Colchicine and Longitudinal Dynamics of Clonal Hematopoiesis: An Exploratory Substudy of the LoDoCo2 Trial.

Abstract

BACKGROUND: Clonal hematopoiesis (CH) is an aging-related hematologic condition associated with increased risk for cardiovascular events. Larger CH clones associate more strongly with cardiovascular risk. Preclinical data indicate that inflammatory signaling drives expansion of CH clones and CH-associated cardiovascular disease. However, the effect of anti-inflammatory therapies on CH clonal dynamics in humans is unclear. OBJECTIVES: The goal of this study was to test the association of randomization to colchicine vs placebo with CH growth in participants with chronic coronary artery disease. It also assessed the association of colchicine use with change in inflammatory biomarkers over time according to CH status. METHODS: In this exploratory substudy of the LoDoCo2 (Low-Dose Colchicine 2) trial, high-coverage targeted sequencing was used to detect CH driver mutations and to quantify variant allele frequency at 4 timepoints: baseline, after a 30-day open-label colchicine run-in phase (0.5 mg daily), 1 year postrandomization to colchicine or placebo, and at end of study (median follow-up of 25.0 months). Clonal dynamics were assessed by using a generalized linear mixed model. High-sensitivity C-reactive protein and interleukin-6 were additionally measured at baseline, randomization, and 1 year postrandomization. RESULTS: In total, 854 participants contributed 2,047 observations across 4 timepoints, including before and after the prerandomization colchicine run-in period. Randomization to placebo was associated with a 14.9% annual increase in CH clone size (βtime = 0.14; 95% CI: 0.08 to 0.21) vs a nonsignificant 6.3% increase with colchicine (βtime on colchicine: 0.06; 95% CI: -0.01 to 0.14), although this difference between treatment arms was not statistically significant (Pinteraction = 0.13). Compared with placebo, colchicine was associated with attenuated clonal growth in TET2 CH (βtime on colchicine: 0.09 [95% CI: -0.04 to 0.22]; βtime placebo: 0.27 [95% CI: 0.16 to 0.37]; Pinteraction= 0.04). Among individuals with non-DNMT3A CH, interleukin-6 levels increased to a lesser extent in those receiving colchicine vs placebo over 1 year (30.0% vs 98.1% increase, respectively; Pinteraction = 0.01). CONCLUSIONS: In this exploratory analysis, treatment with low-dose colchicine was associated with attenuated clonal expansion in TET2 CH. These findings suggest the potential for colchicine to curb the proliferative advantage of key CH driver mutations and to mitigate their associated risk of cardiovascular disease. Further validation in prospective studies is warranted.