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2697 Long-Term Follow-up of AML Patients Treated Intensively before the Era of Targeted Agents. a Big Data Analysis from the Harmony Collaboration

Program: Oral and Poster Abstracts
Session: 613. Acute Myeloid Leukemias: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
adult, Clinical Practice (Health Services and Quality), elderly, Therapies, therapy sequence, Study Population, Human
Sunday, December 11, 2022, 6:00 PM-8:00 PM

Marta Anna Sobas, MD, PhD1*, Angela Villaverde Ramiro2*, Alberto Hernández Sánchez, MD3*, Javier Martinez Elicegui2*, Teresa González, PhD4*, Raúl Azibeiro Melchor5*, María Abáigar6*, Laura Tur7*, Daniele Dall'Olio, PhD8*, Eric Sträng, PhD9*, Jesse M. Tettero10*, Castellani Gastone, PhD11*, Axel Benner12*, Konstanze Döhner, MD13, Christian Thiede, MD14, Amin T. Turki, MD15, Klaus H. Metzeler, MD16, Torsten Haferlach, MD17, Frederick Damm, MD9*, Rosa Ayala18*, Joaquín Martínez-López, MD, PhD19*, Ken I Mills, BSc, PhD, FRCPath20, Jorge Sierra, MD, PhD21, Sören Lehmann22, Matteo G. Della Porta, MD23*, Jiri Mayer24, Dirk Reinhardt, MD25, Rubén Villoria Medina7*, Renate Schulze-Rath26*, Martje Barbus, PhD27*, Jesús María Hernández-Rivas, MD, PhD28, Brian Huntly, MB ChB, FRCPath, FMedSci, PhD29, Gert Ossenkoppele, MD30, Hartmut Dohner, MD31 and Lars Bullinger, MD32

1Department of Hematology, Blood Neoplasm and Bone Marrow Transplantation, Hosp. Clinico Univ. de Santiago de Compostela, Santiago de Compostela, Spain
2Molecular Genetics in Oncohematology, Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
3Hematology Department, University Hospital of Salamanca, Salamanca, Spain
4Unidad 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
5Hospital Universitario de Burgos, Burgos, Spain
6Institute for Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
7GMV Innovating Solutions, Valencia, Spain
8University of Bologna, Bologna, Italy
9Department of Hematology, Oncology and Tumor Immunology, Charité University Medicine Berlin, Berlin, Germany
10Department of Hematology, Amsterdam University Medical Center location Vrije Universiteit Amsterdam, Amsterdam, Netherlands
11Department of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, Bologna, Italy
12Division of Biostatistics, German Cancer Research Center (DKFZ), Heidelberg, Germany
13Division of Hematology and Oncology, University Hospital Ulm, Ulm, Germany
14Department of Internal Medicine I, University Hospital Dresden, Dresden, Germany
15Department of Hematology and Stem Cell Transplantation, University Hospital of Essen, Essen, Germany
16Department for Hematology, Cell Therapy and Hemostaseology, University of Leipzig Medical Center, Leipzig, Germany
17MLL Munich Leukemia Laboratory, Munich, Germany
18Hospital Universitario 12 de Octubre, Madrid, Spain
19Hematology Department, Hospital Universitario 12 de Octubre, CNIO, Complutense University, Madrid, Spain
20Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom
21Hospital Santa Creu Sant Pau, Barcelona, Spain
22Uppsala University Hospital, Uppsala, Sweden
23Cancer Center IRCCS Humanitas Research Hospital, Milan, Italy, Italy
24Hematology and Oncology, University Hospital Brno, Czech Republic, Brno, Czech Republic
25Department of Pediatrics III, University Hospital Essen, University Duisburg-Essen, Essen, Germany
26Bayer AG, Pharmaceuticals Division, Berlin, Berlin, Germany
27AbbVie Deutschland GmbH & Co KG, Wiesbaden, DEU
28Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
29Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, ENG, United Kingdom
30Vrye Universiteit Academic Medical Center, Amsterdam, NLD
31Internal Medicine III, University of Ulm, Ulm, Germany
32Department of Hematology, Oncology and Tumorimmunology (Campus Virchow-Klinikum), Charite University Berlin, Berlin, Germany

Background: Due to better understand of biology of acute myeloid leukemia (AML), in 2017 a new era of targeted therapy has began. Before that, since 1973 younger and fit patients were offered the 3+7 regimen (based on anthracyclines and cytarabine) followed by high-dose cytarabine and, generally allogeneic stem cell transplantation in first complete remission (alloHSCT). In 2008 azacytidine, a hypomethylating (HM) agent was approved in Europe for AML patients, who were not candidate for intensive therapy and alloHSCT. In 2010 the European LeukemiaNet (ELN), based on cytogenetic and molecular genetic characteristics, proposed a risk score classification to facilitate decisions, including indications for alloHSCT. In addition to these advances, improved supportive therapies over the last 25 years are thought to have lowered therapy associated mortality.

Aims: We aimed to analyse changes in outcome of AML patients treated between 1997-2016 prior to the approval of novel drugs, in order to better understand important factors contributing to patient outcome that might also contribute to the efficacy novel treatment approaches.

