Clonal Hematopoiesis Risk Score and All-Cause and Cardiovascular Mortality in Older Adults
abstract
This abstract is available on the publisher's site.
Access this abstract nowIMPORTANCE
Clonal hematopoiesis (CH) with acquired pathogenic variants in myeloid leukemia driver genes is common in older adults but of unknown prognostic value.
OBJECTIVE
To investigate the prevalence of CH and the utility of the CH risk score (CHRS) in estimating all-cause and disease-specific mortality in older adults with CH.
DESIGN, SETTING, AND PARTICIPANTS
This population-based prospective cohort study involved community-dwelling older adults (aged 67-90 years) without hematologic malignant neoplasms (HMs) who were participants in the Atherosclerosis Risk in Communities Visit 5 at 4 US centers: Forsyth County, North Carolina; Jackson, Mississippi; Minneapolis, Minnesota; and Washington County, Maryland. Samples were collected from 2011 to 2013, sequencing was performed in 2022, and data analysis was completed in 2023.
EXPOSURE
The exposure was a diagnosis of CH. CHRS scores (calculated using 8 demographic, complete blood cell count, and molecular factors) were used to categorize individuals with CH into low-risk (CHRS ≤9.5), intermediate-risk (CHRS >9.5 to <12.5), and high-risk (CHRS ≥12.5) groups.
MAIN OUTCOMES AND MEASURES
The primary outcome was all-cause mortality, and secondary outcomes were HM mortality, cardiovascular disease mortality, and death from other causes.
RESULTS
Among 3871 participants without a history of HM (mean [SD] age, 75.7 [5.2] years; 2264 [58.5%] female individuals; 895 [23.1%] Black individuals; 2976 White individuals [76.9%]), 938 (24.2%) had CH. According to the CHRS, 562 (59.9%) were low risk, 318 (33.9%) were intermediate risk, and 58 (6.2%) were high risk. During a median (IQR) follow-up of 7.13 (5.63-7.78) years, 570 participants without CH (19.4%) and 254 participants with CH (27.1%) died. Mortality by CHRS risk group was 128 deaths (22.8%) for low risk, 93 (29.2%) for intermediate risk, and 33 (56.9%) for high risk. By use of multivariable competing risk regression, subdistribution hazard ratios (sHRs) for all-cause mortality were 1.08 (95% CI, 0.89-1.31; P = .42) for low-risk CH, 1.12 (95% CI, 0.89-1.41; P = .31) for intermediate-risk CH, and 2.52 (95% CI, 1.72-3.70; P < .001) for high-risk CH compared with no CH. Among individuals in the high-risk CH group, the sHR of death from HM (6 deaths [10.3%]) was 25.58 (95% CI, 7.55-86.71; P < .001) and that of cardiovascular death (12 deaths [20.7%]) was 2.91 (95% CI, 1.55-5.47; P < .001).
CONCLUSIONS AND RELEVANCE
In this cohort study, the CHRS was associated with all-cause, HM-related, and cardiovascular disease mortality in older adults with CH and may be useful in shared decision-making to guide clinical management and identify appropriate candidates for clinical trials.
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Additional Info
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Clonal Hematopoiesis Risk Score and All-Cause and Cardiovascular Mortality in Older Adults
JAMA Netw Open 2024 Jan 02;7(1)e2351927, S Saadatagah, MM Uddin, LD Weeks, A Niroula, M Ru, K Takahashi, L Gondek, B Yu, AG Bick, BL Ebert, EA Platz, P Natarajan, CM BallantyneFrom MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
As we age, genetic mutations occur in our cells, causing changes not present in the germline DNA — a phenomenon called somatic mosaicism. Like other highly proliferative cells, hematopoietic stem cells are more likely to develop mosaicism, leading to clonal hematopoiesis (CH).1 A subset of CH caused by acquired leukemogenic variants is referred to as CH of indeterminate potential (CHIP) or clonal cytopenia of undetermined significance (CCUS), according to the absence or presence of cytopenia.1
In addition to hematologic malignancies, multiple studies have demonstrated increased mortality risk and elevated risk of cardiovascular disease among individuals with CHIP/CCUS. The CH risk score (CHRS) — a predictive tool that uses demographic variables, complete blood cell count parameters, and molecular features — was recently developed to estimate the risk of myeloid malignant neoplasms in individuals with CHIP/CCUS.2
Unlike most CH studies, which involved middle-aged participants, the current study examined the prognostic value of CHIP/CCUS in a cohort of older adults (aged >65 years) and investigated the utility of CHRS in estimating the risks of overall and disease-specific mortality.3 Among 3871 participants from the ARIC cohort (mean age, 75.7 years), almost a quarter (24.2%) had CH. According to the CHRS, 562 (59.9%) were low-risk, 318 (33.9%) were intermediate-risk, and 58 (6.2%) were high-risk. During follow-up (median, 7.13 years), 19.4% of those without CH and 27.1% of those with CH died. The mortality risk by CHRS risk group was 22.8% for low-risk, 29.2% for intermediate-risk, and 56.9% for high-risk individuals. Among individuals with high-risk CH, hematologic malignancy conferred the greatest relative risk of death (subdistribution HR [sHR], 25.58; 95% CI, 7.55–86.71; P < .001), and cardiovascular death was the most common cause of death (20.7%; sHR, 2.91; 95% CI, 1.55–5.47; P < .001).3
This study confirmed the high prevalence of CH in older adults and suggests that CHRS could help identify those at the greatest risk for death.
References