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2934 Risk Stratification of Patients with RUNX1-mutated Acute Myeloid Leukemia

Program: Oral and Poster Abstracts
Session: 617. Acute Myeloid Leukemias: Biomarkers, Molecular Markers and Minimal Residual Disease in Diagnosis and Prognosis: Poster II
Hematology Disease Topics & Pathways:
Research, Acute Myeloid Malignancies, AML, Translational Research, Diseases, Myeloid Malignancies, Study Population, Human
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Christian Rausch1*, Roman Hornung2*, Aarif M. N. Batcha2,3*, Maja Rothenberg-Thurley, PhD1*, Stefanos A. Bamopoulos, MD4*, Vindi Jurinovic, MSc1,2,5*, Bianka Ksienzyk1*, Stephanie Schneider, PhD1,6*, Annika Maria Dufour, PhD, MSC1*, Michaela Neusser, PhD1*, Maria Cristina Sauerland, MD7*, Dennis Görlich, PhD7, Utz Krug, MD8*, Wolfgang E. Berdel, MD9, Bernhard J. Woermann, MD10, Jan Braess, MD11*, Wolfgang Hiddemann, MD1,12,13*, Manja Meggendorfer, PhD14, Wolfgang Kern, MD14, Torsten Haferlach, MD, PhD14, Johannes Schetelig, MD, MSc15, Moritz Middeke, MD15*, Sebastian Stasik, PhD15*, Katharina Egger-Heidrich, MD15*, Christoph Röllig, MD, MSc15*, Martin Bornhäuser, MD15*, Christian Thiede, MD15, Claudia D Baldus, MD16*, Carsten Müller-Tidow, MD17*, Uwe Platzbecker, MD18, Hubert Serve, MD19, Wendy Stock, MD20, Geoffrey L Uy, MD21, John C. Byrd, MD22, Deedra Nicolet23,24, Ann-Kathrin Eisfeld, MD*23,24,25, Ulrich Mansmann2,3,12,13*, Karsten Spiekermann, MD1,12,13*, Klaus H Metzeler, MD13,26 and Tobias Herold, MD1*

1Department of Medicine III, LMU University Hospital, LMU Munich, Munich, Germany
2Institute of Medical Data Processing, Biometrics and Epidemiology (IBE), Faculty of Medicine, LMU Munich, Munich, Germany
3Data Integration for Future Medicine (DiFuture, www.difuture.de), Faculty of Medicine, LMU Munich, Munich, Germany
4Department of Hematology, Oncology and Tumor Immunology (Campus Benjamin Franklin), Charité University Medicine Berlin, Berlin, DEU
5Research Unit Apoptosis in Hematopoietic Stem Cells, Helmholtz Center Munich, German Research Center for Environmental Health (HMGU), Munich, Germany
6Institute of Human Genetics, LMU University Hospital, LMU Munich, Munich, Germany
7Institute of Biostatistics and Clinical Research, University of Münster, Muenster, Germany
8Department of Medicine III, Hospital Leverkusen, Leverkusen, DEU
9Department of Medicine A, Hematology and Oncology, University Hospital Muenster, Muenster, Germany
10German Society of Hematology and Oncology, Berlin, Germany
11Department of Oncology and Hematology, Hospital Barmherzige Brueder, Regensburg, DEU
12German Cancer Consortium (DKTK) Partner Site Munich, Munich, Germany
13German Cancer Research Center (DKFZ), Heidelberg, Germany
14MLL Munich Leukemia Laboratory, Munich, Germany
15Department of Internal Medicine 1, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany
16Medical Department II, University Cancer Center Schleswig-Holstein, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
17Heidelberg University Hospital, Heidelberg, Germany
18Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, Germany
19Department of Internal Medicine II, Hematology and Oncology, Goethe University Hospital Frankfurt, Frankfurt, Germany
20Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL
21Division of Oncology, Washington University School of Medicine, Saint Louis, MO
22Department of Internal Medicine, University of Cincinnati, Cincinnati, OH
23Clara D. Bloomfield Center for Leukemia Outcomes Research, The Ohio State University, Columbus, OH
24Alliance Statistics and Data Center, The Ohio State University Comprehensive Cancer Center, Columbus, OH
25Division of Hematology, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH
26Department of Hematology, Cellular Therapy, Hemostaseology and Infectious Diseases, University Leipzig Medical Center, Leipzig, NA, Germany

Mutations in RUNX1 (RUNX1mut) occur in ~15% of intensively treated AML cases. RUNX1mut have no specific hotspot and various types of alteration are observed. The European LeukemiaNet (ELN) risk stratification assigns adverse prognosis to RUNX1mut if they do not co-occur with favorable-risk genotypes. Considering the biological complexity of RUNX1 it seems implausible that all alterations have similar consequences.

Using clinical and genetic variables, we developed a prognostic risk stratification model for ELN adverse-risk RUNX1mut AML patients.

We combined data from five groups, totaling 609 patients with intensively treated RUNX1mut AML, to develop the model. Our training set included 448 patients treated on trials of the AML Cooperative Group (AMLCG; Herold et al, Leukemia, 2020; (n=178)), AML Study Group (Gerstung et al, NEJM, 2016; (n=116)) and Study Alliance Leukemia (n=154). Patients from the Munich Leukemia Laboratory (MLL; (n=107)) and of the Alliance group (trials NCT00048958, NCT00899223, NCT00900224; Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org; (n=54)) served as independent validation cohorts. Additionally, 955 patients without RUNX1mut treated on AMLCG trials served as controls. Patients with t(15;17), prior treatment, or RUNX1mut with co-occurring favorable-risk genotypes according to ELN 2017 were excluded.

