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2934 The Differential Impact of Secondary-Type Mutations in a Multinational Cohort of 5311 Intensively Treated Acute Myeloid Leukemia Patients

Program: Oral and Poster Abstracts
Session: 618. Acute Myeloid Leukemias: Biomarkers and Molecular Markers in Diagnosis and Prognosis: Poster II
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, AML, Diseases, Myeloid Malignancies
Sunday, December 8, 2024, 6:00 PM-8:00 PM

Jan-Niklas Eckardt1,2*, Marius Bill, MD, PhD3,4,5,6*, Konstanze Döhner, MD7, Christian Rausch, MD8*, Klaus H Metzeler, MD9, Karsten Spiekermann, MD10,11*, Sebastian Stasik, PhD12*, Tim Sauer, MD13, Sebastian Scholl, MD14*, Andreas Hochhaus, MD15, Martina Crysandt, MD16*, Tim H. H. Brummendorf, MD17, Utz Krug, MD18*, Bernhard Wörmann, MD19*, Hermann Einsele, MD20, Wolfgang Hiddemann, MD11,21*, Dennis Görlich, PhD22, Maria Cristina Sauerland, MD22*, Björn Steffen, MD23*, Andreas Neubauer, MD24, Andreas Burchert, MD25, Kerstin Schaefer-Eckart, MD26, Wolfgang E. Berdel, MD27, Christoph Schliemann, MD28*, Stefan W. Krause, MD29*, Mathias Hänel, MD30, Maher Hanoun, MD, PhD31*, Martin Kaufmann, MD32, Lars Fransecky, MD33*, Jan Braess, MD34*, Johannes Schetelig, MD, MSc35, Jan Moritz Middeke, MD1,2*, Lars Bullinger36,37, Michael Heuser, MD38, Felicitas R Thol, MD38, Hubert Serve, MD39,40, Claudia D Baldus, MD41*, Uwe Platzbecker, MD9, Carsten Mueller-Tidow, MD42*, Barbora Weinbergerova, MD43*, Jiri Mayer, MD44, Pierre-Yves Dumas, MD, PhD45*, Sarah Bertoli, MD46*, Eric Delabesse, MD, PhD47*, Christian Récher, MD, PhD48, Arnaud Pigneux, MD, PhD49*, Tobias Herold, MD10,11, Arnold Ganser, MD38, Hartmut Döhner, MD50, Martin Bornhäuser, MD5,12,51*, Christian Thiede, MD12 and Christoph Röllig, MD, MSc52*

