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304 Machine Learning Allows the Identification of New Co-Mutational Patterns with Prognostic Implications in NPM1 Mutated AML – Results of the European Harmony Alliance

Program: Oral and Poster Abstracts
Type: Oral
Session: 617. Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Molecular Features and Response to Treatment in AML
Hematology Disease Topics & Pathways:
adult, Acute Myeloid Malignancies, AML, Research, Clinical Research, Diseases, Myeloid Malignancies, survivorship, Technology and Procedures, Human, Study Population, machine learning
Saturday, December 10, 2022: 4:45 PM

Alberto Hernández Sánchez, MD1,2*, Angela Villaverde Ramiro2,3*, Eric Sträng, PhD4*, Castellani Gastone, PhD5*, Caroline A. Heckman, PhD6, Jurjen Versluis, MD, PhD7*, María Abáigar3,8*, Marta Anna Sobas, MD, PhD9*, Raúl Azibeiro Melchor10*, Axel Benner11*, Peter JM Valk, PhD12, Klaus H Metzeler, MD13, Teresa González, PhD2,3*, Daniele Dall'Olio, PhD14*, Jesse M. Tettero15*, Javier Martinez Elicegui2,3*, Joaquín Martínez-López, MD, PhD16*, Marta Pratcorona, MD17*, Frederik Damm, MD18*, Ken I Mills, BSc, PhD, FRCPath19, Christian Thiede, MD20, Maria Teresa Voso, MD21, Guillermo Sanz, MD, PhD22,23, Konstanze Döhner, MD24, Michael Heuser, MD25, Torsten Haferlach, MD26, Amin T. Turki, MD27, Rubén Villoria Medina28*, Michel van Speybroeck, MSc29*, Renate Schulze-Rath30*, Martje Barbus, PhD31*, John E Butler32*, Jesús María Hernández-Rivas, MD, PhD1,2,3, Brian Huntly, MB ChB, FRCPath, FMedSci, PhD33, Gert Ossenkoppele, MD34, Hartmut Döhner, MD35 and Lars Bullinger, MD36

1Hematology Department, University Hospital of Salamanca, Salamanca, Spain
2Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
3Cancer Research Center of Salamanca (USAL-CSIC), Salamanca, Spain
4Charité Universitätsmedizin Berlin, Berlin, Germany
5DIMES, University of Bologna, Bologna, Italy
6Institute for Molecular Medicine Finland, Institute For Molecular Medicine Finland FIMM, Helsinki, Finland
7Erasmus University Medical Center Cancer Institute, Rotterdam, Rotterdam, Netherlands
8Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
9Department of Hematology, Blood Neoplasm and Bone Marrow Transplantation, Hosp. Clinico Univ. de Santiago de Compostela, Santiago de Compostela, Spain
10University Hospital of Burgos, Burgos, Spain
11Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
12Department of Hematology, Erasmus University Medical Center Cancer Institute, Rotterdam, Netherlands
13University of Leipzig, Germany, Leipzig, Germany
14University of Bologna, Bologna, Italy
15Department of Hematology, Amsterdam University Medical Center location Vrije Universiteit Amsterdam, Amsterdam, Netherlands
16Hematology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
17Hematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
18Department of Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany
19Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom
20University of Technics Dresden Medical Dept., Dresden, Germany
21University Tor Vergata, Rome, Italy
22CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
23Hospital Universitario y Politécnico La Fe, Valencia, Spain
24Division of Hematology and Oncology, University Hospital Ulm, Ulm, Germany
25Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
26MLL Munich Leukemia Laboratory, Munich, Germany
27Department of Hematology and Stem Cell Transplantation, University Hospital of Essen, Essen, Germany
28GMV Innovating Solutions, Valencia, Spain
29Data Sciences, Janssen Pharmaceutica N.V., Beerse, Belgium
30Bayer AG, Pharmaceuticals Division, Berlin, Berlin, Germany
31AbbVie Deutschland GmbH & Co KG, Wiesbaden, DEU
32Bayer AG, Pharmaceuticals Division, Berlin, Germany
33Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, ENG, United Kingdom
34Amsterdam University Medical Center, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands
35Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
36Department of Hematology, Oncology, and Tumor Immunology, Charité – Universitätsmedizin Berlin, Berlin, Germany

