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

Cardiovascular Disease Among Patients With AML and CHIP-Related Mutations

Oscar Calvillo-Argüelles  1   2   3 , Alice Schoffel  1 , José-Mario Capo-Chichi  4 , Husam Abdel-Qadir  1   5 , Andre Schuh  6 , Montserrat Carrillo-Estrada  1 , Shiying Liu  1 , Vikas Gupta  6 , Aaron D Schimmer  6 , Karen Yee  6 , Liran I Shlush  6   7 , Pradeep Natarajan  8   9   10 , Paaladinesh Thavendiranathan  1
Affiliations

Cardiovascular Disease Among Patients With AML and CHIP-Related Mutations

Oscar Calvillo-Argüelles et al. JACC CardioOncol. .

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.

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Conflict of interest statement

This study was supported by the Ontario Early Research Award. Dr Calvillo-Argüelles is supported by the Hold ’em for Life Oncology Clinician Scientist Award at the University of Toronto’s Faculty of Medicine. Dr Thavendiranathan is supported by the Canadian Institutes of Health Research New Investigator Award (147814) and a Canada Research Chair in Cardio-Oncology. Dr Abdel-Qadir is supported by a National New Investigator Award from the Heart and Stroke Foundation of Canada. Dr Schimmer is supported by the Canadian Institutes of Health Research, the Canadian Cancer Society, and the Ontario Institute of Cancer Research with funding provided by the Ontario Ministry of Research and Innovation, the Princess Margaret Cancer Centre Foundation, and the Ministry of Long Term Health and Planning in the Province of Ontario; and holds the Ronald N. Buick Chair in Oncology Research. Dr Natarajan is supported by grants from the National Heart, Lung, and Blood Institute (R01HL142711, R01HL148050, R01HL151283, and R01HL148565) and Fondation Leducq (TNE-18CVD04). Dr Thavendiranathan has received honoraria from BI, Takeda, and Amgen. Dr. Schuh has received honoraria from Takeda, Novartis, Jazz, and Otsuka Pharmaceuticals; has received research support from Medivir and Takeda; and owns stock in AbbVie Pharmaceuticals. Dr. Schimmer is named as an inventor on patent applications related to the use of double-negative T cells in AML and cancer. Dr Gupta has received honoraria from Novartis, Bristol Myers Squibb Celgene, Pfizer, and Sierra Oncology. Dr Abdel-Qadir has received honoraria from Amgen. Dr Yee has received honoraria from Celgene/Bristol Myers Squibb, Roche, Takeda, Pfizer, TaiHo and Novartis; and has received research funding from Astex, Forma Therapeutics, Jazz, Janssen, Onconova, Medimmune, Genenetch, and Tolero Pharmaceuticals. Dr Natarajan has received grant support from Amgen, AstraZeneca, Boston Scientific, Apple, and Novartis; has received personal fees from AstraZeneca, Apple, Genentech, Novartis, Blackstone Life Sciences, and Foresite Labs; and reports spousal employment at Vertex, all unrelated to the present work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Prevalence of CHIP-Related Mutations According to Age Group Counts of patients within each age group with (red bars) and without (blue bars) clonal hematopoiesis of indeterminate potential (CHIP)–related mutations.
Figure 2
Figure 2
Incidence of Cardiovascular Events and Death as a Competing Risk Cumulative incidence function (CIF) curves illustrating the risk for cardiovascular events (CVEs) and competing risk (CR) stratified by clonal hematopoiesis of indeterminate potential (CHIP)–related mutation status among the complete cohort (left), among patients treated with intensive chemotherapy (right), and among patients not treated with intensive chemotherapy (bottom). In the complete cohort, the 3-year cumulative incidence of CVEs (solid lines) among patients with and without CHIP-related mutations was 22.3% (95% CI: 17.6%-27.3%) vs 15.7% (95% CI: 11.1%-21.1%) (P = 0.17, Gray test). Dotted lines show comparison of CIF of death as a CR between both groups (51.1% [95% CI: 45.1%-56.8%] vs 26.9% [95% CI: 20.7%-33.5%]; P < 0.001). In the intensive chemotherapy group, the 3-year cumulative incidence of CVEs (solid lines) among patients with and without CHIP-related mutations was 25.8% (95% CI: 19.6%-32.4%) vs 15.4% (95% CI: 10.4%-21.4%) (P = 0.044, Gray test). Dotted lines show comparison of CIF of death as a CR between both groups (41.5% [95% CI: 34.3%-48.5%] vs 23.1% [95% CI: 16.7%-30.1%]; P < 0.001). In the nonintensive treatment group, the 3-year cumulative incidence of CVEs (solid lines) among patients with and without CHIP-related mutations was 15.3% (95% CI: 9.4%-22.5%) vs 14.2% (95% CI: 5.4%-27.1%) (P = 0.61, Gray test). Dotted lines show comparison of CIF of death as a CR between both groups (70.5% [95% CI: 59.3%-79.1%] vs 47.2% [95% CI: 27.5%-64.6%]; P = 0.14).
Central Illustration
Central Illustration
CHIP-Related Mutations, CV Events, and Mortality Clonal hematopoiesis of indeterminate potential–related mutations (DNMT3A, TET2, ASXL1, TP53, JAK2, SF3B1, and SRSF2) are commonly present among patients with acute myeloid leukemia (AML) and are associated with higher risk for cardiovascular events (CVEs) in those receiving intensive chemotherapy. The following variables were included in CVE models of the full cohort: age, sex, cardiovascular risk factors (diabetes, dyslipidemia, hypertension, obesity, smoking), cardiovascular disease (heart failure, coronary artery disease, peripheral vascular disease, atrial fibrillation, stroke), and allogeneic hematopoietic cell transplantation. The following variables were included in CVE models of patients treated with intensive chemotherapy: all variables included for the full cohort, baseline left ventricular ejection fraction, and cumulative anthracycline dose. The following variables were included in the all-cause mortality model: all variables included in the full cohort model, European Leukemia Network adverse risk category, secondary AML, and therapy-related AML. †Noncardiovascular mortality was used as competing risk for CV events. CHIP = clonal hematopoiesis of indeterminate potential; CV = cardiovascular; CVD = cardiovascular disease.
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