of NPM1mut + FLT3-ITDhigh + DNMT3Amut identified a subgroup with adverse prognosis (2-year OS of 25%), similar to NPM1mut + TP53mut. The combination of FLT3-ITDlow + DNMT3Amut or FLT3-ITDhigh + DNMT3Awt was associated with intermediate prognosis (2-year OS of 45% and 53% respectively). Notably, mutations of NRAS, KRAS, PTPN11 or RAD21 were identified to be associated with better OS. However, in the context of NPM1mut + DNMT3Amut these mutations did not affect the prognosis when a FLT3-ITD was present. This information is summarized in a 3-category risk classification model (Figure 1).

The revised NPM1mut favorable group presented with a 2-year OS of 73%, while for intermediate and adverse groups the OS was 54% and 27% respectively (p<0.001). Regarding relapse free survival (RFS), the median was not reached in the favorable group, while it was 23 months for intermediate and 6 months for adverse group (p<0.001). It should be noted that 171 patients in the NPM1mut intermediate group would be considered as favorable according to the ELN2017 criteria, as well as 162 patients in the NPM1mut adverse group were previously classified as intermediate risk. Therefore, our model was able to reclassify 33% of NPM1mut AML patients in comparison to ELN2017 criteria.

Multivariate analysis of OS in NPM1mut AML identified the following independent prognostic factors: NPM1mut model (taking favorable group as reference, HR 1.6 for intermediate and HR 2.7 for adverse group, p<0.001); secondary or therapy-related AML (HR 1.8, p<0.001), WBC at diagnosis >100x103/μL (HR 1.5, p<0.001) and age >60 years (HR 1.4, p<0.001).

Conclusion

Analysis of large NPM1mut AML cohorts allows the discovery of co-mutation patterns associated with prognostic outcome. In accordance, we propose a new genetic stratification model for NPM1mut AML that identifies 3 groups with different OS and RFS. This model improves ELN2017 criteria as it is able to correctly reclassify 33% of NPM1mut AML patients.

Keyword(s): Acute myeloid leukemia, Mutation analysis, Prognostic groups, Survival prediction

Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S130

Type: Oral Presentation

Session title: Novel treatment options and prognostic markers in AML

Background

Acute myeloid leukemia (AML) is a heterogeneous disease in terms of clinical features, outcomes and genetics. While mutations of NPM1 are usually considered as a favorable prognostic marker, the vast majority of the patients carry several co-mutations that might influence the prognosis. Therefore, a better understanding of the NPM1mut AML mutational landscape is warranted. The large cohort of AML patients collected within the European HARMONY Alliance provides an excellent basis for this purpose.

Aims

To identify clinically significant co-mutational patterns in NPM1mut AML in order to establish a revised risk stratification model.

Methods

From the HARMONY Alliance AML database, a total of 1001 NPM1mut intensively treated patients were selected. Clinically significant co-mutations were evaluated using graphical patterns created with the Gephi tool and confirmed by detailed survival analysis using Kaplan-Meier and Cox regression models. Finally, a novel multi-state risk stratification model for NPM1mut AML was established.

Results

The study population of 1001 NPM1mut AML patients included 57% females and median age was 53 years. Regarding ELN2017 classification, 68% of patients were classified into the favorable, 29% intermediate and 3% adverse risk groups. The most frequent co-mutations were DNMT3A (54%), followed by FLT3-ITD (38%). In total, 24% of patients presented with a high allelic mutant-to-wildtype ratio ≥0.5 (FLT3-ITDhigh) while 14% had low allelic ratio <0.5 (FLT3-ITDlow). Other frequent co-mutations were NRAS (21%), TET2 (20%) and PTPN11 (15%).

The triple mutation pattern of NPM1mut + FLT3-ITDhigh + DNMT3Amut identified a subgroup with adverse prognosis (2-year OS of 25%), similar to NPM1mut + TP53mut. The combination of FLT3-ITDlow + DNMT3Amut or FLT3-ITDhigh + DNMT3Awt was associated with intermediate prognosis (2-year OS of 45% and 53% respectively). Notably, mutations of NRAS, KRAS, PTPN11 or RAD21 were identified to be associated with better OS. However, in the context of NPM1mut + DNMT3Amut these mutations did not affect the prognosis when a FLT3-ITD was present. This information is summarized in a 3-category risk classification model (Figure 1).

The revised NPM1mut favorable group presented with a 2-year OS of 73%, while for intermediate and adverse groups the OS was 54% and 27% respectively (p<0.001). Regarding relapse free survival (RFS), the median was not reached in the favorable group, while it was 23 months for intermediate and 6 months for adverse group (p<0.001). It should be noted that 171 patients in the NPM1mut intermediate group would be considered as favorable according to the ELN2017 criteria, as well as 162 patients in the NPM1mut adverse group were previously classified as intermediate risk. Therefore, our model was able to reclassify 33% of NPM1mut AML patients in comparison to ELN2017 criteria.

Multivariate analysis of OS in NPM1mut AML identified the following independent prognostic factors: NPM1mut model (taking favorable group as reference, HR 1.6 for intermediate and HR 2.7 for adverse group, p<0.001); secondary or therapy-related AML (HR 1.8, p<0.001), WBC at diagnosis >100x103/μL (HR 1.5, p<0.001) and age >60 years (HR 1.4, p<0.001).

Conclusion

Analysis of large NPM1mut AML cohorts allows the discovery of co-mutation patterns associated with prognostic outcome. In accordance, we propose a new genetic stratification model for NPM1mut AML that identifies 3 groups with different OS and RFS. This model improves ELN2017 criteria as it is able to correctly reclassify 33% of NPM1mut AML patients.

Keyword(s): Acute myeloid leukemia, Mutation analysis, Prognostic groups, Survival prediction

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