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63 Genomic Characterization of Acute Myeloid Leukemia with Aberrations of Chromosome 7: A Multinational Cohort of 523 Patients

Program: Oral and Poster Abstracts
Type: Oral
Session: 617. Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Risk Refinement and Therapy Response
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, Translational Research, genomics, Diseases, Myeloid Malignancies, Biological Processes
Saturday, December 9, 2023: 10:00 AM

Adriane Halik, MD1*, Marlon Tilgner1*, Patricia Silva1*, Natalia Estrada-Barreras1*, Robert Altwasser1*, Ekaterina Jahn, MD2*, Michael Heuser, MD3, Hsin-An Hou, M.D.; Ph.D.4, Marta Pratcorona5*, Robert Kerrin Hills6*, Klaus H Metzeler, MD7, Laurène Fenwarth, MD, MSc8*, Anna Dolnik1*, Christine Terré9*, Klara Kopp1*, Martin Szyska1*, Jan Krönke, MD1*, Loïc Vasseur10*, Bob Lowenberg, MD, PhD11, Jordi Esteve, MD, PhD12, Peter J. M. Valk, PhD13, Matthieu Duchmann, M.D. / Ph.D.14*, Wen-Chien Chou, MD, PhD4, David C. Linch, MD15*, Hartmut Döhner, MD2, Rosemary E. Gale15*, Konstanze Döhner2, Lars Bullinger16,17, Kenichi Yoshida, MD, PhD18 and Frederik Damm, MD1,16*

1Department of Hematology, Oncology, and Cancer Immunology, Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany
2Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
3Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
4Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
5Institut d’investigació Biomèdica Sant Pau (IIB SANT PAU) Department of Medicine, Hospital de la Santa Creu i Sant Pau, Barcelona, ESP
6Nuffield Department of Population Health, University of Oxford, Oxford, UK., Oxford, United Kingdom
7Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, NA, Germany
8Hematology Laboratory, CHU Lille, Lille, France
9Laboratoire de Cytogénétique, Centre hospitalier de Versailles, Chesnay-Roquencourt, France
10Biostatistics and Medical Information Department, Saint Louis University Hospital, AP-HP, Université Paris Cité, Paris, France
11Erasmus University Medical Center Cancer Institute, Rotterdam, Netherlands
12Hematology Department, Hospital Clínic Barcelona, Barcelona, Spain
13Department of Hematology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands
14Institut de Recherche Saint-Louis (IRSL), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS), Université Paris Cité, Paris, France
15Department of Haematology, Royal Free and University College London Medical School, London, United Kingdom
16German Cancer Consortium (Deutsches Konsortium für Translationale Krebsforschung, DKTK), Berlin, Germany
17Department of Hematology, Oncology, and Cancer Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
18Division of Cancer Evolution, National Cancer Center Research Institute, Tokyo, Japan

Introduction: Aberrations of chromosome 7 [abn(7)] are found in ≈ 10% of newly diagnosed acute myeloid leukemia (AML) and associate with a dismal prognosis. A large-scale comprehensive exploration of the underlying genetic heterogeneity in AML with abn(7) has yet to be performed and could add essential insights into the outcome of this poorly understood patient group.

Methods: We collected diagnostic samples from 523 adult AML patients (median age 59 years) with abn(7). Whole-exome sequencing (WES) was performed to discover potentially underestimated genetic lesions in 61 paired diagnostic / remission samples. Subsequently, a gene panel including 66 genes and a SNP backbone for copy-number aberration (CNA) detection was designed and applied to the remaining 471 samples. The majority of patients (78%) were diagnosed with de novo (dn) AML, whereas 22% had secondary (s) or therapy-related (t) AML. Intensive induction treatment was administered to 80% of the patients, while 36 % underwent allogenic stem cell transplantation. Apart from 43% of patients with concomitant complex karyotype (abn(7)/CK+), 24% had -7 as a sole abnormality (-7 sole) and 13% del(7q) sole.

Results: A mean of 15.3 single-nucleotide variants (SNVs) and 7.5 CNAs per patient were found by WES. Here, the most frequent recurrent SNVs were identified in TP53 (29.5%), followed by mutations (mut) in genes involved in epigenetic regulation (DNMT3A, TET2, ASXL1, IDH2), transcription factors (RUNX1), and genes affecting RAS-signaling (NF1, KRAS), Figure 1.

