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3438 Impact of Gender on Molecular AML Subclasses – a Harmony Alliance Study

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Poster III
Hematology Disease Topics & Pathways:
Genomics, Adults, AML, Diseases, Myeloid Malignancies, Biological Processes, Study Population
Monday, December 13, 2021, 6:00 PM-8:00 PM

Tommaso Matteuzzi, PhD1*, Daniele Dall'Olio, PhD1*, Eric Sträng, PhD2*, Alessandra Merlotti, PhD1*, Javier Martinez Elicegui, PhD3*, Axel Benner, PhD4*, Maral Saadati, PhD5*, Julia Krzykalla, PhD4*, Caroline A. Heckman, PhD6, Ana Heredia Casanoves7*, Jurjen Versluis8*, María Abáigar3*, Alberto Hernandez-Sanchez3*, Laura Jamilis7*, Peter JM Valk, PhD9, Klaus H. Metzeler, MD10, Rosa Ayala11*, Joaquin Martinez Lopez12*, Herve Dombret, MD, PhD13, Pau Montesinos, PhD, MD14*, Jorge Sierra, MD, PhD15, Claude Preudomme16*, Frederick Damm2*, Ken I Mills17, Raúl Azibeiro Melchor3*, Jiří Mayer, Prof, MD18, Christian Thiede, MD19, Maria Teresa Teresa Voso, MD20, Sergio Amadori, MD20, Guillermo Sanz, MD, PhD21, Frederico Calado22*, Konstanze Döhner, MD23, Verena I Gaidzik, MD24, Michael Heuser, Prof., MD25*, Torsten Haferlach, MD26, Marta Sobas27*, Amin T. Turki, MD28, Dirk Reinhardt, MD28, Rubén Villoria Medina7*, Michel van Speybroeck, MSc29*, Renate Schulze-Rath30*, Jesús M Hernández Rivas, MD, PhD3, Brian J.P Huntly, MB ChB, FRCPath, FMedSci, PhD31*, Hartmut Döhner, MD32, Gert J. Ossenkoppele, M.D., Ph.D.33, Castellani Gastone, PhD34* and Lars Bullinger2

1Physics and Astronomy Department, University of Bologna, Bologna, Italy
2Charité Universitätsmedizin Berlin, Berlin, Germany
3Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
4Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
5Saadati Solutions, Ladenburg, Germany
6Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
7GMV Innovating Solutions, Valencia, Spain
8Erasmus University Medical Center Cancer Institute, Rotterdam, Rotterdam, Netherlands
9Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands
10Department of Hematology, Cell Therapy and Hemostaseology, University of Munich, Leipzig, Germany
11Department of Hematology, Hospital Universitario 12 de Octubre, Madrid, Spain
12Hematology Department Hospital 12 de Octubre, Hematological Malignancies Clinical Research Unit H12O-CNIO, Madrid, Spain
13Hematology, Hôpital Saint-Louis, Paris, France
14Hospital Universitario y Politécnico La Fe, Valencia, Spain
15Hematology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
16University Hospital, Lille, France
17Patrick G Johnston Centre for Cancer Research, Queens University Belfast, Belfast, United Kingdom
18University Hospital Brno, Brno, Czech Republic
19Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
20University of Roma Tor Vergata, Rome, Italy
21Hematology Deparment, Hospital Universitario La Fe, Valencia, Spain
22Novartis, Oncology Region Europe, Basel, Switzerland
23Ulm University Hospital, Ulm, Germany
24Internal Medicine III, Internal Medicine III, Ulm, Germany
25Department for Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
26MLL Munich Leukemia Laboratory, Munich, Germany
27Department of Hematology, Wroclaw Medical University, Wroclaw, Poland
28Essen University Hospital, Essen, Germany
29Data Sciences, Janssen Pharmaceutica N.V., Beerse, Belgium
30Bayer Pharma AG, Berlin, Berlin, Germany
31Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, United Kingdom
32Internal Medicine III, University of Ulm, Ulm, Germany
33Department of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
34Department of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, Bologna, Italy

