IDH Mutations Are Associated with an Increased Risk of Coronary Artery Disease and Cardiotoxicity in Patients with Established AML
Authors: Kattih Badder , Shirvani Amir , Klement Piroska , Garrido Abel Martin , Gabdoulline Razif , Liebich Alessandro , Brandes Maximilian , Chaturvedi Anuhar , Seeger Timon , Thol Felicitas , Gohring Gudrun , Schlegelberger Brigitte , Geffers Robert , John David , Bavendiek Udo , Bauersachs Johann , Ganser Arnold , Heineke Joerg , Heuser Michael 
Published: November 2020

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: IDH 1 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&lt;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.