How I utilize somatic alterations in the diagnosis, risk stratification, and therapy of hypocellular bone marrow...

Hypocellular bone marrow failure (BMF) may be acquired due to immune-mediated disease, the prototype being immune aplastic anemia (IAA), or inherited, due to germ line defects in genes important for hematopoietic stem cell function and maintenance (inherited BMF syndromes [IBMFS]). Proper diagnosis of the underlying etiology of hypocellular BMF, particularly distinguishing IAA, myelodysplastic syndrome (MDS; most relevant in this setting is hypoplastic MDS), 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 present how distinct patterns of CH can aid in distinguishing different etiologies of hypocellular BMF. In addition, 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.