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302 Frequency and Impact of Pre-Transplant Somatic Co-Occurring Mutations on Clinical Outcomes of Acute Myeloid Leukemia Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation: On Behalf of the EBMT Acute Leukemia Working Party

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:
AML, adult, Acute Myeloid Malignancies, Diseases, Myeloid Malignancies
Saturday, December 10, 2022: 4:15 PM

Ali Bazarbachi, MD, PhD1, Jacques-Emmanuel Galimard, PhD2*, Myriam Labopin, MD3*, Iman Abou Dalle, MD4*, Bruno Lioure, MD5*, Johan A. Maertens, MD, PhD6*, Maija Itälä-Remes, MD, PhD7*, Maria Pilar Gallego Hernanz, MD, PhD8*, Gesine Bug, MD9*, Josep-Maria Ribera, MD, PhD10, Alain Gadisseur, MD, PhD11*, Christoph Schmid, MD12*, Xavier Poiré, MD, PhD13*, Manuel Jurado Chacón, MD14*, Frederic Baron, MD15*, Eolia Brissot16*, Arnon Nagler, MD17, Fabio Ciceri, MD18* and Mohamad Mohty, MD PhD19

1American University of Beirut Dept. of Medicine, Beirut, Lebanon
2Hôpital Saint-Antoine, EBMT Statistical Unit, 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
5Département d'Hématologie et d'Oncologie, CHU Strasbourg, Strasbourg, France
6University Hospital Gasthuisberg, Leuven, Belgium
7Stem Cell Transplantation Unit, Turku University Hospital, Turku, Finland
8Poitiers University Hospital, Poitiers, France
9Goethe University Frankfurt, University Hospital, Dept. of Medicine, Hematology and Oncology, Frankfurt, Germany
10Clinical Hematology Department, Clinical Hematology Department. ICO_Hospital Germans Trias i Pujol. Josep Carreras Research Instoitute, Badalona, Spain
11Department of Haematology, Antwerp University Hospital, Edegem, Belgium
12Department of Hematology and Oncology / Stem Cell Transplantation, Augsburg University Hospital and Medical Faculty, Augsburg, Germany
13Section of Hematology, Cliniques Universitaires St-Luc, Brussels, Brussels, Belgium
14Hematology Department, Servicio de Hematología y Hemoterapia, Hospital Universitario Virgen de las Nieves, Granada, Spain
15University of Liege, Liege, Belgium
16Service d'Hématologie Clinique et de Thérapie Cellulaire, Hospital Saint Antoine, Paris Cedex 12, France
17Hematology and Bone Marrow Transplant Unit, Chaim Sheba Medical Center, Tel Hashomer, Israel
18Unit of Hematology and Bone Marrow Transplantation, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy
19EBMT Paris study office / CEREST-TC, Paris, France, Department of Hematology, Saint Antoine Hospital, Paris, France, INSERM UMR 938, 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 ELN 2017 classification are NPM1, FLT3, CEBPA, RUNX1, ASXL1 and TP53 mutations. 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 regardless of measurable residual disease (MRD) status.

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 2014-2019, with an available pretransplant genetic profile by next generation sequencing (NGS) were included.

Results: We identified 362 allografted AML patients who had NGS performed before allo-HSCT. Most of these patients had de novo AML (85%), with a median age of 56 years (range: 18-78 years). The most frequent detectable mutations by frequency were DNMT3A (33%), FLT3 (27%), NPM1 (26%), TET2 (24%), RUNX1 (22%), BCOR (22%), NRAS (19%), WT1 (18%), ASXL1 (16%), IDH2 (16%,) STAG2 (16%), SRSF2 (14%), IDH1 (12%), TP53 (12%), KRAS (12%), and CEBPA (10%). By multiple correspondence analysis, two independent groups of co-occurring mutations were identified, the first group includes DNMT3A, NPM1 and FLT3, the second group includes ASXL1, SRSF2 and RUNX1. Outcome analysis was performed on the subset of 145 patients allografted in first complete remission with available data for the aforementioned six genes (DNMT3A, NPM1, FLT3, ASXL1, SRSF2 and RUNX1). Most of these patients had de novo AML (86%), with a median age of 54 years (range: 19-75 years). Patients received primarily myeloablative conditioning (58%) and peripheral blood stem cells (91%) from matched sibling donors (35%), matched unrelated (29%), and haploidentical donors (22%). Sixty five percent of these patients had intermediate-risk cytogenetics, while 32% were classified as adverse-risk. Median follow up calculated by reverse Kaplan-Meier was 2.7 years. Overall, the 2-year relapse incidence (RI), leukemia-free survival (LFS) and overall survival (OS) were 25%, 58%, and 68%, respectively. The 2-year RI, LFS and OS were 22%, 72% and 81%, respectively, for patients with NPM1 mutation, 20%, 65% and 70% for patients with RUNX1 mutation, 29%, 64% and 79% for patients with ASXL1 mutation, 33%, 57% and 65% for patients with DNMT3A mutation, 23%, 69% and 69% for patients with SRSF2 mutation, and 28%, 66% and 77% for patients with FLT3 mutation. When mutations were investigated in groups, the 2-year RI, LFS and OS were 22%, 72% and 81%, respectively, for patients with NPM1 mutation regardless of other co-mutations, 37%, 48% and 64% for patients with FLT3 and/or DNMT3A mutation, wild type NPM1, regardless of other co-mutations, 23%, 69% and 77% for patients with RUNX1 and/or ASXL1 and/or SRSF2 mutation and wild type NPM1, FLT3 and DNMT3A, and 21%, 50% and 57% for patients with all six genes unmutated. In conclusion, NGS at diagnosis can be extremely useful in risk stratification of AML patients undergoing allo-HSCT, potentially allowing adequate post-transplant interventions.

Disclosures: Labopin: Jazz Pharmaceuticals: Honoraria. Bug: Jazz: Honoraria; Pfizer: Consultancy; Celgene /BMS: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy. Ribera: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Research support; AMGEN: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Shire: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Research support; Novartis: Membership on an entity's Board of Directors or advisory committees. Schmid: Novartis Pharmaceuticals: Honoraria, Speakers Bureau; Neovii: Honoraria, Speakers Bureau. Ciceri: Kite Pharma: Consultancy. Mohty: Oncopeptides: Honoraria; GSK: Honoraria; Pfizer,: Honoraria; Adaptive Biotechnologies: Honoraria; Novartis: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Jazz Pharmaceuticals: Honoraria, Research Funding; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Gilead: Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

*signifies non-member of ASH