Cardiovascular Disease Among Patients With AML and CHIP-Related Mutations

Oscar Calvillo-Argüelles; Alice Schoffel; José-Mario Capo-Chichi; Husam Abdel-Qadir; Andre Schuh; Montserrat Carrillo-Estrada; Shiying Liu; Vikas Gupta; Aaron D Schimmer; Karen Yee; Liran I Shlush; Pradeep Natarajan; Paaladinesh Thavendiranathan

doi:10.1016/j.jaccao.2021.11.008

Cardiovascular Disease Among Patients With AML and CHIP-Related Mutations

JACC CardioOncol. 2022 Mar 15;4(1):38-49. doi: 10.1016/j.jaccao.2021.11.008. eCollection 2022 Mar.

Authors

Oscar Calvillo-Argüelles^{1

2

3}, Alice Schoffel¹, José-Mario Capo-Chichi⁴, Husam Abdel-Qadir^{1

5}, Andre Schuh⁶, Montserrat Carrillo-Estrada¹, Shiying Liu¹, Vikas Gupta⁶, Aaron D Schimmer⁶, Karen Yee⁶, Liran I Shlush^{6

7}, Pradeep Natarajan^{8

9

10}, Paaladinesh Thavendiranathan¹

Affiliations

¹ Ted Rogers Program in Cardiotoxicity Prevention, Peter Munk Cardiac Center, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
² Department of Cardiology, Department of Medical Oncology, Health Sciences North, Sudbury, Ontario, Canada.
³ Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, Ontario, Canada.
⁴ Department of Clinical Laboratory Genetics, Genome Diagnostics Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
⁵ Women's College Hospital, Toronto, Ontario, Canada.
⁶ Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
⁷ Department of of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
⁸ Cardiovascular Research Center, Massachusetts General Hospital, Boston, Massachusetts.
⁹ Program in Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, Massachusetts.
¹⁰ Department of Medicine, Harvard Medical School, Boston, Massachusetts.

Abstract

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel cardiovascular disease (CVD) risk factor in individuals without acute myeloid leukemia (AML).

Objectives: The aim of this study was to examine the association between mutations associated with CHIP (CHIP-related mutations) identified in patients at AML diagnosis and the risk for cardiovascular events (CVEs).

Methods: This was a retrospective cohort study of 623 patients with AML treated between 2015 and 2018 who underwent DNA analysis. Cause-specific hazard regression models were used to study the associations between pathogenic mutations in common CHIP-related genes (DNMT3A, TET2, ASXL1, JAK2, TP53, SRSF2, and SF3B1) and the rate of CVEs (heart failure hospitalization, acute coronary syndrome, coronary artery revascularization, ischemic stroke, venous thromboembolism, and CVD death) and between CVE development and all-cause mortality.

Results: Patients were 64.6 ± 15.3 years of age, 265 (42.5%) were women, and 63% had at least 1 CHIP-related mutation. Those with CHIP-related mutations were older (69.2 ± 12.3 vs 56.6 ± 16.6 years; P < 0.001) and had a greater prevalence of CVD risk factors and CVD history. In adjusted analysis, the presence of any CHIP-related mutation was associated with a higher rate of CVEs (HR: 1.74; 95% CI: 1.03-2.93; P = 0.037) among intensively treated patients (anthracycline based) but not the whole cohort (HR: 1.26; 95% CI: 0.81-1.97; P = 0.31). TP53 (HR: 4.18; 95% CI: 2.07-8.47; P < 0.001) and ASXL1 (HR: 2.37; 95% CI: 1.21-4.63; P = 0.012) mutations were associated with CVEs among intensively treated patients. Interval development of CVEs was associated with all-cause mortality (HR: 1.99; 95% CI: 1.45-2.73; P < 0.001).

Conclusions: Among patients with AML treated with intensive chemotherapy, mutations in CHIP-related genes were associated with an increased risk for developing incident CVEs after AML diagnosis.

Keywords: ACS, acute coronary syndrome; AML, acute myeloid leukemia; CHIP, clonal hematopoiesis of indeterminate potential; CVD, cardiovascular disease; CVE, cardiovascular event; CVRF, cardiovascular risk factor; HF, heart failure; LVEF, left ventricular ejection fraction; MACCE, major adverse cardiovascular and cerebrovascular event(s); NGS, next-generation sequencing; VAF, variant allele frequency; acute myeloid leukemia; allo-HCT, allogeneic hematopoietic cell transplantation; cardiovascular diseases; clonal hematopoiesis; clonal hematopoiesis of indeterminate potential.