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2236 Impact of KMT2A-PTD Mutational Subgroups on Outcome of AML Patients after Induction Therapy and Allogeneic Hematopoietic Cell Transplantation

Program: Oral and Poster Abstracts
Session: 732. Allogeneic Transplantation: Disease Response and Comparative Treatment Studies: Poster I
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, Clinical Research, Diseases, real-world evidence, Therapies, therapy sequence, Myeloid Malignancies
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Desiree Kunadt1*, Sven Zukunft1*, Klaus H Metzeler, MD2,3, Christoph Röllig, MD, MSc1*, Christoph Schliemann, MD4*, Jan Braess, MD5*, Carsten Müller-Tidow, MD6*, Alwin Kraemer7*, Sebastian Scholl, MD8*, Inken Hilgendorf, MD9*, Edgar Jost, MD10*, Björn Steffen, MD11*, Gesine Bug, MD12*, Hermann Einsele, MD, PhD13*, Kerstin Schäfer-Eckart, MD14*, Stefan W. Krause, MD15*, Mathias Hänel, MD16, Thomas Schroeder17*, Martin Kaufmann, MD18, Jan Moritz Middeke, MD19*, Katja Sockel, MD19*, Leo Ruhnke, MD1*, Uwe Platzbecker, MD20, Hubert Serve, MD11, Matthias Stelljes, MD21, Claudia D Baldus, MD22*, Andreas Neubauer, MD23, Johannes Schetelig, MD, MSc24,25, David Poitz26*, Christian Thiede, MD27, Martin Bornhäuser, MD28,29* and Friedrich Stölzel, MD30,31*

1Department of Internal Medicine I, University Hospital Dresden, Dresden, Germany
2Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, NA, Germany
3Department of Internal Medicine III, Experimental Leukemia and Lymphoma Research (ELLF), University Hospital, LMU Munich, Munich, Germany
4Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Muenster, Muenster, Germany
5Hospital Barmherzige Brueder Regensburg, Regensburg, Germany
6Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany
7Department of Internal Medicine V, University Hospital Heidelberg, Heidelberg, Germany, Heidelberg, DEU
8Klinik für Innere Medizin II, Jena University Hospital, Jena, Germany
9Universitätsklinikum Jena, Klinik für Innere Medizin II, Abteilung für Hämatologie und Internistische Onkologie, Jena, Germany
10Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
11Department of Internal Medicine II, Hematology and Oncology, Goethe University Hospital Frankfurt, Frankfurt, Germany
12Dept. of Medicine 2, Goethe University, University Hospital, Frankfurt, Germany
13Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany
14Department of Internal Medicine V, Paracelsus University Hospital Nuremberg, Nuremberg, Germany
15Universitätsklinikum Erlangen, Erlangen, Germany
16Department of Internal Medicine III, Hematology, Oncology and Cellular Therapies, Hospital Chemnitz, Chemnitz, Germany
17Department of Hematology and Stem Cell Transplantation, University Hospital Essen, Essen, Germany
18Department of Hematology, Oncology and Palliative Care, Robert Bosch Hospital, Stuttgart, Germany
19Department of Internal Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
20University Leipzig Medical Center, Leipzig, Germany
21Department of Internal Medicine A, University of Muenster, Muenster, Germany
22University Hospital Schleswig-Holstein, Department of Hematology and Oncology, Campus Kiel, Kiel, Germany
23Department of Hematology, Oncology and Immunology, Phillips-University Marburg, Marburg, Germany, Marburg, Germany
24TU Dresden, Dresden, Saxony, Germany
25DKMS Group gGmbH, Dresden, Germany
26Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Dresden, TU Dresden, Germany, Dresden, Germany
27Department of Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
28National Center for Tumor Diseases (NCT/UCC) Dresden, Technical University Dresden, Dresden, Germany
29Department of Internal Medicine 1, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
30Department of Internal Medicine II, University Hospital Schleswig-Holstein, Kiel, Germany
31Department of Internal Medicine, University Hospital Carl Gustav Carus, Dresden, DEU


