TET2-Driven Clonal Hematopoiesis and Response to Canakinumab

Abstract

IMPORTANCE Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of atherosclerotic cardiovascular disease, and mouse experiments suggest that CHIP related to Tet2 loss 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 PARTICIPANTSThis 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 in TET2 were more common than DNMT3A (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 either TET2 or DNMT3A (n = 58) showed an equivocal risk for MACE (hazard ratio, 1.65 [95% CI,]; P = .06). Patients with CHIP due to somatic variants in TET2 also had reduced risk for MACE while taking canakinumab (hazard ratio, 0.38 [95% CI, 0.15-0.96]) with equivocal difference compared with others (P for interaction = .14). CONCLUSIONS AND RELEVANCEThese results are consistent with observations of increased risk for cardiovascular events in patients with CHIP and raise the possibility that those with TET2 variants may respond better to canakinumab than those without CHIP. Future studies are required to further substantiate this hypothesis.

Risk of Cancer After Diagnosis of Cardiovascular Disease

“…This process is also associated with risk for coronary disease, causing investigators to revisit the clonal hypothesis of atherosclerosis and its overlap with the clonally-expanding cancer stem cell. While the precise molecular mechanism linking CHIP mutations to heart disease remains undefined, inflammasome activation is thought to be central to this process (46-49). Interestingly, patients in the CANTOS trial with CHIP mutations benefited more from canakinumab than those without a CHIP mutation (49).…”

Cardiovascular Disease in Myeloproliferative Neoplasms

“…This analysis had insufficient power to assess the effect of IL-1β neutralization in those participants with JAK2 mutations. 175 Anti-inflammatory therapies thus merit further exploration in the treatment of MPN and cancer in general. 71 , 174 , 176 …”

Hematopoiesis of Indeterminate Potential and Atherothrombotic Risk

“…30 Consistently, in an exploratory preliminary analysis, patients with a TET2 mutant have an improved response to canakinumab (hazard ratio [HR] = 0.38) relative to the response to overall response to canakinumab (HR = 0.93) in the CANTOS trial. 37 In addition to the pharmacological evidence, human genetic studies provide more support for a causal role of inflammation in CVD. IL-6 can be a downstream product of IL-1β signaling and increased IL-6 production and activity are considered to be a common mediator in chronic inflammation associated with CVD.…”