The Differential Impact of Secondary-Type Mutations in a Multinational Cohort of 5311 Intensively Treated Acute Myeloid Leukemia Patients
Year: 2024
Type: conference-abstract
Abstract: Secondary-type mutations (STM) are defined as alterations in ASXL1, BCOR, EZH2, SF3B1, SRSF2, STAG2, U2AF1, and ZRSR2 in the recent update of the WHO classification on myeloid neoplasms. The International Consensus Classification (ICC) extends its definition to also include alterations of RUNX1. Patients bearing STMs are considered adverse risk in the absence of other class-defining markers according to the recent update of the European LeukemiaNet (ELN) 2022 recommendations. However, it is unclear if all STMs convey an equally adverse prognostic effect or if individual STMs have a differential prognostic impact. We pooled data on molecular genetics, cytogenetics, and outcomes of 5311 newly diagnosed and intensively treated AML patients from previous randomized multicenter trials of the German SAL (n=1606), the German-Austrian AMLSG (n=1354, dataset from Gerstung et al., Nature Genetics 2017), the German AMLCG (n=1138), the French DATAML (n=1040), and the Czech CELL (n=173). Patients were retrospectively categorized into ELN2022. All analyses were carried out for WHO 2022 definitions (STMWHO) and ICC 2022 definitions (STMICC). We found 1485 (28%) of patients to harbor STMWHO and 1698 patients (32.0%) with STMICC. Patients with STMWHO and STMICC were significantly older than non-STM patients (median 60 vs 53 and 59 vs 52 years, p<0.001) and more frequently male (STMWHO: 62.5% and STMICC: 61.1% male vs 48.3% and 48.1%, p<0.001). STM-bearing patients had significantly higher rates of secondary AML (STMWHO: 19.8% and STMICC: 19.2% vs 6.9% and 6.3%) while de novo AML rates were significantly lower (STMWHO: 75.5% and STMICC: 75.8% vs 87.7% and 88.3%) compared to non-STM patients. Patients with STMs presented with significantly lower white blood cell count as well as significantly lower bone marrow and peripheral blood blast counts. After intensive induction therapy, 65.1% or 65.7% of patients with STMWHO or STMICC achieved complete remission (CR) compared to 77.2% or 77.7% of patients without STM according to either definition (OR 0.55 and p<0.001 for both). To test whether STMs constitute an individual risk group aside from ELN2022 adverse, these groups were separated. Patients with STMs and co-occurring defining favorable or intermediate risk features were assigned to ELN2022 favorable or intermediate risk, respectively. Patients with STM and no other class-defining alterations had longer event-free survival (EFS; STMWHO: 4.7 months, hazard ratio [HR] 1.66, p<0.001; STMICC: 4.9 months. HR 1.69, p<0.001) than ELN2022 adverse risk patients (3.0 months, HR 2.02, p<0.001, and 2.7 months, HR 2.12, p<0.001, respectively), longer relapse-free survival (RFS; STMWHO: 12.6 months, HR 1.53, p<0.001, STMICC: 11.9 months, HR 1.60, p<0.001 vs 8.0 months, HR 1.91, p<0.001 and 7.4 months, HR 1.93, p<0.01, respectively), and longer overall survival (OS; STMWHO: 14.6 months, HR 1.64, p<0.01 and STMICC: 14.7 months, HR 1.68, p<0.01 vs 9.5 months, HR 2.09, p<0.001 and 8.3 months, HR 2.22, p<0.001, respectively). The odds of achieving CR were significantly decreased for alterations in ASXL1, BCOR, SF3B1, SRSF2, STAG2, U2AF1, or RUNX1 compared to wildtype (univariable OR range: 0.38-0.68; BCOR p=0.003; all other p<0.001), with no significant differences for EZH2 (OR: 0.87, p=0.387) or ZRSR2 (OR: 0.96, p=0.882). Median EFS was significantly reduced for patients harboring alterations in ASXL1, BCOR, SF3B1, SRSF2, STAG2, U2AF1, or RUNX1 (HR range: 1.17-1.79; STAG2 p=0.017, all other p<0.001) while there was no difference for EZH2 (HR: 1.11, p=0.167) or ZRSR2 (HR: 1.17, p=0.232) compared to wildtype patients. Significantly reduced median RFS was found for patients with altered ASXL1, BCOR, SF3B1, SRSF2, U2AF1, and RUNX1 (HR range: 1.28-1.88, BCOR p=0.007, SF3B1 p=0.005, all other p<0.001) while EZH2, STAG2, and ZRSR2 showed no significant differences (HR range: 0.93-1.17). Finally, OS was significantly reduced for patients harboring alterations in ASXL1, BCOR, SF3B1, SRSF2, U2AF1, and RUNX1 (HR range: 1.26-1.87, BCOR p=0.002, all other p<0.001) again with no difference for alterations of EZH2, STAG2, and ZRSR2 (HR range: 1.16-1.28). Our analysis highlights that STMs represent an unfavorable risk level between the ELN2022 intermediate and adverse categories while contrasts between individual STMs exist, as not all alterations convey the same degree of adverse prognostic impact.
