| Title: | Incident cytopenia and risk of subsequent myeloid neoplasm in age-related clonal hematopoiesis: a multi-biobank case-control study |
| Journal: | EClinicalMedicine |
| Published: | 4 Jun 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40524801/ |
| DOI: | https://doi.org/10.1016/j.eclinm.2025.103283 |
| URL: | https://www.thelancet.com/action/showPdf?pii=S2589537025002159 |
Publication 15149
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Abstract
Background: Cross sectional studies have demonstrated patients with clonal hematopoiesis of indeterminate potential (CHIP) are at increased risk of developing multiple adverse outcomes, including cytopenia and myeloid neoplasm (MN). One prior study suggests cytopenia or cytosis is a required intermediate step in disease progression from CHIP to MN.</p>
Methods: We analyzed genomic sequencing data from the NIH All of Us Research Program, Vanderbilt's BioVU repository, and UK Biobank participants (N = 805,249). The study period ranged from 1 January 2006 to 31 December 2023. Genetic mutations, demographic data, laboratory values, and MN outcomes were used to create a case-control study to estimate the risk of incident cytopenia and MN among cases with CHIP and matched controls without CHIP.</p>
Findings: After applying inclusion and exclusion criteria, the study cohort contained 9374 cases with CHIP and 24,749 matched controls without CHIP. Among the 34,123 participants, 190 (0.56%) developed incident cases of MN and 4151 (12.1%) developed an incident cytopenia. Individuals with CHIP at enrollment who subsequently developed a cytopenia progressed to MN at a rate of 0.5% per year, compared to 0.05% per year for those with CHIP and normal cell counts. Longitudinal analysis across three cohorts demonstrated an increased risk of cytopenia in CHIP patients and identified those at the highest risk of progression. Cytopenia risk factors included smoking (HR = 1.17, 95% CI: [1.05-1.32], P = 5.87 × 10-3), male sex (HR = 1.45, 95% CI: [1.30-1.62], P = 2.17 × 10-11), variant allele frequency ≥0.20 (HR = 1.36, 95% CI: [1.21-1.54], P = 7.56 × 10-7), age ≥65 (HR = 1.41, 95% CI: [1.25-1.57], P = 3.98 × 10-9), mean corpuscular volume ≥100 fL (HR = 2.12, 95% CI: [1.68-2.68], P = 2.58 × 10-10), red cell distribution width ≥15% (HR = 2.59, 95% CI: [2.26-2.98], P = 1.14 × 10-40), mutations in high-risk CHIP genes (HR = 1.48, 95% CI: [1.26-1.75], P = 2.39 × 10-6), and ≥2 CHIP mutations (HR = 1.95, 95% CI: [1.61-2.36], P = 9.73 × 10-12).</p>
Interpretation: Longitudinal analysis across three large cohorts found that it is rare for patients with CHIP to develop MN without first developing cytopenia. The risk for MN among patients with CHIP resides almost entirely among those with cytopenia. These findings suggest that cytopenia is a critical step in progression from CHIP to MN, underscoring its utility as an endpoint in cancer prevention trials for CHIP patients.</p>
Funding: National Institutes of Health, Burroughs Wellcome Fund, Edward P. Evans Foundation, Pew Charitable Trusts, Alexander and Margaret Stewart Trust, Beverly and George Rawlings Directorship.</p>
12 Authors
- James Brogan
- Ashwin Kishtagari
- Robert W. Corty
- Yash Pershad
- Caitlyn Vlasschaert
- Brian Sharber
- J. Brett Heimlich
- Leo Luo
- P. Brent Ferrell
- Michael R. Savona
- Yaomin Xu
- Alexander G. Bick
1 Application
| Application ID | Title |
|---|---|
| 43397 | Multivariate analysis of phenome, genome relationships using large EHR/Biobank data: a `big data` discovery approach towards personalized medicine |
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