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721 Secondary-Type Mutations Do Not Impact the Favorable Outcome of NPM1-Mutated Acute Myeloid Leukemia Patients – Results from a Large Cohort of Intensively Treated Patients

Program: Oral and Poster Abstracts
Type: Oral
Session: 613. Acute Myeloid Leukemias: Clinical and Epidemiological: Innovations in Prognostication
Hematology Disease Topics & Pathways:
AML, Acute Myeloid Malignancies, Non-Biological therapies, Chemotherapy, Diseases, Therapies, Myeloid Malignancies
Monday, December 11, 2023: 10:30 AM

Marius Bill, MD, PhD1*, Jan-Niklas Eckardt1*, Christian Rausch2*, Klaus H Metzeler, MD3, Karsten Spiekermann, MD4*, Sebastian Stasik, PhD5*, Tim Sauer, MD6*, Sebastian Scholl, MD7*, Andreas Hochhaus, MD8, Martina Crysandt, MD9*, Tim H. Brümmendorf10, Utz Krug, MD11*, Bernhard Wörmann, MD12*, Wolfgang Hiddemann, MD4*, Dennis Görlich, PhD13, Maria Cristina Sauerland, MD13*, Björn Steffen, MD14*, Hermann Einsele, MD, PhD15*, Andreas Neubauer, MD16, Andreas Burchert, MD17, Kerstin Schaefer-Eckart, MD18, Wolfgang E. Berdel, MD19, Christoph Schliemann, MD20*, Stefan W. Krause, MD21*, Mathias Hanel, MD22, Maher Hanoun, MD, PhD23*, Martin Kaufmann, MD24, Lars Fransecky25*, Jan Braess, MD26*, Leo Ruhnke, MD27*, Johannes Schetelig, MD, MSc28,29, Jan Moritz Middeke, MD1*, Hubert Serve, MD30, Claudia D Baldus, MD31*, Uwe Platzbecker, MD32, Carsten Müller-Tidow, MD6*, Martin Bornhäuser, MD5*, Tobias Herold, MD4*, Christian Thiede, MD5 and Christoph Röllig, MD, MSc27*

1Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
2Laboratory for Leukemia Diagnostics, Department of Medicine III,, LMU University Hospital, LMU Munich, Munich, Germany
3Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, NA, Germany
4Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany
5Department of Internal Medicine 1, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
6Heidelberg University Hospital, Heidelberg, Germany
7Klinik für Innere Medizin II, Jena University Hospital, Jena, Germany
8Department Hematology and Oncology, Klinik für Innere Medizin II, Jena, Germany
9Department of Hematology and Oncology, University Hospital RWTH Aachen and Center for Integrated Oncology Aachen-Bonn-Cologne-Düsseldorf (CIOABCD), Aachen, Germany
10Center for Integrated Oncology - Aachen Bonn Cologne Duesseldorf (CIO-ABCD), Aachen, Germany
11Department of Medicine III, Hospital Leverkusen, Leverkusen, DEU
12Department of Hematology, Oncology and Tumor Immunology, Charité, Berlin, Germany
13Institute of Biostatistics and Clinical Research, University of Münster, Muenster, Germany
14Department of Hematology and Oncology, Unversity Hospital Frankfurt, Frankfurt, Frankfurt am Main, Germany
15Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
16Department of Hematology, Oncology and Immunology, Phillips-University Marburg, Marburg, Germany, Marburg, Germany
17Hämatologie, Onkologie und Immunologie, Universitätsklinikum Gießen und Marburg, Standort Marburg, Marburg,, Germany
18Med. Clinic 5, BMT Unit, Nurnberg, DEU
19Department of Medicine A, Hematology and Oncology, University Hospital Muenster, Muenster, Germany
20Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany
21Universitätsklinikum Erlangen, Erlangen, Germany
22Department of Internal Medicine III, Klinikum Chemnitz, Chemnitz, Germany
23Department of Hematology, University Hospital Essen, Essen, Germany
24Department of Hematology, Oncology and Palliative Care, Robert Bosch Hospital, Stuttgart, Germany
25Department of Internal Medicine II (Hematology/Oncology), University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany
26Hospital Barmherzige Brueder Regensburg, Regensburg, Germany
27Department of Internal Medicine I, University Hospital Dresden, Dresden, Germany
28TU Dresden, Dresden, Saxony, Germany
29DKMS Group gGmbH, Dresden, Germany
30Department of Internal Medicine II, Hematology and Oncology, Goethe University Hospital Frankfurt, Frankfurt, Germany
31University Hospital Schleswig-Holstein, Department of Hematology and Oncology, Campus Kiel, Kiel, Germany
32University Leipzig Medical Center, Leipzig, Germany

Introduction: In 2022, the ELN risk classification for AML was updated for the second time. One of the major novelties of the ELN2022 is that all secondary-type mutations (STMs, i.e., mutations in the genes SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2) were now added to the adverse risk characteristics. However, a pertinent question also raised by the ELN expert panel is whether STMs abrogate the positive prognostic value of co-occurring, favorable NPM1 mutations.

Aim: The aim of this study was to analyze the prognostic value of STMs in AML patients (pts) who also harbor an NPM1 mutation.

Methods: We investigated a pooled cohort of 936 NPM1-mutated AML pts who were treated in previously reported multicenter trials of the Study Alliance Leukemia or the AML Cooperative Group. Eligibility was determined based on diagnosis of non-APL, age ≥ 18 years, NPM1 mutation detected in targeted sequencing, curative treatment intent, and available biomaterial at diagnosis. Standard techniques for chromosome banding and fluorescence-in-situ-hybridization (FISH) were used for karyotyping. Next-generation panel sequencing was performed to detect genetic alterations that are recurrently found in myeloid neoplasms.

