Secondary myelodysplastic syndrome and leukemia in acquired aplastic anemia and paroxysmal nocturnal hemoglobinuria

Blood. 2020 Jul 2;136(1):36-49. doi: 10.1182/blood.2019000940.


Acquired aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are pathogenically related nonmalignant bone marrow failure disorders linked to T-cell-mediated autoimmunity; they are associated with an increased risk of secondary myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Approximately 15% to 20% of AA patients and 2% to 6% of PNH patients go on to develop secondary MDS/AML by 10 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Age of Onset
  • Anemia, Aplastic / drug therapy
  • Anemia, Aplastic / genetics
  • Anemia, Aplastic / pathology*
  • Antibodies, Monoclonal, Humanized / adverse effects
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Benzoates / adverse effects
  • Benzoates / therapeutic use
  • Bone Marrow / pathology
  • Chromosome Aberrations
  • Chromosomes, Human, Pair 7 / genetics
  • Clonal Evolution / drug effects
  • Clone Cells / drug effects
  • Clone Cells / pathology
  • Disease Progression
  • Granulocyte Colony-Stimulating Factor / adverse effects
  • Granulocyte Colony-Stimulating Factor / therapeutic use
  • Hemoglobinuria, Paroxysmal / drug therapy
  • Hemoglobinuria, Paroxysmal / genetics
  • Hemoglobinuria, Paroxysmal / pathology*
  • Humans
  • Hydrazines / adverse effects
  • Hydrazines / therapeutic use
  • Leukemia, Myeloid, Acute / epidemiology
  • Leukemia, Myeloid, Acute / etiology*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Models, Biological
  • Monosomy
  • Mutation
  • Myelodysplastic Syndromes / epidemiology
  • Myelodysplastic Syndromes / etiology*
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / pathology
  • Oncogene Proteins, Fusion / genetics
  • Pyrazoles / adverse effects
  • Pyrazoles / therapeutic use
  • Selection, Genetic
  • Telomere Shortening


  • Antibodies, Monoclonal, Humanized
  • Benzoates
  • Hydrazines
  • Oncogene Proteins, Fusion
  • Pyrazoles
  • Granulocyte Colony-Stimulating Factor
  • eculizumab
  • eltrombopag