Eltrombopag addition alters clonal hematopoiesis dynamics in untreated severe aplastic anemia patients over 24 months

BACKGROUND: A Phase 3 randomized trial compared immunosuppressive therapy with or without eltrombopag in untreated patients with aplastic anemia (AA) and showed that addition of eltrombopag increased the rate, rapidity, and durability of hematological response, without increasing transformation to myeloid malignancies. We sought to systematically investigate clonal hematopoiesis (CH) dynamics from patient samples from this trial. METHODS: Peripheral blood and bone marrow aspirates were collected at diagnosis (i.e., baseline) and at 6 and 24 months from patients with severe or very severe AA. Genetic testing for somatic mutations was performed using 31-gene "core" and 291-gene "extended" custom targeted panels and analyzed longitudinally. RESULTS: Samples were collected from patients at baseline (n=170) and 6 (n=150) and 24 months (n=103); 85 patients' samples were tested at all three timepoints. Somatic mutations were present in 30% of patients at baseline, 55.3% at 6 months and 79.6% at 24 months, with a mean number of mutations per patient of 0.4, 1.2, and 2.5, at baseline and 6 and 24 months, respectively. CONCLUSIONS: CH was frequent in patients with AA and its prevalence appeared to be higher at posttherapy timepoints than at diagnosis. CH in AA may reflect the survival and expansion of selected residual hematopoietic stem/progenitor cells associated with immune-mediated damage. (Funded by Cancer Research UK, Bloodwise UK, and Novartis AG; ClinicalTrials.gov number, NCT02099747; EudraCT number, 2014-000363-40.).