Results: In our multicenter cohort of 936 NPM1-mutated AML pts, median follow-up for the entire cohort was 8.0 years. We found 125 patients (13.4%) harboring at least one STM (SRSF2 [n=48; 5.1%], STAG2 [n=32; 3.2%], EZH2 [n=22, 2.4%], BCOR [n=16; 1.7%], SF3B1 [n=13; 1.4%], ASXL1 [n=12; 1.3%], ZRSR2 [n=5; 0.5%], and U2AF1 [n=4; 0,4%]). A comparison of pretreatment clinical and genetic features revealed that pts with a STM were significantly older (p=.003, median 59 vs. 55 years), had lower white blood cell counts (p<.001, 22.2*109/L vs. 39.7*109/L,) and platelet counts (p<.001, 46.5*109/L vs. 65.0 109/L). The strongest pair-wise associations between gene mutations were observed between U2AF1 and RUNX1 (p<.001) as well as SRSF2 and IDH2 (p<.001).

With respect to outcome, complete remission (CR) rate did not differ significantly between NPM1-mutated patients with or without additional STMs (p=.41, 74.4% vs. 77.7%, OR 0.83 [95%-CI 0.54-1.29]). Median RFS for NPM1-mutated pts with STMs was 32.9 months (95%-CI: 13.0-46.0) while patients without STMs had a median RFS of 24.3 months (95%-CI: 18.7-33.3) corresponding to a HR of 1.04 (p=0.80, 95%-CI 0.79-1.37; Figure A). Median OS for NPM1-mutated pts with or without STMs was 27.2 months (95%-CI: 14.2-49.0) and 29.1 months (95%-CI: 23.5-41.4), respectively, corresponding to a HR of 1.11 (p=.37, 95%-CI 0.88-1.41; Figure B).

To focus solely on the impact of STMs, we subsequently excluded patients with co-occurring mutations in TP53 or myelodysplasia-related cytogenetics, which all define an ELN adverse risk. Again, we observed no differences in CR rate (p=.54, 78% vs. 75.4%), RFS (p=.59, median 33.2 months vs. 26.6 months), or OS (p=.33, median 27.4 month vs. 32.6 month) between NPM1-mutated patients with or without STMs. Next, we restricted our analysis to pts who are classified favorable risk according to ELN2022. Again, we found no significant outcome differences based on the STM status (unmutated vs. mutated: CR rate, 80% vs. 70.7% [p=.072]; RFS, median 49.7 months vs. 46.0 months [p=.702]; OS, median 45.3 months vs. 59.8 months [p=.092]).

Conclusion: NPM1 mutations rank as the second most frequent mutations in AML and the most common in patients with a normal karyotype and serve as an established favorable prognostic marker. Our data from a large cohort demonstrate that additional STMs have no adverse effect on the clinical outcome of NPM1-mutated patients. As a result, these patients should still be considered ELN favorable risk.

Disclosures: Metzeler: BMS: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria; Otsuka: Honoraria; Janssen: Honoraria; Novartis: Consultancy. Sauer: Novartis: Consultancy; BMS: Consultancy; Ridgeline Discovery: Consultancy; Takeda: Consultancy; Pfizer: Honoraria; Gilead: Honoraria; Stemline: Consultancy; AbbVie: Consultancy, Other: Travel, Accommodation, Expenses; Amgen: Consultancy; Astellas: Consultancy; Jazz: Honoraria, Other: Travel, Accommodation, Expenses. Hochhaus: Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Research Funding; Incyte: Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Crysandt: Pfizer: Other: Travel grant. Brümmendorf: Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding, Speakers Bureau; Gilead: Consultancy, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy, Honoraria, Speakers Bureau. Krug: AbbVie: Honoraria; Sanofi: Honoraria; Leo Pharma: Honoraria; BMS: Honoraria. Einsele: Novartis: Honoraria, Other: Consulting or advisory role, Travel support; Takeda: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; Sanofi: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; Janssen: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; Amgen: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; GlaxoSmithKline: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; Bristol Myers Squibb/Celgene: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding. Burchert: Novartis: Honoraria, Research Funding; MSD: Research Funding; Incyte: Honoraria. Schliemann: Bristol Myers Squibb: Honoraria, Other; Jazz Pharmaceuticals: Honoraria, Other, Research Funding; Novartis AG: Honoraria; Roche: Honoraria; Pfizer: Honoraria, Other; AngioBiomed: Research Funding; Boehringer Ingelheim: Research Funding; Laboratoires Delbert: Honoraria; AstraZeneca: Honoraria; Astellas Pharma Inc.: Honoraria; AbbVie Inc.: Honoraria, Other. Hanel: Novartis: Research Funding. Fransecky: Gilead: Consultancy, Research Funding, Speakers Bureau; Jazz: Consultancy; Servier: Consultancy; Amgen: Consultancy; Pfizer: Consultancy. Ruhnke: BeiGene, Inc.: Other; Jazz Pharmaceuticals: Other; Neovii Pharmaceuticals: Other; AbbVie Inc.: Research Funding. Schetelig: BeiGene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria; Eurocept: Honoraria; AstraZeneca: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Baldus: Jazz Pharmaceuticals: Consultancy; Astellas: Consultancy; BMS: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy; Gilead: Consultancy; Jannsen: Consultancy. Platzbecker: Jazz: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Silence Therapeutics: Consultancy, Honoraria, Research Funding; Celgene: Honoraria; Geron: Consultancy, Research Funding; Merck: Research Funding; Fibrogen: Research Funding; Roche: Research Funding; Syros: Consultancy, Honoraria, Research Funding; Curis: Consultancy, Research Funding; Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; Janssen Biotech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; medical writing support, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BeiGene: Research Funding; BMS: Research Funding. Röllig: AbbVie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria.

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