Eltrombopag plus immunosuppression for severe aplastic anemia shows clonal evolution patterns

BACKGROUND: Clonal hematopoiesis (CH) is a feature of severe aplastic anemia (SAA), but its clinical significance is debated. METHODS: We integrated longitudinal clinical and CH data from patients with SAA treated with immunosuppression plus eltrombopag (IST-EPAG) in a phase 2 trial to characterize clonal dynamics during recovery and progression to myeloid cancer or paroxysmal nocturnal hemoglobinuria (PNH); CH was defined as the presence of somatic mutations at a variant allele frequency of 0.1% or greater. RESULTS: In total, 204 SAA patients treated with IST-EPAG were evaluated from disease onset to median follow-up of 5.5 years. CH was observed in 128 of 204 (63%) patients before treatment and in 131 of 180 (73%) after therapy who were evaluated at the 6-month timepoint and were not off-study. Patients mostly had CH in (N=53, 26%), DNMT3A (N=42, 21%), BCOR (N=35, 17%), and (N=25, 12%). There appeared to be two distinct patterns of malignant clonal evolution. Early evolutions, within 1 year from treatment, were primarily chromosome 7 aberrations and occurred in 11 (5%) patients. In another eight (4%) patients, late evolutions, 4-5 years after therapy, were initiated by early selection of mutated or -mutated clones. Evolution to PNH, observed in 10 of 204 patients (5%), was associated with expansion of clones usually present before treatment. CONCLUSIONS: Among patients with SAA treated with IST-EPAG, early and late patterns of clonal evolution to myeloid cancer were observed: Chromosome 7 abnormalities occurred within 1 year, whereas later events (4-5 years) involved stepwise mutation acquisition in preexisting or mutated clones.