1Else Kroener Fresenius Center for Digital Health, TUD Dresden University of Technology, Dresden, Germany
2Department of Internal Medicine I, University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany
3Department of Internal Medicine 1, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
4Mildred Scheel Early Career Center, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
5National Center for Tumor Diseases Dresden (NCT/UCC), Technical University Dresden, Dresden, Germany
6German Cancer Consortium (DKTK), Partner Site Dresden, Dresden, Germany
7Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
8Laboratory for Leukemia Diagnostics, Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany
9Department for Hematology, Cell Therapy, Hemostaseology and Infectious Diseases, University of Leipzig Medical Center, Leipzig, Germany
10Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
11German Cancer Consortium (DKTK), Partner Site Munich, Munich, Germany
12Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
13Department of Internal Medicine V, Heidelberg University Hospital, Heidelberg, Germany
14Klinik für Innere Medizin II, Jena University Hospital, Jena, Germany
15Klinik für Innere Medizin II, Abt. Hämatologie und lnternistische Onkologie, Universitätsklinikum Jena, Jena, Germany
16Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
17Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Faculty of Medicine, University Hospital RWTH Aachen, Aachen, Germany
18Department of Medicine III, Hospital Leverkusen, Leverkusen, DEU
19Department of Hematology, Oncology and Tumor Immunology, Charité Berlin, Berlin, Germany
20Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
21Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany
22Institute of Biostatistics and Clinical Research, University of Münster, Muenster, Germany
23Goethe-University Frankfurt, University Hospital, Department of Medicine II - Hematology and Oncology, Frankfurt am Main, Germany
24Department of Hematology, Oncology and Immunology, Phillips-University Marburg, Marburg, Germany, Marburg, Germany
25Department of Hematology, Oncology and Immunology, University Hospital Marburg, Marburg, Germany
26Department of Internal Medicine V, Paracelsus Medizinische Privatuniversität and University Hospital Nuernberg, Nuernberg, Germany
27Department of Medicine A (Hematology, Hemostaseology, Oncology, Pneumology), University Hospital Muenster, Muenster, Germany
28Department of Medicine A, University Hospital Muenster, Muenster, Germany
29Universitätsklinikum Erlangen, Erlangen, Germany
30Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany
31Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany
32Department of Hematology, Oncology and Palliative Care, Robert Bosch Hospital, Stuttgart, Germany
33Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
34Hospital Barmherzige Brueder Regensburg, Regensburg, Germany
35Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
36German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany
37Department of Hematology, Oncology, Tumor Immunology, Charité University Medicine, Berlin, Germany
38Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
39Department of Medicine, Hematology/Oncology, Goethe-University Frankfurt, University Hospital, Frankfurt am Main, Germany
40German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Frankfurt, Germany
41University Medical Center Schleswig-Holstein, University Cancer Center Schleswig-Holstein, Kiel, Germany
42Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
43FN Brno, Brno, CZE
44Internal Medicine Hematology and Oncology, University Hospital Brno and Masaryk University, Brno, Czech Republic
45Hôpital Haut-Lévèque, Hematology Department, CHU Bordeaux, Pessac, France
46IUCT-Oncopole, Hematology Department, CHU de Toulouse - Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
47IUCT-Oncopole, Hematology Laboratory, CHU de Toulouse - Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
48Hematology Department, CHU deToulouse - Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France
49Department of Clinical Hematology, Haut-Lévèque Hospital, CHU Bordeaux, Pessac, France
50Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany
51German Cancer Consortium (DKTK), Partner Site Dresden, and German Cancer Research Center (DKFZ), Heidelberg, Germany
52Department of Internal Medicine I, University Hospital Dresden, Dresden, Germany

Secondary-type mutations (STM) are defined as alterations in ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2 in the recent update of the WHO classification on myeloid neoplasms. The International Consensus Classification (ICC) extends its definition to also include alterations of RUNX1. Patients bearing STMs are considered adverse risk in the absence of other class-defining markers according to the recent update of the European LeukemiaNet (ELN) 2022 recommendations. However, it is unclear if all STMs convey an equally adverse prognostic effect or if individual STMs have a differential prognostic impact.

We pooled data on molecular genetics, cytogenetics, and outcomes of 5311 newly diagnosed and intensively treated AML patients from previous randomized multicenter trials of the German SAL (n=1606), the German-Austrian AMLSG (n=1354, dataset from Gerstung et al., Nature Genetics 2017), the German AMLCG (n=1138), the French DATAML (n=1040), and the Czech CELL (n=173). Patients were retrospectively categorized into ELN2022. All analyses were carried out for WHO 2022 definitions (STMWHO) and ICC 2022 definitions (STMICC).

