Clonal Hematopoiesis: From Mechanisms to Clinical Intervention

Abstract

Our knowledge of how clonal hematopoiesis relates to diverse health conditions has grown vastly over the past years, touching upon many specialties beyond cancer medicine. Given that clonal hematopoiesis can act as a precursor to overt disease in many settings, the promise of early intervention has garnered much attention. In this review, we discuss the state of clonal hematopoiesis research and outline the challenges in developing clinical trials of early interventions. We anticipate that incidental findings of clonal hematopoiesis will become more common in the near future, but evidence-based efforts of how to manage these findings is currently lacking.

Significance: Our knowledge regarding the relevance of clonal hematopoiesis has increased drastically over the past years. However, evidence of how to manage these findings is currently lacking. In this review, we summarize the current state of clonal hematopoiesis research and outline the challenges of developing clinical trials in this field. We anticipate that incidental findings of clonal hematopoiesis will become more common in the near future and argue that there is urgency to start designing and conducting prospective trials.

Figure 1.. Clonal Hematopoiesis (CH) is ubiquitous and associated with context-specific adverse health outcomes.

A: The acquisition of mutations in hematopoietic stem cells (HSCs) is strongly correlated with age and can be detected in almost all adults. Some clones carry biologically relevant variants and possess increased fitness over their wildtype counterparts B: CH is associated with adverse health outcomes through diverse mechanisms. TET2 mutant mature myeloid cells have been shown to be involved in proinflammatory signaling associated with acceleration of atherosclerosis. JAK2 mutant cells have been associated with the release of neutrophil extracellular traps that contribute to thrombogenesis. Clonal evolution through the acquisition of secondary mutations – including in the context of cytotoxic stress – has been demonstrated to lead to myeloid malignancies. C: Latency between detection of CH in the peripheral blood and clinical manifestation of CH sequelae opens the prospect of early intervention, suggesting a therapeutic window. While most individuals do not experience severe sequelae of CH, certain stressors – including inflammatory or cytotoxic stress – contribute to the expansion of certain CH clones and manifestation of the associated sequelae. Minimizing exposure to these stressors in high-risk individuals might be a successful strategy to mitigate some of these CH associated adverse health outcomes.

Figure 2.. Incidental findings of CH in a variety of clinical contexts.

A: Incidental findings of clonal hematopoiesis can arise during testing for a variety of other conditions. B: Clinical trials registered on clinicaltrials.gov assessing cell-free DNA (cfDNA) categorized by enrollment category “cancer” vs. “other”. Bubble size represents planned enrollment as of June 25^th 2021.