How I utilize somatic alterations in the diagnosis, risk stratification, and therapy of hypocellular bone marrow failure.
Hypocellular bone marrow failure (BMF) may be acquired due to immune-mediated disease, the prototype being immune aplastic anemia (IAA), or inherited, due to germline defects in genes important for hematopoietic stem cells' function and maintenance (inherited bone marrow failure syndromes [IBMFS]). Proper diagnosis of the underlying etiology of hypocellular bone marrow failure, particularly distinguishing immune AA, myelodysplastic syndrome (MDS) (most relevant in this setting, hypoplastic MDS [MDS-h]), and the IBMFS, is important given the differences in clinical management. Clonal hematopoiesis (CH), in this context comprising somatic mutations or chromosomal abnormalities, is incorporated into standard algorithms for classification, risk stratification, and treatment decisions for hematologic malignancies, but the clinical significance in BMF is not well established. Disease-specific clonal signatures have been reported across the BMF spectrum, and here we show how distinct patterns of CH can aid in distinguishing different etiologies of hypocellular BMF. Additionally, detection of somatic alterations in many BMF disorders can estimate risk for secondary myeloid neoplasms, guide surveillance and, in some instances, allow for early therapeutic intervention.