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

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: To test the association of randomization to colchicine vs. placebo with CH growth in participants with chronic coronary artery disease, as well as the association of colchicine use with change in inflammatory biomarkers over time by CH status.

Methods: In this exploratory substudy of the Low-Dose Colchicine 2 (LoDoCo2) trial, high-coverage targeted sequencing was used to detect CH driver mutations and quantify variant allele frequency at four time points: baseline, after a 30-day open-label colchicine run-in phase (0.5 mg daily), one year post-randomization to colchicine or placebo, and at end of study (median follow-up of 25.0 months). Clonal dynamics were assessed using a generalized linear mixed model. Interleukin-6 (IL-6) and high-sensitivity C-reactive protein were additionally measured at baseline, randomization, and one year post-randomization.

Results: In total, 854 participants contributed 2,047 observations across four time points, including before and after the pre-randomization colchicine run-in period. Randomization to placebo was associated with a 14.9% annual increase in CH clone size (β=0.14 [95%CI 0.08 to 0.21]) vs. a non-significant 6.3% increase with colchicine (β on colchicine: 0.06 [95%CI -0.01 to 0.14]), although this difference between treatment arms was not statistically significant (P=0.13). Compared with placebo, colchicine was associated with attenuated clonal growth in TET2 CH (β on colchicine: 0.09 [95%CI -0.04 to 0.22]; vs. placebo: β=0.27 [95%CI 0.16 to 0.37]; P=0.04). Among individuals with non-DNMT3A CH, IL-6 levels increased to a lesser extent in those receiving colchicine vs. placebo over one year (29.4% vs. 97.3% increase, respectively; P=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 mitigate their associated risk of cardiovascular disease. Further validation in prospective studies is warranted.