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

MOLECULAR PROFILES IN AML PATIENTS OLDER THAN 70 YEARS OF AGE
Author(s): ,
Montserrat Hoyos Colell
Affiliations:
Klinik für Innere Medizin III,Universitätsklinikum Ulm,Ulm,Germany;Hematology,Hospital de la Santa Creu i Sant Pau, IIB Sant Pau and Jose Carreras Research Institute. Universitat Autonoma de Barcelona,Barcelona,Spain
,
Anna Dolnik
Affiliations:
Klinik für Innere Medizin III,Universitätsklinikum Ulm,Ulm,Germany
,
Tamara J Blätte
Affiliations:
Klinik für Innere Medizin III,Universitätsklinikum Ulm,Ulm,Germany
,
Sabrina Skambraks
Affiliations:
Klinik für Innere Medizin III,Universitätsklinikum Ulm,Ulm,Germany
,
Susanne Lux
Affiliations:
Klinik für Innere Medizin III,Universitätsklinikum Ulm,Ulm,Germany
,
Zuyao Xia
Affiliations:
Klinik für Innere Medizin III,Universitätsklinikum Ulm,Ulm,Germany
,
Verena I Gaidzik
Affiliations:
Klinik für Innere Medizin III,Universitätsklinikum Ulm,Ulm,Germany
,
Peter Paschka
Affiliations:
Klinik für Innere Medizin III,Universitätsklinikum Ulm,Ulm,Germany
,
Daniela Weber
Affiliations:
Klinik für Innere Medizin III,Universitätsklinikum Ulm,Ulm,Germany
,
Mohammed Wattad
Affiliations:
Klinik für Hämatologie, internistische Onkologie und Stammzelltransplantation,Evangelisches Krankenhaus Essen-Werden,Essen,Germany
,
Gerhard Held
Affiliations:
Innere Medizin I,Universitätsklinikum des Saarlandes und Medizinische Fakultät der Universität des Saarlandes ,Homburg,Germany
,
Heinz A Horst
Affiliations:
Klinik für Innere Medizin II,Universitätsklinikum Schleswig-Holstein Campus Kiel,Kiel,Germany
,
Felicitas Thol
Affiliations:
Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation,Medizinische Hochschule Hannover,Hannover,Germany
,
Michael Heuser
Affiliations:
Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation,Medizinische Hochschule Hannover,Hannover,Germany
,
Arnold Ganser
Affiliations:
Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation,Medizinische Hochschule Hannover,Hannover,Germany
,
Veronica Teleanu
Affiliations:
Klinik für Innere Medizin III,Universitätsklinikum Ulm,Ulm,Germany
,
Jorge Sierra
Affiliations:
Hematology,Hospital de la Santa Creu i Sant Pau, IIB Sant Pau and Jose Carreras Research Institute. Universitat Autonoma de Barcelona,Barcelona,Spain
,
Hartmut Döhner
Affiliations:
Klinik für Innere Medizin III,Universitätsklinikum Ulm,Ulm,Germany
,
Konstanze Döhner
Affiliations:
Klinik für Innere Medizin III,Universitätsklinikum Ulm,Ulm,Germany
Lars Bullinger
Affiliations:
Klinik für Innere Medizin III,Universitätsklinikum Ulm,Ulm,Germany
(Abstract release date: 05/17/18) EHA Library. Hoyos Colell M. 06/15/18; 214704; PF213
Montserrat Hoyos Colell
Montserrat Hoyos Colell
Contributions
Abstract

Abstract: PF213

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background

Acute myeloid leukemia (AML) arises in all age groups, but it is mainly a disease of the older patients with a median age of about 70 years at diagnosis. Age has a major impact on both the management and outcome of patients with AML. Older patients frequently present with unfavorable prognostic factors that are related to patient characteristics (general health condition, specific comorbidities), but also to those related to the leukemia cells, including a higher frequency of secondary AML arising from previous myelodysplastic syndrome and adverse genetic changes. While in the past, large cohorts of younger AML patients treated within multicenter clinical trials have been extensively studied on the molecular level, the genomic aberrations underlying the AML of older patients have by far been less well characterized.

Aims
In accordance, the aim of this study was the evaluation of the mutational spectrum of a large cohort of AML patients ≥70 years (median age 77 yrs) who have been entered into the AMLSG BiO Registry (ClinicalTrials.gov Identifier: NCT01252485).

