IDH mutations in leukemia cells and anthracycline-induced cardiotoxicity

IDH mutations in leukemia cells and anthracycline-induced cardiotoxicity. IDH mutations in leukemia cells are associated with increased risk of anthracycline-induced cardiotoxicity.

In adult AML, IDH mutations are associated with an increase in the prevalence of coronary heart disease and cardiotoxicity during anthracycline treatment, at least partly mediated by the tumor metabolite R-2HG.

This column selects the oncology and cardiology-related academic content of the 62nd American Society of Hematology (ASH) online annual meeting for compilation and interpretation. During the period, special hematology experts will be invited to make professional comments in conjunction with domestic academic progress; stay tuned , Welcome to leave a message to discuss.

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

Badder Kattih, MD1, Amir Shirvani2, et al.;1Department of Cardiology, University Hospital Frankfurt, Frankfurt Am Main, Germany;2Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany

Clonal hematopoiesis caused by acquired somatic mutations of hematopoietic cells is an independent driving factor for increased all-cause mortality and increased risk of coronary heart disease and heart failure. The carcinogenic mutations of isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) can lead to the conversion of αKG into R-2-hydroxyglutarate (R-2HG). R-2HG is a competitive inhibitor of TET2 and has Known tumor metabolites. In preclinical studies, the tumor metabolite R-2HG (produced by IDH mutant cells) is associated with pathological cardiac remodeling and dysfunction. In patients with acute myeloid leukemia (AML), it is unclear whether the IDH mutations in leukemia cells are related to the aggravation of cardiovascular disease or cardiotoxicity associated with anthracycline chemotherapy.

Research method

In this observational study, 363 adult AML patients stratified according to IDH gene mutation status were analyzed based on propensity scores. In order to analyze whether the IDH mutation status of AML patients is related to the aggravation of cardiotoxicity, the study analyzed the control group (AML patients without IDH mutations) and the exposed group (AML patients with IDH mutations) at baseline and at different time points during treatment. ) Left ventricular ejection fraction (LVEF).

Research results

26 (7.2%) and 39 (10.7%) adult AML patients had IDH1 and IDH2 mutations, respectively. The median age of the overall population is 60 years. During a median follow-up of 7.6 years, the estimated 2-year recurrence-free survival (RFS) and overall survival (OS) of the entire study cohort were 49.4% (5-year RFS 38.9%) and 59.2% (5-year OS 43.1). %).

The prevalence of coronary heart disease in patients with IDH1 mutant AM L was significantly higher than that in the control group (26.1% vs. 6.4%, p = 0.002).

The inverse probability weighted analysis of propensity scores was performed on 295 patients receiving cytarabine and anthracycline-containing intensive chemotherapy. The analysis results show that compared with IDH1/2 wild-type patients, IDH1/2 mutant AML patients have an increased risk of decreased heart function during treatment [LVEF during pretreatment compared with 10 months after diagnosis: IDH1/2 mutant LVEF decreased from 59.2% to 41.9% (P<0.001), IDH1/2 wild-type LVEF decreased from 58.5% to 55.4% (P=0.27)], which indicates that IDH mutations in AML patients are related to treatment-related decline in cardiac function. It has nothing to do with baseline characteristics.

In order to verify whether the tumor metabolite R-2HG can cause the heart cells of IDH mutant AML patients to be vulnerable, during anthracycline treatment, human induced pluripotent stem cell (hiPS)-derived cardiomyocytes were exposed to R-2HG (or Control). After adding R-2HG in the treatment of anthracyclines, an exaggerated sarcomere disorder was found in the cardiomyocytes derived from hiPS by immunostaining.

By RNA sequencing of hiPS-derived cardiomyocytes exposed to R-2HG during anthracycline therapy, this study proved the transcriptional basis of the biological process that mediates increased cardiotoxicity.