Researchers developed a clonal hematopoiesis risk score (CHRS) for patients with clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS), and they evaluated its capacity to predict myeloid neoplasm (MN) risk in a recent study. Results were presented in the journal NEJM Evidence.
The study investigators obtained data from 438,890 individuals without MN who participated in the UK Biobank. Data on genetic mutations, laboratory values, and MN outcomes from 193,743 individuals were included in a subset used for derivation of the prognostic model, with the remaining 245,147 individuals included in a validation cohort. The primary study outcome was incident MN occurring after month 6 of study enrollment.
A total of 11,337 individuals in the derivation cohort were identified as meeting criteria for having either CHIP (10,479 individuals) or CCUS (858 individuals). The median follow-up duration was 11.7 years. In this cohort, there were 269 incident MN events reported, reflecting a rate of 2.37% in this population.
Several factors appeared associated with MN risk. These included high-risk mutations, single DNMT3A mutations, having 2 or more mutations, an age of 65 or more years, the presence of CCUS rather than CHIP, a mean corpuscular volume 100 fL or more, a red cell distribution width of 15% or more, and a variant allele fraction of 0.2 or more for any clonal hematopoiesis variant. Most of these features were linked to greater MN risk.
DNMT3A mutations were associated with a greater MN risk in individuals with CHIP/CCUS than in people without CHIP/CCUS. However, among individuals with CHIP/CCUS, DNMT3A mutations were associated with a lower risk of MN in comparison with other genotypes.
Using CHRS values developed with the prognostic model, the researchers categorized individuals with CHIP/CCUS into 3 risk groups. A low-risk group included 10,018 (88.4%) individuals, while an intermediate-risk group included 1196 (10.5%), and a high-risk group included 123 (1.1%).
In these groups, the 10-year cumulative incidence of MN was 0.669 + 0.0827% for the low-risk group, 7.83 + 0.807% for the intermediate-risk group, and 52.2 + 4.96% for the high-risk group. Ten-year survival rates were 93.7 + 0.243%, 84.0 + 1.06%, and 51.2 + 4.51%, respectively. In comparison, individuals without CHIP/CCUS in this study had a 10-year survival rate of 95.8 + 0.0471%.
“The CHRS robustly defines three distinct CHIP/CCUS risk groups and shows the low absolute risk of progression to overt MN in the vast majority of CHIP and CCUS,” the study investigators wrote in their report. They also concluded the CHRS may have a role in identifying individuals with CHIP/CCUS who may require greater surveillance and intervention.
Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, or device companies. Please see the original reference for a full list of disclosures.
Weeks LD, Niroula A, Neuberg D, et al. Prediction risk for myeloid malignancy in clonal hematopoiesis. NEJM Evid. Published online April 25, 2023. doi:10.1056/EVIDoa2200310