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608 Does RAD21 Co-Mutation Have a Role in DNMT3A Mutated AML? Results of Harmony Alliance AML Database

Program: Oral and Poster Abstracts
Type: Oral
Session: 617. Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Further unraveling the genetic background of AML
Hematology Disease Topics & Pathways:
Genomics, Adults, AML, Bioinformatics, Clinical Research, Health Outcomes Research, Diseases, Myeloid Malignancies, Biological Processes, Genomic Profiling, Technology and Procedures, Study Population
Monday, December 13, 2021: 10:45 AM

Raúl Azibeiro Melchor, MD1*, Alberto Hernández Sánchez, MD1*, Teresa González, PhD2*, Marta Sobas3*, Javier Martinez Elicegui4*, Angela Villaverde Ramiro4*, Axel Benner, PhD5,6*, Eric Sträng, PhD7*, Castellani Gastone, PhD8*, Caroline A. Heckman, PhD9, Ana Heredia Casanoves10*, Jurjen Versluis11*, María Abáigar12*, Laura Jamilis10*, Peter JM Valk, PhD13, Klaus H. Metzeler, MD14, Rosa Ayala, MD, PhD15*, Herve Dombret, MD, PhD16, Jorge Sierra, MD, PhD17, Claude Preudomme18*, Frederick Damm19*, Ken I Mills20, Jiří Mayer, Prof, MD21, Christian Thiede, MD22, Maria Teresa Teresa Voso, MD23, Sergio Amadori24, Guillermo Sanz, MD, PhD25, Frederico Calado26*, Konstanze Döhner, MD27, Verena I Gaidzik, MD28, Michael Heuser, MD29, Torsten Haferlach, MD30, Amin T. Turki, MD31, Dirk Reinhardt, MD32, Rubén Villoria Medina10*, Michel van Speybroeck, MSc33*, Renate Schulze-Rath34*, John E Butler35*, Brian J.P Huntly, MB ChB, FRCPath, FMedSci, PhD36*, Jesús M Hernández Rivas, MD, PhD37, Lars Bullinger38, Hartmut Döhner, MD27 and Gert J. Ossenkoppele, M.D., Ph.D.39

1Hematology Department, Hospital Clínico Universitario de Salamanca (CAUSA/IBSAL), Salamanca, Spain
2Unidad de Diagnóstico Molecular y Celular del Cáncer, Centro de Investigación del Cáncer-Universidad de Salamanca (IBMCC, USAL-CSIC); Genética Molecular en Oncohematología, Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain
3Department of Hematology, Blood Neoplasm and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland
4Molecular Genetics in Oncohematology, Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
5Abteilung für Biostatistik, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
6Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
7Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine Berlin, Berlin, Germany
8Department of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, Bologna, Italy
9Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
10GMV Innovating Solutions, Valencia, Spain
11Department of Medical Oncology, Dana-Farber Cancer Institute, Jamaica Plain, MA
12Molecular Genetics in Oncohematology, Institute of Biomedical Research of Salamanca (IBSAL) - Cancer Research Center of Salamanca (USAL-CSIC), Salamanca, Spain
13Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands
14Department of Hematology, Cell Therapy and Hemostaseology, University of Munich, Leipzig, Germany
15Hematology Department, Hospital Universitario 12 de Octubre, MADRID, Spain
16IRSL, EA3518 Leukemia Translational Laboratory, Paris, France
17Hematology Department, Hospital de la Santa Creu i Sant Pau, Sant Pau Biomedical Research (IIB) and Jose Carreras Leukemia Research Institutes, Autonomous University of Barcelona, Barcelona, Spain
18University Hospital, Lille, France
19Hematology, Oncology, and Tumorimmunology, Charité – Universitätsmedizin Berlin, Berlin, Germany
20Patrick G Johnston Centre for Cancer Research, Queens University Belfast, Belfast, United Kingdom
21Department of Internal Medicine Hematology and Oncology, University Hospital Brno and Masaryk University, Brno, Czech Republic
22Internal Medicine I, University of Technics Dresden Medical Dept., Dresden, Germany
23Department of Hematology, University of Rome “Cattolica S. Cuore”, Rome, Italy
24Department of Biomedicine and Prevention, University of Rome Tor Vergata, Roma, RM, Italy
25Hematology Deparment, Hospital Universitario La Fe, Valencia, Spain
26Novartis, Oncology Region Europe, Basel, Switzerland
27Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
28Internal Medicine III, Internal Medicine III, Ulm, Germany
29Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
30MLL Munich Leukemia Laboratory, Munich, Germany
31Department of Hematology and Stem Cell Transplantation, University Hospital of Essen, West-German Cancer Center, Germany, Essen, Germany
32Department of Pediatric Hematology and Oncology, Essen University Hospital, Essen, Germany
33Data Sciences, Janssen Pharmaceutica N.V., Beerse, Belgium
34Bayer Pharma AG, Berlin, Berlin, Germany
35Bayer AG, Berlin, Germany
36Wellcome - MRC Cambridge Stem Cell Institute, Cambridge, United Kingdom
37Universidad de Salamanca, IBSAL, Centro de Investigación del Cáncer, IBMCC-CSIC, Salamanca, Spain
38German Cancer Research Center (DKFZ), Heidelberg, Germany
39Department of Hematology, Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands

