Monocytosis may occur in numerous inflammatory conditions but is also the defining feature of chronic myelomonocytic leukemia (CMML). Clonal somatic mutations detectable in CMML may occur with aging in otherwise healthy individuals, so-called "clonal hematopoiesis"(CH). We investigated whether the combination of CH and monocytosis would represent an early developmental stage of CMML. We studied community-dwelling individuals with monocytosis (≥1 × 109/L and ≥10% of leukocytes) in the population-based Lifelines cohort (n = 144 676 adults). The prevalence and spectrum of CH were evaluated for individuals ≥60 years with monocytosis (n = 167 [0.8%]), and control subjects 1:3 matched for age and sex (n = 501). Diagnoses of hematological malignancies were retrieved by linkage to the Netherlands Cancer Registry (NCR). Monocyte counts and the prevalence of monocytosis increased with advancing age. Older individuals with monocytosis more frequently carried CH (50.9% vs 35.5%; P < .001). Monocytosis is associated with enrichment of multiple gene mutations (P = .006) and spliceosome mutations (P = .007) but not isolated mutated DNMT3A, TET2, or ASXL1. Persistent monocytosis over 4 years was observed in 30/102 evaluable individuals and associated with a higher prevalence of CH (63%). Myeloid malignancies, including 1 case of CMML, developed in 4 individuals with monocytosis who all carried CH. In conclusion, monocytosis and CH both occur at an older age and do not necessarily reflect clonal monocytic proliferation. In a fraction of older subjects with monocytosis, CH might constitute early clonal dominance in developing malignant myelomonocytic disease. Mutational spectra deviating from age-related CH require attention.
The authors would like to thank all participants of the Lifelines cohort and everybody contributing to the study set-up and
design. The authors would also like to thank all local investigators and operational team members of the MDS-RIGHT project
for their contribution. In addition, the authors would like to thank Statistics Netherlands and the registration team of the Netherlands Comprehensive Cancer Organisation (IKNL) for the collection of data for the Netherlands Cancer Registry, as well as IKNL staff for scientific advice. Finally, the authors thank the
Genome Technology Center, Radboud University Medical Center, for performing NovaSeq sequencing.
This work is part of the MDS-RIGHT project, which has received funding from the European Union’s Horizon 2020
research and innovation program under grant agreement No 634789 – “Providing the right care to the right patient with MyeloDysplastic Syndrome at the right time.” This work was further supported by a grant from the Dutch Cancer Foundation (KWF10813). The Lifelines Biobank initiative has been made
possible by subsidy from the Dutch Ministry of Health, Welfare, and Sport, the Dutch Ministry of Economic Affairs, the University
Medical Center Groningen (UMCG the Netherlands), University Groningen, and the Northern Provinces of The Netherlands.
L.M.’s studies on myeloid malignancies are supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) (Accelerator Award Project 22796, 5x1000 Project 21267, Investigator
Grant 2017 Project 20125). The funder of this study had no role in study design, in collection, analysis and interpretation of
data, in the writing of the report, or in the decision to submit the paper for publication.
© 2022 by The American Society of Hematology.