We found 1485 (28%) of patients to harbor STMWHO and 1698 patients (32.0%) with STMICC. Patients with STMWHO and STMICC were significantly older than non-STM patients (median 60 vs 53 and 59 vs 52 years, p<0.001) and more frequently male (STMWHO: 62.5% and STMICC: 61.1% male vs 48.3% and 48.1%, p<0.001). STM-bearing patients had significantly higher rates of secondary AML (STMWHO: 19.8% and STMICC: 19.2% vs 6.9% and 6.3%) while de novo AML rates were significantly lower (STMWHO: 75.5% and STMICC: 75.8% vs 87.7% and 88.3%) compared to non-STM patients. Patients with STMs presented with significantly lower white blood cell count as well as significantly lower bone marrow and peripheral blood blast counts. After intensive induction therapy, 65.1% or 65.7% of patients with STMWHO or STMICC achieved complete remission (CR) compared to 77.2% or 77.7% of patients without STM according to either definition (OR 0.55 and p<0.001 for both). To test whether STMs constitute an individual risk group aside from ELN2022 adverse, these groups were separated. Patients with STMs and co-occurring defining favorable or intermediate risk features were assigned to ELN2022 favorable or intermediate risk, respectively. Patients with STM and no other class-defining alterations had longer event-free survival (EFS; STMWHO: 4.7 months, hazard ratio [HR] 1.66, p<0.001; STMICC: 4.9 months. HR 1.69, p<0.001) than ELN2022 adverse risk patients (3.0 months, HR 2.02, p<0.001, and 2.7 months, HR 2.12, p<0.001, respectively), longer relapse-free survival (RFS; STMWHO: 12.6 months, HR 1.53, p<0.001, STMICC: 11.9 months, HR 1.60, p<0.001 vs 8.0 months, HR 1.91, p<0.001 and 7.4 months, HR 1.93, p<0.01, respectively), and longer overall survival (OS; STMWHO: 14.6 months, HR 1.64, p<0.01 and STMICC: 14.7 months, HR 1.68, p<0.01 vs 9.5 months, HR 2.09, p<0.001 and 8.3 months, HR 2.22, p<0.001, respectively). The odds of achieving CR were significantly decreased for alterations in ASXL1, BCOR, SF3B1, SRSF2, STAG2, U2AF1, or RUNX1 compared to wildtype (univariable OR range: 0.38-0.68; BCOR p=0.003; all other p<0.001), with no significant differences for EZH2 (OR: 0.87, p=0.387) or ZRSR2 (OR: 0.96, p=0.882). Median EFS was significantly reduced for patients harboring alterations in ASXL1, BCOR, SF3B1, SRSF2, STAG2, U2AF1, or RUNX1 (HR range: 1.17-1.79; STAG2 p=0.017, all other p<0.001) while there was no difference for EZH2 (HR: 1.11, p=0.167) or ZRSR2 (HR: 1.17, p=0.232) compared to wildtype patients. Significantly reduced median RFS was found for patients with altered ASXL1, BCOR, SF3B1, SRSF2, U2AF1, and RUNX1 (HR range: 1.28-1.88, BCOR p=0.007, SF3B1 p=0.005, all other p<0.001) while EZH2, STAG2, and ZRSR2 showed no significant differences (HR range: 0.93-1.17). Finally, OS was significantly reduced for patients harboring alterations in ASXL1, BCOR, SF3B1, SRSF2, U2AF1, and RUNX1 (HR range: 1.26-1.87, BCOR p=0.002, all other p<0.001) again with no difference for alterations of EZH2, STAG2, and ZRSR2 (HR range: 1.16-1.28).

Our analysis highlights that STMs represent an unfavorable risk level between the ELN2022 intermediate and adverse categories while contrasts between individual STMs exist, as not all alterations convey the same degree of adverse prognostic impact.