Differences between RUNX1mut patients and controls were investigated using univariate logistic regression. Testing was performed using likelihood ratio tests and adjusted for study group. Univariate analyses were adjusted for multiple testing using the Benjamini-Hochberg procedure. We obtained risk prediction models using multivariate Cox regression. Missing values were imputed using the missForest approach. Model selection was performed using forward selection based on the Bayesian information criterion. Cut-offs were based on the 25th- 50th- and 75th-percentile score values obtained in the training data. Performance was evaluated using Kaplan-Meier curves. For internal validation Harrell’s C index was estimated using cross-study validation. For external validation, the final risk prediction models were separately applied to the external datasets.

RUNX1mut were more common in older, male patients and sAML (table). White blood cells, lactate dehydrogenase and bone marrow blasts were lower in RUNX1mut patients. Mutations in several myelodysplasia-related genes were enriched in RUNX1mut patients (ASXL1, BCOR, BCORL1, EZH2, KMT2A, PHF6, and STAG2, SF3B1, SRSF2, and U2AF1), whereas DNMT3A, NPM1 and FLT3 were more frequently altered in controls. A strong association with mutations of the splicing factor complex was identified (49% vs. 13%, p<0.0001). Contradicting previous reports, we found no association with IDH mutations.

The risk prediction score we obtained for OS is as follows: 0.03054 x age (y) + 0.74996 x adverse MRC + 0.43779 x FLT3-ITD + 0.00317 x WBC count (10^9/L) - 0.00158 x platelet count (10^9/L) + 0.37401 x NRAS-mutation, where the obtained cut-off values are: <1.592 (low risk); 1.592 to 2.303 (moderate risk) >2.303 (high risk). Binary variables are coded as 0 or 1. Harrell's C index estimated using internal validation was 0.6. Kaplan-Meier curves estimated using the training set suggest strong differences in survival between the risk categories. Median overall survival (OS) was 2.5, 1.0 and 0.6 years for low-, intermediate-, and high-risk. External validation using the Alliance cohort shows similar results (Figure). Results obtained for the MLL cohort show smaller differences. However, we still observe clear separation of risk groups with a significant difference between low- and high-risk groups (adjusted p-value: 0.0266). Scores for relapse-free survival (RFS) as well as for OS and RFS censored for allogeneic transplant show similar results.

We analyzed a large collection of intensively treated RUNX1mut AML patients and observed heterogenous outcomes that could be predicted by applying few variables (age, MRC-score, FLT3/NRAS mutation-status, and WBC/platelet count). The OS of RUNX1mut high-risk patients is discouraging, highlighting the unmet need of these patients. In addition, our work demonstrates that ELN risk groups can be further stratified and that integrated approaches using routinely available variables can further advance risk prediction.

Disclosures: Krug: AbbVie: Honoraria; Sanofi: Honoraria; Leo Pharma: Honoraria; BMS: Honoraria. Meggendorfer: MLL Munich Leukemia Laboratory: Current Employment. Kern: MLL Munich Leukemia Laboratory: Current Employment, Other: Equity Ownership. Haferlach: MLL Munich Leukemia Laboratory: Current Employment, Other: Equity Ownership. Schetelig: Eurocept: Honoraria; Novartis: Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Middeke: AbbVie: Membership on an entity's Board of Directors or advisory committees. Röllig: Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding. Baldus: Jazz Pharmaceuticals: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy; Amgen: Consultancy; Astellas: Consultancy; BMS: Consultancy; Jannsen: Consultancy. Platzbecker: BeiGene: Research Funding; Janssen Biotech: Consultancy, Research Funding; Curis: Consultancy, Research Funding; AbbVie: Consultancy; Novartis: Consultancy, Honoraria, Research Funding; Syros: Consultancy, Honoraria, Research Funding; Geron: Consultancy, Research Funding; Silence Therapeutics: Consultancy, Honoraria, Research Funding; Servier: Consultancy, Honoraria, 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; Jazz: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Honoraria; Takeda: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Roche: Research Funding; Merck: Research Funding; MDS Foundation: Membership on an entity's Board of Directors or advisory committees; Fibrogen: Research Funding. Stock: Newave: Honoraria; Amgen: Honoraria; Servier: Other: Data Safety Monitoring Board/Advisory Board; Kura: Research Funding; Kite: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria; Glaxo Smith Kline: Consultancy. Uy: Jazz: Other: Advisory Board. Byrd: Kurome: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; OSU Drug Devel. Inst.: Consultancy; Vincerx: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Orange Grove Bio: Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees, Research Funding; Orbimed: Consultancy, Research Funding; Eilean Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; American Cancer: Membership on an entity's Board of Directors or advisory committees. Eisfeld: Karyopharm Therapeutics: Other: spouse employment; Astra Zeneca: Honoraria, Other: CEI Advisory Board; OncLive: Honoraria. Metzeler: BMS: Consultancy, Honoraria; AbbVie: Honoraria, Research Funding; Pfizer: Honoraria; Otsuka: Honoraria; Janssen: Honoraria; Novartis: Consultancy.

*signifies non-member of ASH