Methods

Patients included into the study were treated with low dose cytarabine, decitabine or azacitidine, or best supportive care. In total, we studied n=295 cases by an in-house targeted resequencing panel covering the entire coding region of 94 myeloid disease related genes. We used the Haloplex High Sensitivity enrichment system (Agilent), followed by Illumina sequencing and an in-house data analysis workflow. Using a respective high sensitivity molecular barcode approach, we could reliably detect low abundance mutations with a variant allele frequency (VAF) ≤1%.

Results

In 295 cases the average gene coverage was 350x(fold) for consensus reads. In line with other smaller studies, we found a very high incidence of TP53 (30%), ASXL1 (11%), and RUNX1 (21%) mutations, along with a high incidence of TET2 (31.5%) and DNMT3A (24%) as well as splicing factor SRSF2 (24%) mutations (Figure).

While we found on average three mutations per patient using our 94-gene panel, we found a broad distribution of the VAF. Most patients presented with a dominant clone displaying a VAF of ~50%, i.e. all tumor cells harbor the respective mutation. In agreement with findings in younger patients, these mutations often affect genes involved in DNA methylation, chromatin modification, the cohesin or spliceosome complex. Often, the subclonal mutations with VAF ≤30% involve mutations in tumor-relevant signaling pathways.

Conclusion

In summary, our study demonstrates that the mutational spectrum of older AML patients differs significantly from that of young patients with a high incidence of high-risk molecular aberrations. Results from correlation of molecular with clinical data will be presented at the meeting.

Session topic: 3. Acute myeloid leukemia - Biology & Translational Research

Keyword(s): Acute Myeloid Leukemia, Elderly, Molecular markers

Abstract: PF213

Type: Poster Presentation

Presentation during EHA23: On Friday, June 15, 2018 from 17:30 - 19:00

Location: Poster area

Background

Acute myeloid leukemia (AML) arises in all age groups, but it is mainly a disease of the older patients with a median age of about 70 years at diagnosis. Age has a major impact on both the management and outcome of patients with AML. Older patients frequently present with unfavorable prognostic factors that are related to patient characteristics (general health condition, specific comorbidities), but also to those related to the leukemia cells, including a higher frequency of secondary AML arising from previous myelodysplastic syndrome and adverse genetic changes. While in the past, large cohorts of younger AML patients treated within multicenter clinical trials have been extensively studied on the molecular level, the genomic aberrations underlying the AML of older patients have by far been less well characterized.

Aims
In accordance, the aim of this study was the evaluation of the mutational spectrum of a large cohort of AML patients ≥70 years (median age 77 yrs) who have been entered into the AMLSG BiO Registry (ClinicalTrials.gov Identifier: NCT01252485).

Methods

Patients included into the study were treated with low dose cytarabine, decitabine or azacitidine, or best supportive care. In total, we studied n=295 cases by an in-house targeted resequencing panel covering the entire coding region of 94 myeloid disease related genes. We used the Haloplex High Sensitivity enrichment system (Agilent), followed by Illumina sequencing and an in-house data analysis workflow. Using a respective high sensitivity molecular barcode approach, we could reliably detect low abundance mutations with a variant allele frequency (VAF) ≤1%.

Results

In 295 cases the average gene coverage was 350x(fold) for consensus reads. In line with other smaller studies, we found a very high incidence of TP53 (30%), ASXL1 (11%), and RUNX1 (21%) mutations, along with a high incidence of TET2 (31.5%) and DNMT3A (24%) as well as splicing factor SRSF2 (24%) mutations (Figure).

While we found on average three mutations per patient using our 94-gene panel, we found a broad distribution of the VAF. Most patients presented with a dominant clone displaying a VAF of ~50%, i.e. all tumor cells harbor the respective mutation. In agreement with findings in younger patients, these mutations often affect genes involved in DNA methylation, chromatin modification, the cohesin or spliceosome complex. Often, the subclonal mutations with VAF ≤30% involve mutations in tumor-relevant signaling pathways.

Conclusion

In summary, our study demonstrates that the mutational spectrum of older AML patients differs significantly from that of young patients with a high incidence of high-risk molecular aberrations. Results from correlation of molecular with clinical data will be presented at the meeting.

Session topic: 3. Acute myeloid leukemia - Biology & Translational Research

Keyword(s): Acute Myeloid Leukemia, Elderly, Molecular markers

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