Disclosures: Eckardt: Cancilico GmbH: Current Employment, Current equity holder in private company; Amgen: Honoraria; Novartis Oncology: Honoraria, Research Funding; AstraZeneca: Honoraria; Janssen: Consultancy, Honoraria. Döhner: AbbVie, AOP Health, Janssen, Jazz, Novartis, Bristol Myers Squibb, Celegne: Consultancy, Honoraria; Novartis, AbbVie, Astellas, Bristol Myers Squibb, Celegne, Jazz Pharmaceuticals, Kronos Bio, Servier: Research Funding. Rausch: International Medical Education: Other: travel grant; Jazz Pharmaceuticals: Other: travel grant; Servier: Other: travel grants. Metzeler: Otsuka: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Servier: Honoraria; Menarini Stem Line: Honoraria; BMS/Celgene: Consultancy, Honoraria; AstraZeneca: Honoraria; Astellas: Honoraria; Abbvie: Honoraria, Research Funding; Sysmex: Honoraria. Spiekermann: Tubulis GmbH: Patents & Royalties: pending patent application FLT3-mAb 20D9. Sauer: Abbvie: Other: financial support . Hochhaus: Terns: Honoraria, Other: Advisory Board; Enliven: Honoraria, Other: Advisory Board; Novartis: Honoraria, Other: Advisory Board, Research Funding. Crysandt: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: 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; Pierre Fabre: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Brummendorf: Ariad: Consultancy, Honoraria; Roche: Honoraria; Merck: Honoraria; Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Combination of Imatinib with hypusination inhibitors, Research Funding; Repeat Dx: Consultancy, Research Funding. Einsele: BMS: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Berdel: Elvesca Biotherapeutics: Current equity holder in private company, Patents & Royalties: Ownership, Patent; Anturec Pharmaceuticals: Current equity holder in private company, Patents & Royalties: Ownership, Patent, Intelectual Property, Research Funding; Philogen: Current holder of stock options in a privately-held company, Other: Travel- & congress-support, Research Funding. Schliemann: AstraZeneca: Honoraria; Anturec Pharmaceuticals: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel- & congress-support; Pfizer: Honoraria, Other: Travel- & congress-support; Jazz Pharmaceuticals: Honoraria, Other: Travel- & congress-support, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel- & congress-support; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Laboratories Delbert: Honoraria, Membership on an entity's Board of Directors or advisory committees. Krause: Eickeler: Honoraria; Abbvie: Other: travel expense; Jazz pharmaceuticals: Other: travel expense; Alexion: Other: travel expense. Hänel: Kite/Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Falk Foundation: Honoraria; Gilead Sciences: Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; BristolMyersSquibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; BristolMyersSquibb/Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer Vital: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Schetelig: Janssen: Consultancy, Honoraria; MSD: Consultancy; Novartis: Honoraria; Eurocept: Honoraria; Astellas: Honoraria; Medac: Honoraria; AstraZeneca: Consultancy, Honoraria. Middeke: Cancilico: Current equity holder in private company; Novartis Oncology: Research Funding. Bullinger: Sanofi: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Hexal: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Menarini: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bayer: Research Funding; Astellas: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Heuser: LabDelbert: Consultancy; Miltenyi: Consultancy; Qiagen: Honoraria; Bristol-Myers-Squibb: Honoraria; Janssen: Consultancy, Honoraria; PinotBio: Consultancy, Research Funding; Sobi: Honoraria; Novartis: Consultancy, Research Funding; Loxo Oncology: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Research Funding; BergenBio: Research Funding; Glycostem: Consultancy, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Pfizer: Consultancy, Honoraria; AvenCell: Consultancy. Thol: BMS: Consultancy; Novartis: Consultancy; AbbVie: Consultancy, Honoraria; Menarini: Consultancy; Rigel: Consultancy; Astellas: Honoraria. Serve: IKP Stuttgart: Consultancy, Honoraria, Other: advisory role; Gilead Sciences: Consultancy, Honoraria; Novartis: Honoraria. Baldus: Janssen, Astellas, Pfizer, Astrazeneca, Servier, BMS: Consultancy, Honoraria. Platzbecker: Amgen: Consultancy, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Research Funding; Curis: Consultancy, Honoraria, Research Funding; Geron: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Novartis: Consultancy, Research Funding. Mayer: Novartis: Research Funding; AstraZeneca: Research Funding; AOP Health: Research Funding; Merck & Co., Inc., Rahway, NJ, USA: Research Funding. Dumas: Daiichi-Sankyo, Astellas, Novartis, Abbvie, Servier, BMS, Jazz Pharmaceutical, Janssen: Consultancy. Herold: Jazz Pharmaceuticals: Honoraria; Servier Deutschland: Honoraria. Döhner: Abbvie: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Astra Zeneca: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Stemline: Consultancy, Honoraria; Syndax: Consultancy, Honoraria; Astellas: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Kronos Bio: Research Funding.

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