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657 Pre-Transplant Somatic Co-Occurring Mutations (by next generation sequencing) in Acute Myeloid Leukemia: Frequency and Impact on Clinical Outcomes after Allogeneic Hematopoietic Cell Transplantation - a Large Study on Behalf of the EBMT Acute Leukemia Working PartyClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 732. Allogeneic Transplantation: Disease Response and Comparative Treatment Studies: Use of Molecular Techniques for Risk Stratification
Hematology Disease Topics & Pathways:
Biological therapies, AML, Acute Myeloid Malignancies, Research, Translational Research, Clinical Research, Diseases, Therapies, registries, Myeloid Malignancies, Transplantation
Sunday, December 10, 2023: 5:00 PM

Ali Bazarbachi, MD, PhD1, Jaques-Emmanuel Galimard2*, Myriam Labopin3*, Iman Abou Dalle, MD4*, Jaime Sanz, MD, PhD5*, He Huang6*, Jiri Mayer, MD7, Carlos Solano, MD, PhD8, Celestine Simand, MD9*, Laimonas Griskevicius10*, Johan Maertens11*, Maija Itäla-remes, MD, PhD12*, Ain Kaare, MD13*, Maria Pilar Gallego Hernanz, MD14*, Gesine Bug, MD15*, Josep-Maria Ribera, MD, PhD16, Alain Gadisseur, MD, PhD17*, Christoph Schmidt, MD, PhD18*, Mi Kwon19, Xavier Poire, MD20*, Paola Coccia21*, Manuel Jurado Chacón22*, Frederic Baron23*, Eolia Brissot24*, Arnon Nagler, MD, M.Sc25*, Fabio Ciceri26* and Mohamad Mohty, MD, PhD27

1Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut, Beirut, Lebanon
2EBMT Acute Leukemia Working Party, Paris, France
3EBMT Statistical Unit, Sorbonne University, Saint-Antoine Hospital, AP-HP, INSERM UMRs 938, Paris, France
4Bone Marrow Transplantation Program, Department of Internal Medicine, American University of Beirut medical center, Beirut, Lebanon
5Hematology Department, Hospital Universitari i Politècnic La Fe, Valencia, España, Valencia, Spain
6The department of Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, AL, China
7Department of Internal Medicine-Hematology and Oncology, Masaryk University and University Hospital, Brno, Czech Republic
8Hospital Clinico Universitario, Valencia, Spain
9Hematology, Institut de Cancerologie Strasbourg Europe (ICANS), Strasbourg, France
11University Hospital Gasthuisberg, Leuven, Belgium
12Department of Clinical Haematology and Stem Cell Transplant Unit, University Hospital Turku, Turku, Finland
13Tartu Univerity Clinics, Tartu, Estonia
14Hematology Department, CHU de Poitiers, Poitiers, France
15Klinik fuer Innere Medzin III, Ulm, Germany
16ICO-Hospital Germans Trias i Pujol, Institut de Recerca contra la Leucèmia Josep Carreras (IJC), Universitat Autònoma de Barcelona, Badalona, Spain
17Antwerp University Hospital, Edegem, Belgium
18Department of Medicine 2, University Hospital Augsburg, Augsburg, Germany
19General University Hospital Gregorio Marañón, Madrid, Spain
20Section of hematology, Institut Roi Albert II, Cliniques Universitaires St-Luc, Brussels, Belgium
21Azienda Ospedali Riuniti di Ancona, Ancona, Ancona, Italy
22Hospital Univ. Virgen de las Nieves, Granada, Spain
23CHU Sart Tilman, Division of Hematology, University of Liège, Liège, Belgium
24Hôpital Saint-Antoine, Sorbonne University, INSERM UMRs 938, Paris, France
25Hematology and Bone Marrow Transplantation Division, Chaim Sheba Medical Center,, Tel-Hashomer, Israel
26Unit of Hematology and Stem Cell Transplantation, Ospedale San Raffaele, University Vita-Salute San Raffaele, Milan, Italy
27Saint-Antoine Hospital, Sorbonne University, Paris, France

Background: Acute myeloid leukemia (AML) is a very heterogeneous hematological malignancy, which includes numerous genetically defined subsets. The genomic classification of AML with the identification of mutations in transcription factors, epigenetic modifiers, spliceosome, cohesin complex, and signaling pathways has led to a more accurate risk stratification model. The main genetic aberrations included in the European LeukemiaNet (ELN) 2022 classification are NPM1 (risk group according to karyotype and FLT3-ITD status), FLT3-ITD (intermediate risk), bZIP in-frame mutated CEBPA (favorable risk), and RUNX1, ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2 and TP53 mutations (all belonging to the adverse risk group). In the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT), the frequency and prognostic value of different gene-gene interactions has not been studied and may differ from that of patients treated with chemotherapy alone. We aimed at evaluating, through the European Society for Blood and Marrow Transplantation (EBMT) database, the frequency and impact of different recurrent somatic mutations, either alone or in association, on prediction of relapse and survival in patients receiving allo-HSCT.

