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389 IDH Mutations Are Associated with an Increased Risk of Coronary Artery Disease and Cardiotoxicity in Patients with Established AML

Program: Oral and Poster Abstracts
Type: Oral
Session: 613. Acute Myeloid Leukemia: Molecular Mutations and Their Prognostic Implications
Hematology Disease Topics & Pathways:
AML, Diseases, Biological Processes, Myeloid Malignancies, Clinically relevant, hematopoiesis
Sunday, December 6, 2020: 12:15 PM

Badder Kattih, MD1*, Amir Shirvani2*, Piroska Klement3*, Abel Martin Garrido4*, Razif Gabdoulline3*, Alessandro Liebich3*, Maximilian Brandes3*, Anuhar Chaturvedi, PhD3*, Timon Seeger5*, Felicitas Thol3, Gudrun Gohring, Prof., MD6*, Brigitte Schlegelberger, MD6, Robert Geffers, PhD7*, David John8*, Udo Bavendiek2*, Johann Bauersachs2*, Arnold Ganser3, Joerg Heineke4* and Michael Heuser3

1Department of Cardiology, University Hospital Frankfurt, Frankfurt Am Main, Germany
2Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
3Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
4Department of Cardiovascular Physiology, Medical Faculty Mannheim of Heidelberg University, Mannheim, Germany
5Department of Cardiology, University Hospital Heidelberg, Heidelberg, Germany
6Department of Human Genetics, Hannover Medical School, Hannover, Germany
7Genome Analytics Research Group, Helmholtz Centre for Infection Research, Braunschweig, Germany
8Institute for Cardiovascular Regeneration, Goethe University Frankfurt, Frankfurt am Main, Germany

Introduction: Clonal hematopoiesis initiated by acquired somatic mutations in hematopoietic cells has been identified as an independent driver of increased all-cause mortality, risk of coronary artery disease and heart failure. Oncogenic mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) lead to conversion of αKG to R-2-hydroxyglutarate (R-2HG), which is a competitive inhibitor of TET2 and a known oncometabolite. Oncometabolite R-2HG (produced by IDH mutant cells) has been implicated in pathological cardiac remodeling and dysfunction in preclinical studies. Whether IDH mutant leukemic cells in patients with established AML are also associated with the development of cardiovascular diseases or exacerbate cardiotoxicity during anthracycline containing chemotherapy is still unknown.

Methods: In this observational study, a propensity score-based analysis was performed in 363 adult AML patients being stratified by mutation status in the IDH gene. To analyze whether the IDH mutation status in AML patients was associated with increased cardiotoxicity, we analyzed echocardiographic left ventricular ejection fraction (LVEF) in the control group (AML patients without IDH mutation) and the exposed group (AML patients with IDH mutation) at baseline and at different time points during AML therapy.

Results: IDH1 and IDH2 mutations occurred in 26 (7.2%) and 39 adult AML patients (10.7%), respectively. The median age of the total population was 60 years. The estimated 2-year relapse-free survival and overall survival rates in the overall study cohort were 49.4% (5-year RFS 38.9%) and 59.2% (5-year OS 43.1%) during a median follow-up of 7.6 years. IDH1 mutant AML patients exhibited a significantly higher prevalence of coronary artery disease (26.1% vs. 6.4%, p=0.002). A propensity score analysis by inverse probability-weighting was performed based on the 295 patients who received intensive cytarabine and anthracycline-containing chemotherapy. This analysis revealed an increased risk for a declining cardiac function during AML treatment in IDH1/2 mutated compared to IDH1/2 wild type patients [LVEF pretreatment compared to 10 months after diagnosis: 59.2% to 41.9% (P<0.001) vs 58.5% to 55.4% (P=0.27), respectively], suggesting that the IDH mutations in AML patients were associated with a declining cardiac function during AML therapy, which was independent of measured baseline characteristics. To validate whether the oncometabolite R-2HG drives vulnerability of cardiac cells in patients with IDH mutant AML, human iPS-derived cardiomyocytes were exposed to R-2HG (or control) during anthracycline treatment. Indeed, an exaggerated sarcomere disarray when R-2HG was added to anthracycline treatment was identified by immunostaining in human induced pluripotent stem cell (hIPS) derived cardiomyocytes. By RNA sequencing of R-2HG exposed hiPS-derived cardiomyocytes during anthracycline treatment, we demonstrate the transcriptomic basis for putative biological processes mediating the increased cardiotoxicity.

Conclusion: The presence of an IDH mutation in adult AML was associated with a higher prevalence of coronary artery disease and an exacerbated cardiotoxicity during anthracycline treatment, which was at least in part mediated by the oncometabolite R-2HG.

Disclosures: Thol: Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Ganser: Novartis: Consultancy; Celgene: Consultancy. Heuser: BerGenBio ASA: Research Funding; Roche: Research Funding; Astellas: Research Funding; Janssen: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; PriME Oncology: Honoraria; Daiichi Sankyo: Consultancy, Research Funding; Stemline Therapeutics: Consultancy; Bayer: Consultancy, Research Funding; Karyopharm: Research Funding.

*signifies non-member of ASH