Methods: Quality controlled, Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) harmonized data of the HARMONY alliance database coming from 100 organisations in 18 European countries were used for this study. Out of all AML records, 5359 patients diagnosed and treated with intensive regimens between 1997-2016 were identified. Patients treated with intensive regimens were identified regardless from age by the type of chemotherapy (n=4287) or by the age ≤70 (n=1072) if there was no information concerning the therapy. Patients with acute promyelocytic leukemia and those treated with targeted therapy were excluded from the analysis. Patients were categorized into 4 calendar periods: 1997-2001 (gr1), 2002-2006 (gr2), 2007-2011 (gr3) and 2012-2016 (gr4). The main outcome parameters analyzed were patient characteristics, overall survival (OS) and relapse-free survival (RFS). OS and RFS were determined using Kaplan-Meier analysis.

Results: 5359 AML patients were included into the analysis: 1127 in gr1, 1294 in gr2, 1821 in gr3 and 1117 in gr4. The median follow-up of all patients was of 1.9 [0-17.6] while of those who survived of 5.8 [0-17.6] years. 46.6% of patients were female. The median age of all patients was 53 years (18-85). There were 3745 patients <60, 1229 between 60–69 and 385 ≥70 years old. There were no differences in ELN risk between groups. Intensive regimens in ≥70 years AML, were less frequent through calendar period: 12% in gr1 vs 6% in gr2 vs 6% in gr3 vs 7% in gr4. AlloHSCT was performed in first remission in 1770 (33%) patients and according to calendar period: 24.1% in gr1, 37.5% in gr2, 39% in gr3, and 27% in gr4 (p<0.001). OS significantly improved over the time: 15.5 (95CI: 13.8-17.6) in gr1 vs 26.3 (23.7-31.6) in gr2 vs 39.3 (32.5-47.1) in gr3 vs 37.8 (31.6-49.2) months in gr4 (p<0.001). The OS improvement was observed for both sexes, across all 4 calendar periods, but mostly for women: 32.4 (28.8-37.8) vs 25.0 (22.5-27.7) months (p<0.001). A significant improvement in OS across the four groups was observed in AML with alloHSCT: 33 (26–56.8) vs 45.4 (34.1–65.6) vs 63 (46-not-reached) months, with group 4 not yet reaching median survival, Fig A. Interestingly, the median age to perform alloHSCT in group 1 was of 42.1 (18 - 71), while in group 2, 3 and 4 it was 46.9 (16 - 69) vs 49.9 (17 - 75) and 53 (18 - 77) years, respectively (p=0.028), Fig B.

Conclusion: Here we report the results of a large cohort of AML patients intensively treated between 1997-2016. Improvement of survival was observed for patients treated between 2007-2016 vs 1997-2007 in parallel with performing alloHSCT at more advanced age, most likely due to better supportive care and a greater proportion of reduced-intensity conditioning alloHSCT. As the majority of AML patients are diagnosed at advanced age, alloHSCT should be considered a curative treatment option. Less frequency of intensive regimens in elder AML since 2002 could be related with introduction of HM agents. Less number of alloHSCT in gr4 most likely represents a bias of our data base or could be related to better patient’s selection (ELN criteria) and need to be analysed in a further study. The better improvement in OS in women could be explained by the fact that globally, including AML, women live longer than men.

Disclosures: Sobas: Celgene/BMS: Honoraria; Novartis: Honoraria. Döhner: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Research Funding; Kronos: Research Funding. Thiede: Kronos Bio, Inc.: Honoraria; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Pharmaceuticals: Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AgenDix GmbH: Current Employment, Current equity holder in private company. Turki: CSL Behring: Consultancy; MSD: Speakers Bureau; Jazz Pharma: Speakers Bureau. Metzeler: Daiichi Sankyo: Honoraria; Pfizer: Consultancy; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy; Celgene/BMS: Consultancy, Honoraria, Research Funding; Curis: Research Funding; Astellas: Honoraria; AbbVie: Honoraria. Haferlach: Munich Leukemia Laboratory: Current Employment, Other: Part ownership. Sierra: Jazz: Research Funding; Pfizer: Research Funding; Novartis: Honoraria. Mayer: Novartis: Other: Travel support, Research Funding; BeiGene: Research Funding. Reinhardt: BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cerus: Membership on an entity's Board of Directors or advisory committees; Medac: Membership on an entity's Board of Directors or advisory committees; EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; BlueBird Bio: Research Funding. Schulze-Rath: Bayer Pharma AG: Current Employment, Current equity holder in private company. 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; GSK: Consultancy, Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; 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; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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: Astellas: Consultancy, Honoraria; JAZZ: Consultancy, Honoraria; Abbvie,: Consultancy, Honoraria; AGIOS: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; AMGEN: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Dohner: Astellas: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Honoraria, Research Funding; AstraZeneca: Honoraria; Berlin-Chemie: Consultancy, Honoraria; Brystol Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Honoraria; Daiichi Sankyo Co, LTD: Consultancy, Honoraria; Gilead Sciences Inc: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Jazz: Consultancy, Honoraria, Research Funding; Kronos Bio, Inc: Research Funding; Novartis AG: Consultancy, Honoraria, Research Funding; Pfizer Inc: Research Funding; Servier: Consultancy, Honoraria; Syndax Pharmaceuticals Inc: Consultancy, Honoraria. Bullinger: Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer Oncology: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: 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; Astellas: Honoraria; 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.

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