The large acute myeloid leukemia (AML) patient-derived data sets collected within the European HARMONY alliance allows to study the molecular heterogeneity underlying AML in detail. Especially, how cytogenetic and molecular genetic aberrations differentially affect patients. Here, we report first results on the differences in mutational patterns in males and females. We studied a cohort of AML patients characterized by a panel of 70 molecular abnormalities comprising both cytogenetic and genetic observations. We quantified the differences of molecular patterns between sexes in two ways: 1) by comparing the number of gene-gene mutation co-occurrence and mutual mutation exclusivity with a χ2 test, 2) exploiting the Hierarchical Dirichlet process (HDP) for molecular components discovery. In particular, we added sex as a further layer of the hierarchy allowing the same molecular components to be differently re-weighted based on gender. The HARMONY AML cohort comprised 2796 patients with detailed molecular information from targeted sequencing of 41 genes and detailed cytogenetic information condensed into 29 cytogenetic properties, known, a priori, to be relevant for the disease. Male to female ratio was 52% vs. 48% and median age was 52.0 (18.2 – 91.4) years. The entry data of the analysis were in the form of a binary matrix reporting the presence/absence of a given alteration in a patient. The χ2 test based on the relative co-occurrence of mutation pairs suggested a significant difference between men and women solely for RUNX1 and NPM1. The number of co-occurrences was higher in male than in females. No significant mutual exclusive mutations were found between the populations. By using a two hierarchic levels HDP clustering we identified 11 overall molecular components shared by all AML patients. Six of these components are characterized by one or more genetic drivers, namely: NPM1, RUNX1, Complex-Karyotype-TP53, FLT3-IDH2, IDH2, CEPBA-biallelic, while the others were driven by cytogenetic abnormalities: t(6;9), t(8;21), inv(3), rearrangement of 11q23, inv(16). These results were in agreement with the current WHO AML classification and with other recent studies, which have attempted to improve stratification/classification of patients based on their molecular aberration patterns. While the molecular components were the same for all patients, major differences were observed in the contribution of NPM1 and RUNX1 components to males’ and females’ genotypes. On one side, NPM1 component has a double weight in females with respect to males. On the other hand, RUNX1 impacts males much more than females. The other aberrations were equally represented in both sexes. To test the robustness of the differences found between sexes, we compared these results with random splits of the datasets finding no differences in component weights, thereby validating our observations.

Big data collections such as the HARMONY Alliance data base ensure data comparability via OMOP common data model harmonization approaches thereby offering the possibility to study large cohort that allow meaningful subgroup analyses such as the one focusing on gender imbalances. Proving the concept of the HARMONY Alliance data hub, our study confirms a female preponderance for NPM1 mutations and an association of RUNX1 mutations with male gender. Impact on patient outcome is currently evaluated and will be presented at the annual meeting.

Disclosures: Heckman: Celgene/BMS: Research Funding; Orion Pharma: Research Funding; Novartis: Research Funding; Oncopeptides: Consultancy, Research Funding; Kronos Bio, Inc.: Research Funding. Dombret: Abbvie: Honoraria; Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; NOVARTIS: Research Funding; pfizer: Honoraria, Research Funding; servier: Research Funding; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. Montesinos: Tolero Pharmaceutical: Consultancy; Agios: Consultancy; Stemline/Menarini: Consultancy; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Forma Therapeutics: Consultancy; Glycomimetics: Consultancy; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astellas Pharma, Inc.: Consultancy, Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Sierra: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Research Funding; Janssen: Other: Educational grant; Roche: Other: Educational grant; Pfizer: Honoraria; BMS Celgene: Honoraria, Research Funding; Alexion: Other: Educational grant; Amgen: Other: Educational grant; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mayer: Principia: Research Funding. Voso: Jazz: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Abbvie: Speakers Bureau. Sanz: Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: 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, Other: Travel, accommodations, and expenses, Speakers Bureau; Helsinn Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, accommodations, and expenses, Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Calado: Novartis: Current Employment. Döhner: Agios and Astex: Research Funding; Daiichi Sankyo: Honoraria, Other: Advisory Board; Jazz Roche: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Honoraria, Other: Advisory Board; Astellas: Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Gaidzik: Pfizer: Speakers Bureau; Janssen: Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Heuser: BergenBio: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; BMS/Celgene: Research Funding; Bayer AG: Honoraria, Research Funding; Astellas: Research Funding; Daichi Sankyo: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Research Funding; Tolremo: Honoraria; AbbVie: Honoraria; Janssen: Honoraria. Haferlach: MLL Munich Leukemia Laboratory: Other: Part ownership. Sobas: Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Turki: CSL Behring: Consultancy; Jazz Pharma: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau. Schulze-Rath: Bayer: Current Employment. Hernández Rivas: Pfizer: 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, Research Funding; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees. Döhner: Abbvie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Astex Pharmaceuticals: Honoraria; AstraZeneca: Honoraria; Berlin-Chemie: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; GEMoaB: Honoraria; Gilead: Honoraria; Helsinn: Honoraria; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Oxford Biomedica: Honoraria; Pfizer: Research Funding; Roche: Honoraria. Ossenkoppele: Abbvie, AGIOS, BMS/Celgene Astellas,AMGEN, Gilead,Servier,JAZZ,Servier Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Bullinger: Janssen: Consultancy, Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Hexal: Consultancy; Amgen: Honoraria; Seattle Genetics: Honoraria; Gilead: Consultancy; Bayer: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Astellas: Honoraria; Menarini: Consultancy; Pfizer: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria.

*signifies non-member of ASH