IDH mutations linked to cardiotoxicity among adults with AML
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Adults with acute myeloid leukemia with IDH mutations appeared to be at increased risk for coronary artery disease and exacerbated cardiotoxicity during treatment with anthracyclines, according to study results.
“Somatic mutations in hematopoietic stem cells can cause clonal hematopoiesis of indeterminant potential, building clones of mutations in blood cells. These mutant cells represent important and independent cardiovascular risk factors that double the risk for atherosclerosis events, which frequently occur in patients with aortic valve stenosis, contribute to stenosis and worsen cardiovascular outcomes,” Badder Kattih, MD, researcher in the department of cardiology at University Hospital Frankfurt in Germany, said during a presentation at the virtual ASH Annual Meeting and Exposition. “Notably, IDH mutations are major drivers of clonal dominance in AML. However, the impact of these mutations on cardiovascular risk in patients with AML remains elusive.”
Kattih and colleagues conducted a retrospective, observational study at Hannover Medical School in Germany to assess whether IDH mutations were associated with an increased risk for cardiotoxicity among 363 adults (median age, 60 years; range, 18-90; 58% men) with AML stratified by IDH mutation status. Twenty-six patients (7.2%) had IDH1 mutations and 39 patients (10.7%) had IDH2 mutations.
Researchers assessed echocardiographic left ventricular ejection fraction (LVEF) at baseline and at 3 months, 6 months and 10 months after anthracycline treatment among those with and without IDH mutations.
Median follow-up was 7.6 years.
The estimated RFS rate among the overall cohort decreased from 49.4% at 2 years to 38.9% at 5 years, and OS decreased from 59.2% at 2 years to 43.1% at 5 years.
Results showed coronary artery disease was more common among patients with IDH1 mutations vs. IDH wild-type disease (26.1% vs. 6.4%; P = .002).
Results of a subgroup analysis that included 295 patients who received intensive cytarabine and anthracycline-based chemotherapy showed an increased risk for declining cardiac function during treatment among those with IDH1 and IDH2 mutations vs. those with IDH wild-type disease. LVEF among patients with IDH1 and IDH2 mutations declined from 59.2% at baseline to 41.9% at 10 months after diagnosis (P < .001) vs. 58.5% to 55.4% among those with IDH wild-type disease.
“This suggests that the myocardium of [patients with IDH2 mutations] is more vulnerable to intensive chemotherapy,” Kattih said.
Researchers then assessed whether the IDH mutant-derived oncometabolite R-2HG affects the vulnerability of cardiac cells in patients with IDH-mutant AML by exposing human-induced pluripotent stem cell-derived cardiomyocytes to R-2HG during anthracycline treatment. They identified an exaggerated sarcomere disarray by immunostaining in human-induced pluripotent stem cell-derived cardiomyocytes.
“By RNA sequencing of R-2HG-exposed, human-induced pluripotent stem cell-derived cardiomyocytes during anthracycline treatment, we identified further upregulation of genes in both the biological processes, which indicated that the oncometabolite R-2HG exacerbates the cardiotoxicity of doxorubicin in human-induced pluripotent stem cell-derived cardiomyocytes,” Kattih said. “Future prospective studies will address whether IDH mutation inhibitors can reduce the risk for cardiac dysfunction and whether heart failure medication can ameliorate the cardiovascular risk associated with IDH mutations and intensive chemotherapy.”
Perspective
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James K. McCloskey II, MD
One of the most exciting areas of myeloid malignancies has been this collision of hematology, oncology and cardiology. We have known for quite some time about the cardiovascular implications of clonal hematopoiesis of indeterminant potential. This study attempted to identify whether mutations in IDH increase the risk for cardiovascular disease in our patients with AML. This work is building on cohort studies and animal models in which we have identified other clonal abnormalities that increase the risk for significant vascular toxicity or comorbidity in patients irrespective of whether or not they have a myeloid malignancy.
In this study, the researchers clearly demonstrated that having an IDH mutation, specifically IDH1 mutation, increased the risk for cardiovascular events. They also found that patients with IDH-mutant disease had increased risk for cardiac compromise with anthracycline-based induction, which was very interesting. They were able to correlate this with basic science findings where they looked at the change in the transcriptome and RNA sequencing in human myocytes that had been exposed to anthracyclines in the IDH-controlled or -mutant environment. Fitting in that basic science piece really makes this compelling.
This is just the tip of the iceberg. In the future, we may find that clonal hematopoiesis, by effects on the endothelium, has a lot more to do with cardiovascular risk than we could have ever imagined, which may have a lot of implications outside the realm of AML or even malignancies in general. Hopefully, our understanding of this process will help make treatments safer for our patients with leukemia in addition to helping us address the health needs of all patients, considering that the highest risk to our day-to-day patients in the United States is cardiovascular disease.
Hackensack University Medical Center
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Kattih B, et al. Abstract 389. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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