Acquired aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are pathogenically related non-malignant bone marrow failure disorders linked to T-cell mediated autoimmunity and associated with an increased risk of secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Approximately 15-20% of AA patients and 2-6% of PNH patients go on to develop secondary MDS/AML by ten years of follow-up. Factors determining an individual patient's risk of malignant transformation remain poorly defined. Recent studies identified nearly ubiquitous clonal hematopoiesis (CH) in AA patients. Similarly, CH with additional, non-PIGA, somatic alterations occurs in the majority of patients with PNH. Factors associated with progression to secondary MDS/AML include longer duration of disease, increased telomere attrition, presence of adverse prognostic mutations and multiple mutations, particularly when occurring early in the disease course and at a high allelic burden. Here, we will review the prevalence and characteristics of somatic alterations in AA and PNH and will explore their prognostic significance and mechanisms of clonal selection. We will then discuss the available data on post-AA and post-PNH progression to secondary MDS/AML and provide practical guidance for approaching patients with PNH and AA who have CH.

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