Incidence of Cytopenia in Clonal Hematopoiesis of Indeterminate Potential

Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a risk factor for myeloid neoplasms (MN) and multiple other diseases of aging. CHIP with concurrent cytopenia is a five-fold stronger risk factor for these diseases. However, the incidence of cytopenia in individuals with CHIP is not well-described. We quantify the incidence of cytopenia among 9,278 individuals with CHIP across three cohorts and identify risk factors for cytopenia among these individuals.

Methods: Participants with genome sequencing from the All of Us Research Program (AoU) and Vanderbilt BioVU biorepository, and exome sequencing from UK Biobank (UKB), were screened for CHIP using Mutect2 to identify somatic mutations in canonical driver genes (Vlasschaert et al. Blood 2023). Survival analysis was conducted to compare the risk of developing a persistent cytopenia in participants with CHIP and matched controls using hematologic laboratory values, demographic variables, CHIP driver genes, and clone size as covariates. Participants were included if they had multi-timepoint complete blood count (CBC) data without evidence of a cytopenia or MN prior to sequencing. Cytopenia was defined as two observations of hemoglobin < 12.0 g/dL (females) or 13.0 g/dL (males), platelets < 150,000 cells/µL, or white blood cell count < 3,700 cells/µL at least 120 days apart without an intervening normal measurement. Participants with CHIP were matched 1:3 with controls on age, sex, and smoking status. The follow-up period commenced at the date of sequencing and terminated at the earliest occurrence of incident cytopenia, MN, or last CBC.

Results: Sequencing data were available for 852,639 participants. A total of 168,428 participants, including 9,279 with CHIP, met inclusion criteria. The final case-control cohort contained 9,278 cases and 24,758 matched controls. Median time at risk was 2.28 years [interquartile range: 1.41 - 2.89] in AoU, 3.51 years [1.16 - 7.73] in BioVU and 5.94 years [4.76 - 6.72] in UKB. Incident cytopenia occurred in 1,235 cases (13.3%) and 2,839 controls (11.5%), showing a statistically significant difference across all three cohorts (HR_AoU = 1.16, 95% confidence interval: [1.01 - 1.34], P=0.04; HR_BioVU = 1.17 [1.04 - 1.31], P<0.01; HR_UKB = 1.19 [1.08 - 1.32], P<0.01).

In BioVU and UKB, risk factors for incident cytopenia included male sex, age ≥ 65, mean corpuscular volume ≥ 100, red cell distribution width ≥ 15, ≥ 2 CHIP mutations, or a high-risk mutation (in SRSF2, SF3B1, ZRSR2, IDH1, IDH2, FLT3, RUNX1, JAK2). In AoU, only male sex and RDW ≥ 15 conferred increased risk of cytopenia. Individuals with multiple of these risk factors had a significantly greater risk of incident cytopenia. For example, BioVU participants with CHIP and no risk factors had an 8% incidence of cytopenia at 2 years. This increased to 20% among participants with 2 or 3 risk factors and 40% among participants with 4 or 5 risk factors.

Participants with CHIP and incident cytopenia had significantly higher rates of subsequent MN compared to those without cytopenia across all three cohorts (HR_AoU = 4.68, 95% confidence interval: [2.12 - 10.30], P<0.01; HR_BioVU = 2.63 [1.67 - 4.13], P<0.01; HR_UKB = 6.70 [4.07 - 11.03], P<0.01).

Conclusion: Longitudinal analysis of 9,278 participants with CHIP across three cohorts demonstrated significantly higher incidence of cytopenia in participants with CHIP than matched controls and identified risk factors for developing a persistent cytopenia. Our results enable longitudinal risk stratification and personalized risk prediction among individuals with CHIP. Identifying individuals at the highest risk of developing cytopenia and subsequent MN will inform the design of interventional CHIP clinical trials.

Kishtagari:Sevier Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Syndex: Current equity holder in publicly-traded company; Morphosys: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Geron Coporation: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Bick:TenSixteen Bio: Consultancy.