Genetic profiling of acute myeloid leukemia (AML) has increasingly revealed the possibility of adjusted therapeutic options. Recently, updates in genetic risk classifications introduced novel molecular features, but also excluded aberrations like partial tandem duplications in the lysine (K)-specific methyltransferase 2A (KMT2A-PTD), formerly associated with adverse prognosis. Furthermore, there is growing evidence that molecular subtypes confer differential prognosis. Therefore, we analyzed a large cohort of AML pts to decipher the prognostic impact of KMT2A-PTD mutations (KMT2A-PTDmut) including variants e9e3, e10e3 and e11e3 and their role in allogeneic hematopoietic cell transplantation (alloHCT).


Genomic DNA and total RNA of pts enrolled within the SAL registry (NCT03188874) was extracted at diagnosis. Samples were screened for KMT2A-PTDmut using the Mentype AMLplexQS Kit (Biotype, Dresden, Germany). Statistical as-treated analyses included standard statistical methods for categorial and continuous variables. Effects of alloHCT modeled as a time dependent covariate were estimated using Cox regression. Complete remission (CR) and survival rates were defined according to the current European Leukemia Net criteria. Logistic regression was used to evaluate CR rates and Cox regression to estimate hazard ratios (HR). The significance level was set at 0.05. All patients gave written informed consent. The study was conducted in accordance to the Declaration of Helsinki and was approved by the responsible ethics committees.


Among 1409 pts, 206 pts harbored KMT2A-PTDmut, while 1203 pts showed wildtype (WT) alleles. KMT2A-PTDmut status was more often associated with secondary AML (p = .001) and less likely with concomitant NPM1 mutations (p < .001). Variants e9e3 (40.8%) and e10e3 (36.6%) were more frequently detected than e11e3 (22.6%).

A total of 136 KMT2A-PTDmut and 859 WT pts received intensive induction therapy (IT). Rates of first complete remission (CR1) did not differ (p = .14). However, 5-year RFS was significantly lower in KMT2A-PTDmut pts compared to WT pts (15% vs. 25%), with median RFS of 23 vs. 29 months (HR = 1.4, p = .008). Accordingly, median OS was shorter (29 vs. 61 months; HR = 1.6, p = .002) and 5-year OS was lower for KMT2A-PTDmut pts compared to the WT counterparts (28% vs. 51%).

In CR1, 81.6% of KMT2A-PTDmut pts proceeded to alloHCT and 18.4% of KMT2A-PTDmut pts received chemotherapy-based consolidation only. Median RFS improved from 15 to 37 months (HR = 0.5, p = .13) and chance of 5-year RFS enhanced from 17% to 21% when KMT2A-PTDmut pts underwent alloHCT in CR1 compared to KMT2A-PTDmut pts receiving chemo-consolidation. Median OS increased from 30 to 43 months when being allografted (HR = 0.5, p = .2), paralleled by increased rates of 5-year OS (33% chemo-consolidation vs. 47% alloHCT).

Concerning KMT2A-PTD variants, there was no difference in likelihood to achieve CR1 between the three variants (p = .4). However, a trend towards shorter median OS (e9e3: 41 months, e10e3: 27 months, e11e3: 27 months) and worse median RFS (e9e3: 24 months, e10e3: 23 months, e11e3: 23 months) compared to WT pts (median OS: 61 months, median RFS: 29 months) could be revealed. Variant e10e3 was associated with worst prognosis (OS: HR = 2.1, p = .006; RFS: HR = 1.6, p = .06) and e9e3 with best prognosis (OS: HR = 1, p = .9; RFS: HR = 1.1, p = .7).

e9e3 demonstrated best prognosis for both consolidation strategies. Median OS was not reached until last follow-up. Median RFS was higher in alloHCT pts (15 vs. 38 months, HR = 0.5, p = .3). e10e3 and e11e3 also had a higher median OS (12 vs. 43 months, HR = 0.3, p = .3 and 12 months vs. median survival not reached, HR = 0.2, p = .3, respectively) and RFS (11 vs. 41 months, HR = 0.3, p = .3 and 11 months vs. median survival not reached, HR = 0.2, p = .3, respectively) when allografted.