Background: Mutations of NPM1 are generally considered as a favorable prognostic marker in acute myeloid leukemia (AML), although patients present with distinct co-mutations that might influence outcomes. The recently updated European LeukemiaNet classification (ELN2022) does now group NPM1mut AML patients with FLT3-ITD (regardless of the allelic ratio) as intermediate prognosis, while NPM1mut without FLT3-ITD is part of the favorable group. However, the mutational landscape of NPM1mut AML is more complex and analysis of a large cohort of patients might allow further dissection to identify less frequent co-mutational patterns of prognostic and predictive importance.

Aims: To identify clinically significant co-mutational patterns in NPM1mut AML to further refine risk stratification models for this subset of patients.

Methods: From the HARMONY Alliance database, a total of 1093 intensively treated NPM1mut patients were selected. Patients treated with targeted therapies (e.g. FLT3 or IDH1/2 inhibitors) were not included and NPM1 MRD information was not available at this stage of the analysis. A machine learning algorithm was developed in order to identify combinations of up to 4 co-mutated genes with potential impact on overall survival (OS). A heuristic search algorithm was implemented and bootstrap sampling was applied to estimate the impact of all possible gene combinations on OS. In addition, a global dashboard was developed where it was possible to compare mutational combinations with Kaplan Meier and Cox regression models. Finally, clinically significant co-mutational patterns were summarized in a novel risk stratification model for NPM1mut AML, which was validated using a publicly available external patient cohort (Awada et al, Blood, 2021).

Results: The study population of 1093 NPM1mut AML patients included 57% females and median age was 53 years. Regarding ELN2022 classification, 57% of patients were classified into the favorable, 42% into intermediate and only 1% into adverse risk groups. The most frequent co-mutations were DNMT3A (54%) and FLT3-ITD (42%), followed by NRAS, FLT3-TKD and TET2 (20% each). Mutations on IDH1 (13%) and IDH2 (15%) showed a similar behavior for all the analyses performed, so for simplification purposes we will refer to IDHmut when any of them was mutated and to IDHwt when both were wildtype.

The triple combination of NPM1mut + FLT3-ITD + DNMT3Amut identified a subgroup of patients with adverse prognosis (2-year OS of 33%), similar to patients with TP53mut. Of note, not all FLT3-ITD patients carried an intermediate or adverse prognosis, as we were able to identify a subgroup (FLT3-ITD + IDHmut + DNMT3Awt) with excellent prognosis (2-year OS of 80%), which represented 4% of NPM1mut AML. However, in the absence of FLT3-ITD and the presence of DNMT3Amut, the addition of IDHmut decreased OS towards the intermediate risk (2-year OS 59%). Notably, not all DNMT3Amut patients carried an intermediate or adverse prognosis. In the absence of FLT3-ITD and with IDHwt, mutations on either NRAS, KRAS, PTPN11 or RAD21 revealed a subgroup with favorable prognosis even when DNMT3A was mutated (2-year OS 80%) and this group represented 11% of NPM1mut AML. This information is summarized in a 4-category risk stratification model (figure 1).

The revised NPM1mut favorable group presented with a 3-year OS of 78%, which was 63%, 48% and 29% for intermediate-1, intermediate-2 and adverse risk groups respectively (p<0.001). Regarding 3-year relapse free survival (RFS), it was 71%, 59%, 39% and 26% accordingly (p<0.001).

In the validation cohort, 3-year OS of was 73% for NPM1mut favorable group, being 59%, 40% and 22% for intermediate-1, intermediate-2 and adverse groups respectively (p<0.001).

