Bone Marrow Failure Disorders

Clonal evolution to a secondary myeloid malignancy is a major complication in long-term aplastic anemia (AA) survivors treated with immunosuppressive therapy (IST), and has been reported to occur in 10% to 15% of patients with severe AA (SAA) after IST. In a retrospective evaluation of all 666 patients with SAA treated at the NIH Clinical Center on Hematology Branch protocols, with either horse-anti-thymocyte globulin (ATG), rabbit-ATG, or alemtuzumab-based regimens for treatment-naive or relapsed/refractory AA from 1989 to 2019, investigators identified 96 who had clonal evolution. Mutations identified in individual SAA patients prior to clonal evolution included NPM1 mutation (detected 2 years prior to diagnosis of clonal evolution); RUNX1 variant (detected 1 year prior to diagnosis of clonal evolution); and in a third patient, multiple mutations over a 7-year period, including 2 years after the diagnosis of clonal evolution to a myeloid malignancy. The investigators noted that “[a]pproximately 10% of SAA patients treated with IST in this large cohort developed high-risk clonal evolution, supporting the importance of regular long-term clinical follow-up.”