Targeted sequencing revealed 1829 SNVs with a VAF≥ 2% in 64 genes (mean: 3.8 SNVs / patient). 30% of patients harbored at least one mutation in genes located within the commonly deleted region of 7q, most frequently KMT2C, EZH2, CUX1, SAMD9L, SAMD9, LUC7L2, and BRAF. The number of driver gene mutations was higher in CK- than in CK+ patients (4.5 vs. 3.3 SNVs). We found KRAS (OR 3.76, CI 1.17-16.87, P= .044) and RUNX1 (OR 3.61, CI 1.62-8.78, P= .003) mutations to be enriched in -7 sole patients, and FLT3 mutations to be associated with del(7q) sole status (OR 0.33, CI 0.13-0.82, P= .019). With respect to previously unknown lesions, a high amount of KMT2C mutations (16.6%) and recurrent alterations in FAT1 and TACC2 were discovered (6.4% each; Fig. 1). For KMT2C – located on chr7q36.1 – a total of 98 SNVs with mainly missense (73.5%) and truncating (20.4%) mutations at known cancer hotspots were noted. KMT2Cmut was associated with dnAML and AML with maturation morphology. In the entire cohort, the most common co-occurring chromosomal alterations discovered by high-resolution CNA analysis were deletions in chromosomes 5, 17, and 12. Our approach enabled the identification of small fragment deletions (≤10Mb) affecting the TP53, NF1, and ETV6 loci in 5-9% of all cases, which were missed by conventional G-banding. Cancer Cell Fraction and Bradley-Terry models were used to simulate the sequential order of genomic aberrations. While mutations in TP53 and epigenetic-related genes were early events, -7 and del(7q) were often subclonal and SNVs in NRAS, KMT2C very late events in leukemogenesis.

Survival analyses in intensively-treated patients (n= 414) revealed that 61% reached complete remission, 67% relapsed, and median overall survival (OS) was 11.9 months. AbnTP53 and high WBC count were independently associated with shorter relapse-free survival (RFS). For OS, besides older age and high WBC count, we identified abnTP53, PTPN11mut, TET2mut, -5, and -18 as poor prognostic factors in multivariate analysis (Table 1). In contrast, IDH2mut conferred an independent favorable prognostic effect for RFS and OS. Notably, abnTP53 outcompeted the prognostic impact of CK+ (Table 1). Compared to TP53wt, patients with abnTP53/CK+ and abnTP53/CK- had a similar poor outcome with median RFS of 6 and 4 months (CK+/CK-, P<.001) and OS of 6.8 and 8.6 months (CK+/CK-, P<.001). In contrast to other genomic studies in myelodysplastic syndrome, we found abnTP53 to be associated with poor outcome irrespective of the single- or multihit mutation status following definitions of the latest ICC classification (Blood, 2022).

Conclusion: Our results offer novel insights into the genomic landscape and clonal trajectory of AML with abn(7). This work unravels formerly underestimated genetic lesions (KMT2Cmut) and alterations with high prognostic impact (abnTP53 and IDH2mut) for better future risk stratification.

Disclosures: Halik: Jazz Pharmaceuticals: Other: Travel expenses not related to this work or event. Heuser: LabDelbert: Consultancy; Amgen: Consultancy; Servier: Consultancy; Loxo Oncology: Research Funding; PinotBio: Consultancy, Research Funding; Novartis: Honoraria; Pfizer: Consultancy, Honoraria; Certara: Honoraria; Sobi: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Glycostem: Consultancy, Research Funding; BergenBio: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Astellas: Research Funding; Agios: Research Funding; Abbvie: Consultancy, Research Funding; Karyopharm: Research Funding; Janssen: Honoraria. Metzeler: BMS: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria; Otsuka: Honoraria; Janssen: Honoraria; Novartis: Consultancy. Esteve: Jazz Pharmaceuticals: Consultancy, Research Funding; Pfizer: Research Funding; Gilead: Consultancy; Kronos Bio: Research Funding; Abbvie: Consultancy; Astellas: Consultancy. Linch: Autolus Therapeutics: Consultancy. Döhner: Abbvie: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Kronos-Bio: Research Funding; Pfizer: Research Funding; Stemline: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Syndax: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Berlin-Chemie: Consultancy, Honoraria. Döhner: Ulm University Hospital: Current Employment; AbbVie: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Astellas: Research Funding; Agios: Research Funding. Bullinger: Daiichi Sankyo: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer Oncology: Research Funding; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria. Damm: Gilead: Honoraria; Incyte: Honoraria; Roche: Honoraria; Novartis: Honoraria; AbbVie: Honoraria; AstraZeneca: Honoraria.

*signifies non-member of ASH