Multivariate OS analysis in NPM1mut AML identified the following independent prognostic factors: revised NPM1mut model (taking favorable group as reference, HR 1.77 for intermediate-1, HR 2.92 for intermediate-2 and HR 5.13 for adverse group, p<0.001); secondary or therapy-related AML (HR 1.93, p<0.001), age >60 years (HR 1.84, p<0.001), WBC at diagnosis >100x103/uL (HR 1.59, p<0.001), and male gender (HR 1.21, p=0.04).

Conclusion/summary: Analysis of large NPM1mut AML cohorts allows the identification of clinically significant co-mutational patterns. We propose a new genetic stratification model for NPM1mut AML that identifies 4 groups with different OS and RFS.

Disclosures: Heckman: IMI2 projects HARMONY and HARMONY PLUS: Research Funding; Orion: Research Funding; Novartis: Research Funding; Kronos Bio: Research Funding; Oncopeptides: Research Funding; Celgene: Research Funding; WntResearch: Research Funding. Sobas: Celgene/BMS: Honoraria; Novartis: Honoraria. Metzeler: Daiichi Sankyo: Honoraria; AbbVie: Honoraria; Pfizer: Consultancy; Celgene/BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Astellas: Honoraria. Pratcorona: Novartis: Honoraria. Thiede: AgenDix GmbH: Current Employment, Current equity holder in private company; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen Pharmaceuticals: Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kronos Bio, Inc.: Honoraria. Voso: Astellas: Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; jazz: Consultancy, Speakers Bureau. Sanz: Novartis Oncology: Consultancy; takeda: Honoraria; Janssen Pharmaceuticals, Inc.: Other: Teaching and Speaking; Celgene Corporation: Consultancy; La Hoffman Roche Ltd.: Other: Advisor or review panel participant; Helsinn: Honoraria, Other: Advisor or review panel participant; Abbvie Pharmaceuticals: Other: Advisor or review panel participant; Takeda Pharmaceuticals Ltd: Other: Advisor or review panel participant. Döhner: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Agios: Research Funding; BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: 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; Kronos: Research Funding. Heuser: Loxo Oncology: Research Funding; BergenBio: Research Funding; Bayer Pharma AG: Research Funding; Astellas: Research Funding; Tolremo: Consultancy; Roche: Consultancy, Research Funding; PinotBio: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Kura Oncology: Consultancy; Glycostem: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; BMS: Consultancy; Agios: Consultancy, Research Funding; Takeda: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Eurocept: Honoraria; Abbvie: Consultancy, Honoraria, Research Funding. Haferlach: Munich Leukemia Laboratory: Current Employment, Other: Part ownership. Turki: Jazz Pharma: Speakers Bureau; MSD: Speakers Bureau; CSL Behring: Consultancy. van Speybroeck: Janssen: Current Employment. Schulze-Rath: Bayer Pharma AG: Current Employment, Current equity holder in private company. Butler: Bayer Pharma AG: Current Employment. Hernández-Rivas: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research support, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research Support; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Beigene: Membership on an entity's Board of Directors or advisory committees; Lilly: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Rovi: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Ossenkoppele: Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; JAZZ: Consultancy, Honoraria; AMGEN: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AGIOS: Consultancy, Honoraria; Abbvie,: Consultancy, Honoraria. Döhner: Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Kronos Bio, Inc.: Research Funding; Brystol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo Co, LTD: Consultancy, Honoraria; Berlin-Chemie: Consultancy, Honoraria; AstraZeneca: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Consultancy, Honoraria, Research Funding; Agios Pharmaceuticals: Consultancy, Honoraria, Research Funding; AbbVie Inc.: Consultancy, Honoraria, Research Funding; Pfizer Inc.: Research Funding; Gilead Sciences, Inc.: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Syndax Pharmaceuticals Inc.: Consultancy, Honoraria. Bullinger: 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; Astellas: Honoraria; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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.

*signifies non-member of ASH