TET2-Driven Clonal Hematopoiesis and Response to Canakinumab

Importance

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of atherosclerotic cardiovascular disease, and mouse experiments suggest that CHIP related toTet2loss of function in myeloid cells accelerates atherosclerosis via augmented interleukin (IL) 1β signaling.

Objective

To assess whether individuals with CHIP have greater cardiovascular event reduction in response to IL-1β neutralization in the Canankinumab Anti-inflammatory Thrombosis Outcomes Trial (CANTOS).

Design, Setting, and Participants

This randomized clinical trial took place from April 2011 to June 2017 at more than 1000 clinical sites in 39 countries. Targeted deep sequencing of genes previously associated with CHIP in a subset of trial participants using genomic DNA prepared from baseline peripheral blood samples were analyzed. All participants had prior myocardial infarction and elevated high-sensitivity C-reactive protein level above 0.20 mg/dL. Analysis took place between June 2017 and December 2021.

Interventions

Canakinumab, an anti–IL-1β antibody, given at doses of 50, 150, and 300 mg once every 3 months.

Main Outcomes and Measures

Major adverse cardiovascular events (MACE).

Results

A total of 338 patients (8.6%) were identified in this subset with evidence for clonal hematopoiesis. As expected, the incidence of CHIP increased with age; the mean (SD) age of patients with CHIP was 66.3 (9.2) years and 61.5 (9.6) years in patients without CHIP. Unlike other populations that were not preselected for elevated C-reactive protein, in the CANTOS population variants inTET2were more common thanDNMT3A(119 variants in 103 patients vs 86 variants in 85 patients). Placebo-treated patients with CHIP showed a nonsignificant increase in the rate of MACE compared with patients without CHIP using a Cox proportional hazard model (hazard ratio, 1.32 [95% CI, 0.86-2.04];P = .21). Exploratory analyses of placebo-treated patients with a somatic variant in eitherTET2orDNMT3A(n = 58) showed an equivocal risk for MACE (hazard ratio, 1.65 [95% CI, 0.97-2.80];P = .06). Patients with CHIP due to somatic variants inTET2also had reduced risk for MACE while taking canakinumab (hazard ratio, 0.38 [95% CI, 0.15-0.96]) with equivocal difference compared with others (Pfor interaction = .14).

Conclusions and Relevance

These results are consistent with observations of increased risk for cardiovascular events in patients with CHIP and raise the possibility that those withTET2variants may respond better to canakinumab than those without CHIP. Future studies are required to further substantiate this hypothesis.

Trial Registration

ClinicalTrials.gov Identifier:NCT01327846