Based on our retrospective analysis, KMT2A-PTDmut are associated with reduced prognosis and survival in AML patients compared to WT pts. However, poor prognosis was effectively mitigated by alloHCT. Concerning KMT2A-PTD variants, we hypothesize alloHCT to be beneficial for improved survival. This effect seemed to be less pronounced for variant e9e3and more distinct for variant e11e3. Therefore, some KMT2A-PTD variants could be potentially implemented in AML risk stratification. However, prospective studies and larger patient numbers are needed.

Disclosures: Kunadt: Jazz Pharmaceuticals: Honoraria, Other: Travel grants; Medac GmbH: Other: Travel grants. Metzeler: BMS: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria; Otsuka: Honoraria; Janssen: Honoraria; Novartis: Consultancy. Röllig: Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Astellas: Consultancy, Honoraria. Schliemann: Laboratoires Delbert: Honoraria; Boehringer Ingelheim: Research Funding; AngioBiomed: Research Funding; Pfizer: Honoraria, Other; Roche: Honoraria; Novartis AG: Honoraria; Jazz Pharmaceuticals: Honoraria, Other, Research Funding; Bristol Myers Squibb: Honoraria, Other; AstraZeneca: Honoraria; Astellas Pharma Inc.: Honoraria; AbbVie Inc.: Honoraria, Other. Hilgendorf: Novartis: Consultancy, Honoraria; Takeda: Honoraria; BeiGene: Honoraria; Medac: Honoraria; AbbVie: Honoraria; Amgen: Honoraria; Jazz: Honoraria; Fondatione Internationale Menarini: Honoraria; Janssen: Honoraria. Jost: Amgen: Honoraria; Medac: Other: travel costs; JAZZ: Honoraria; BMS Celgene: Honoraria. Bug: Novartis: Honoraria; Jazz: Honoraria, Other: travel grant; BMS: Honoraria; Gilead: Honoraria, Other: travel grant; Neovii: Other: trvel grant; Pfizer: Honoraria. Einsele: Sanofi: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; GlaxoSmithKline: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; Takeda: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; Amgen: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; Janssen: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding; Novartis: Honoraria, Other: Consulting or advisory role, Travel support; Bristol Myers Squibb/Celgene: Honoraria, Other: Consulting or advisory role, Travel support, Research Funding. Hänel: Novartis, SOBI, Gilead, Falk Foundation: Honoraria; Novartis, BMS/Celgene, Gilead, Pfizer, Incyte, Sanofi/Aventis, Roche, Amgen, SOBI, Janssen: Consultancy. Ruhnke: BeiGene, Inc.: Other; AbbVie Inc.: Research Funding; Jazz Pharmaceuticals: Other; Neovii Pharmaceuticals: Other. Platzbecker: Servier: Consultancy, Honoraria, Research Funding; Fibrogen: 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; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Geron: Consultancy, Research Funding; Jazz: Consultancy, Honoraria, Research Funding; Curis: Consultancy, Research Funding; Merck: Research Funding; Amgen: Consultancy, Research Funding; Janssen Biotech: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Honoraria; Syros: Consultancy, Honoraria, Research Funding; Silence Therapeutics: Consultancy, Honoraria, Research Funding; Roche: Research Funding; BeiGene: Research Funding; BMS: Research Funding. Baldus: Astellas: Consultancy; Gilead: Consultancy; Jannsen: Consultancy; Jazz Pharmaceuticals: Consultancy; BMS: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy. Schetelig: Eurocept: Honoraria; Novartis: Honoraria; AstraZeneca: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Stölzel: medac: Speakers Bureau.

*signifies non-member of ASH