Methods: This is a retrospective, registry-based, multicenter analysis from the EBMT with the approval of the EBMT Acute Leukemia Working Party. Adult patients aged more than 18 years with a diagnosis of AML who received an allo-HSCT between 2013-2022, with an available genetic profile determined at diagnosis by next generation sequencing (NGS) were included.

Results: We identified 836 allografted AML patients who had NGS performed at diagnosis. Most of these patients had de novo AML (88%), with a median age of 53 years (range: 18-78 years). Karyotype was favorable in 7%, intermediate in 69% and adverse in 24% of patients. At transplant, 74% of patients were in first remission (CR1) and 13% in CR2. The most frequent detectable mutations by frequency were DNMT3A (33%), FLT3 (29%), NPM1 (29%), TET2 (28%), NRAS (23%), RUNX1 (22%), WT1 (22%), BCOR (19%), ASXL1 (17%), IDH2 (17%), IDH1 (15%), SRSF2 (13%), STAG2 (12%), CEBPA (11%), TP53 (10%), KRAS (10%), and PTPN11 (10%). By multiple correspondence analysis, two independent groups of co-occurring mutations were identified, the first group included DNMT3A, NPM1 and FLT3, the second group included ASXL1, SRSF2 and RUNX1. Outcome analysis was performed on the subset of 298 patients allografted in CR1 with available data for the aforementioned six genes (DNMT3A, NPM1, FLT3, ASXL1, SRSF2 and RUNX1). Most of these patients had de novo AML (90%), with a median age of 53 years (range: 19-75 years). Patients received primarily reduced intensity conditioning (58%) and peripheral blood stem cells (93%) from matched sibling donors (35%), matched unrelated (28%), and haploidentical donors (21%). Seventy percent of these patients had intermediate-risk cytogenetics, while 27% were classified as adverse-risk. Median follow up calculated by the reverse Kaplan-Meier method was 2.5 years. Overall, the 2-year relapse incidence (RI), leukemia-free survival (LFS) and overall survival (OS) were 24%, 62% and 69%, respectively. When outcome analysis was performed according to the presence or absence of single mutations, none of the six mutations significantly affected RI or LFS. The 2-year OS was positively affected by the presence of NPM1 mutation (78% vs 66%; p=0.02) and FLT3 (79% vs 65%, p=0.01) but not significantly affected by the other 4 mutations. When mutations were investigated in groups, the 2-year RI, LFS and OS were 24%, 70% and 78%, respectively, for patients with NPM1 mutation regardless of other co-mutations, 35%, 56% and 69% for patients with FLT3-ITD and/or DNMT3A mutation, wild type NPM1, regardless of other co-mutations, 17%, 70% and 74% for patients with RUNX1 and/or ASXL1 and/or SRSF2 mutation without FLT3-ITD and with wild type NPM1 and wild type DNMT3A, and 20%, 56% and 61% for patients with all six genes unmutated.

Conclusion: NGS at diagnosis can be extremely useful in risk stratification of AML patients undergoing allo-HSCT, potentially allowing adequate post-transplant interventions. Notably, the 2-year LFS of 70% for patients harboring RUNX1 and/or ASXL1 and/or SRSF2 mutation indicates that allo-HSCT can overcome the adverse risk associated with these somatic mutations at diagnosis.

Disclosures: Mayer: BeiGene: Research Funding. Bug: Pfizer: Honoraria; Novartis: Honoraria; Jazz: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Ribera: AMGEN: Research Funding; Novartis: Consultancy; Takeda: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding. Kwon: Jazz: Speakers Bureau; Pfizer: Speakers Bureau; Kite-Gilead: Consultancy, Speakers Bureau. Ciceri: ExCellThera: Other: Scientific Advisory Board . Mohty: JAZZ PHARMACEUTICALS: Honoraria, Research Funding.

*signifies non-member of ASH