Clonal hematopoiesis in the setting of sickle cell disease and its relevance to curative therapies

Sickle cell disease (SCD) is an inherited hemoglobinopathy characterized by chronic hemolytic anemia, painful vaso-occlusive episodes, and end-organ damage. Population-level studies indicate individuals with SCD are at an increased risk for myeloid neoplasia (MN). While the absolute risk of MN remains low, fatal cases of myelodysplastic syndrome and acute myeloid leukemia suggest MN risk is enhanced in the setting of curative cellular therapies for SCD, including allogeneic hematopoietic cell transplantation and autologous gene therapy. Clonal hematopoiesis (CH), the expansion of a genetically related population of hematopoietic stem or progenitor cells, is commonly caused by mutations in myeloid leukemia driver genes and is a recognized precursor state for MNs, including myelodysplastic syndrome and acute myeloid leukemia. This review synthesizes current data on MN incidence in SCD populations, prevalence of adverse-risk CH in SCD, and clustering of high-risk subtypes of MN among cases involving SCD patients. CH emerges as a potential biological mechanism linking SCD to increased susceptibility to MN with implications for clinical research and counseling of patients with SCD.