Background: The development of new genetic profiling techniques such as Next Generation Sequencing (NGS) have helped to unravel the genomic landscape of a large number of hematological diseases. In acute myeloblastic leukemia (AML), many mutations have been found at diagnosis or during the course of the disease, either alone or in combination.

Nevertheless, the clinical significance of most of them has not been well established. That is particularly true regarding infrequent gene mutations and their co-mutations as they are underrepresented in most case series that have been analyzed so far. The big data platform of HARMONY alliance provides the excellent basis for addressing this problem as it assimilates clinical and genomic information about AML patients from over 100 organisations in 18 European countries comprising more than 5000 patients. Anonymised and harmonized using OMOP standards, data collected in HARMONY are optimal for studying the impact of gene-gene-interactions overcoming differences related to data providers.

Aims: To identify clinically significant genetic patterns of 2 or more concurrent mutations using the Harmony alliance AML database

Methods: From the HARMONY alliance database, we selected ~3600 AML patients with NGS molecular panel analysis.

We first performed survival analysis between each gene combination and then we rendered those with statistically significant differences in one easy-to-read graph using the Gephi platform (Fig. A). We then highlighted promising or unexpected associations and analyzed them one by one in greater detail. Finally, these results were validated on an independent cohort.

Results: We found that the co-mutation of RAD21 (RAD21mut) in DNMT3A mutated (DNMT3Amut) AML impacted outcome compared to DNMT3Amut alone patients (Fig. B, 3-year survival, 81% vs 52%, p=0.016). However, this effect was exclusively seen in allogeneic transplant recipients.

In order to identify possible bias that could be generated if RAD21mut were associated with other well-known favorable prognosis mutations, we compared the frequency of each mutation in our DNMT3Amut / RAD21mut subgroup with the global AML cohort. NPM1 co-mutation was more frequent in the DNMT3Amut / RAD21mut group (Fig. C 3, 84% of patients with NPM1 mutation (NPM1mut) vs 26% in the global cohort), potentially explaining the higher survival.

Next, we tried to isolate the positive effect of NPM1 on outcome by comparing DNMT3Amut / NPM1mut patients with and without the RAD21 co-mutation. This analysis showed a favorable outcome only in RAD21mut patients compared to RAD21 wildtype (Fig. D, 3-year survival, 83% in RAD21mut / DNMT3Amut / NPM1mut vs 50% in DNMT3Amut / NPM1mut with RAD21 wildtype, p=0.016), one more time only in allogeneic transplant recipients.

Finally in order to validate our results we reproduced this study from the beginning using an independent cohort of 3125 AML patients. The Gephi graph confirmed an association of DNMT3Amut / RAD21mut patients with better survival over DNMT3A alone (3 year-survival, 75% vs 37%, p<0.001). NPM1 co-mutation was again more frequent in the good prognosis group (76% vs 27%) but comparing RAD21mut / DNMT3Amut / NPM1mut patients with DNMT3Amut / NPM1mut alone still revealed good prognosis to be related with RAD21mut (3 year-survival, 87.5% in patients with RAD21mut vs 38% with RAD21 wildtype, p<0.001).

Conclusions: Using the HARMONY alliance database we tested for potential gene co-mutations in AML patients, often very infrequently represented in other studies. Our data suggest that RAD21mut has a positive effect on outcome in patients receiving an allogeneic transplant with concurrent mutation of DNMT3A and NPM1. Even though NPM1mut is much more frequent in the DNMT3Amut / RAD21mut group, its association with favourable outcome seems to depend on the presence of an additional RAD21mut

Keywords: AML, gene combinations, RAD21, DNMT3A, NPM1, HARMONY, big data.

Figure: Graphical results. A. View obtained from the Gephi platform with the gene combinations and their effect on survival. B. Survival curves respectively of the DNMT3A+RAD21 cohort and the DNMT3A-only one.

  1. Representation of the proportions of each mutation in the overall cohort (red) compared to the DNMT3A+RAD21 cohort (blue). D. Survival curves respectively of the NPM1+DNMT3A+RAD21 cohort and the NPM1+DNMT3A one.

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

*signifies non-member of ASH