Clonal hematopoiesis of indeterminate potential as a prognostic factor: A systematic review and meta-analysis

With advances in sequencing, individuals with clonal hematopoiesis of indeterminate potential (CHIP) are increasingly being identified, making it essential to understand its prognostic implications. We conducted a systematic review of studies comparing the risk of clinical outcomes in individuals with and without CHIP. We searched MEDLINE and EMBASE, and included original research reporting an outcome risk measure in individuals with CHIP, adjusted for the effect of age. From 3305 studies screened, we included 88 studies of 45 to 470960 participants. Most studies had low to moderate risk of bias in all domains of the QUIPS tool. Random effects meta-analyses were performed for outcomes reported in at least 3 studies. CHIP conferred increased risk of all-cause mortality (hazard ratio [HR] 1.34 [95% CI 1.19-1.50]), cancer-mortality (HR 1.46 [1.13-1.88]), composite cardiovascular events (HR 1.40 [1.19-1.65]), coronary heart disease (HR = 1.76 [1.27-2.44]), stroke (HR 1.16 [1.05-1.28]), heart failure (HR 1.27 [1.15-1.41]), hematologic malignancy (HR 4.28 [2.29-7.98]), lung cancer (HR 1.40 [1.27-1.54]), renal impairment (HR 1.25 [1.18-1.33]) and severe COVID19 (odds ratio [OR] 1.46 [1.18-1.80]). CHIP was not associated with cardiovascular mortality (HR 1.09 [0.97-1.22]), except in subgroup analysis restricted to larger clones (HR 1.31 [1.12-1.54]). Isolated DNMT3A mutations did not increase risk of myeloid malignancy, all-cause mortality or renal impairment. Reasons for heterogeneity between studies included differences in definitions and measurement of CHIP and outcomes, and populations studied. In summary, CHIP is associated with diverse clinical outcomes, with clone size, specific gene and inherent patient characteristics important mediators of risk.