Source: Blood
Authors: Jan-Niklas Eckardt, Marius Bill, Konstanze Döhner, Christian Rausch, Klaus H Metzeler, Karsten Spiekermann, Sebastian Stasik, Tim Sauer, Sebastian Scholl, Andreas Hochhaus, Martina Crysandt, Tim H. H. Brummendorf, Utz Krug, Bernhard Wörmann, Hermann Einsele, Wolfgang Hiddemann, Dennis Görlich, Maria Cristina Sauerland, Björn Steffen, Andreas Neubauer, Andreas Burchert, Kerstin Schaefer-Eckart, Wolfgang E. Berdel, Christoph Schliemann, Stefan W. Krause, Mathias Hänel, Maher Hanoun, Martin Kaufmann, Lars Fransecky, Jan Braess, Johannes Schetelig, Jan Moritz Middeke, Lars Bullinger, Michael Heuser, Felicitas R Thol, Hubert Serve, Claudia D Baldus, Uwe Platzbecker, Carsten Mueller-Tidow, Barbora Weinbergerova, Jiri Mayer, Pierre-Yves Dumas, Sarah Bertoli, Eric Delabesse, Christian Récher, Arnaud Pigneux, Tobias Herold, Arnold Ganser, Hartmut Döhner, Martin Bornhäuser, Christian Thiede, Christoph Röllig
Institutions: University Hospital Carl Gustav Carus, Else Kröner Fresenius Center for Digital Health, Technische Universität Dresden, Nationales Centrum für Tumorerkrankungen Dresden, German Cancer Consortium (DKTK) Dresden, University Hospital Ulm, LMU Klinikum, Ludwig-Maximilians-Universität München, University Hospital Leipzig, Leipzig University, Deutsches Konsortium für Translationale Krebsforschung, Heidelberg University, University Hospital Heidelberg, Jena University Hospital, RWTH Aachen University, Universitätsklinikum Aachen, Klinikum Leverkusen, Stiftung Charité, Charité - Universitätsmedizin Berlin, University of Würzburg, Universitätsklinikum Würzburg, University of Münster, Goethe University Frankfurt, University Hospital Frankfurt, Philipps University of Marburg, Universitätsklinikum Gießen und Marburg, Paracelsus Medizinische Privatuniversität, University Hospital Münster, Universitätsklinikum Erlangen, Klinikum Chemnitz, Essen University Hospital, Robert Bosch Hospital, University Hospital Schleswig-Holstein, Krankenhaus Barmherzige Brüder, German Cancer Research Center, Medizinische Hochschule Hannover, Masaryk University, University Hospital Brno, Centre Hospitalier Universitaire de Bordeaux, Centre Hospitalier Universitaire de Toulouse, Institut universitaire du cancer de Toulouse Oncopole
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4405042146