Patterns of clonal hematopoiesis in aplastic anemia under immunosuppressive therapy

Aplastic anemia (AA) is an immune-mediated bone marrow failure disorder with 15-20% risk of clonal evolution. We analyzed 371 patients with AA receiving immunosuppressive therapy (IST). All patients underwent PNH testing and 357 evaluable for cytogenetic analysis. Two hundred and thirty-seven received serial targeted sequencing. Clonal characteristics were compared before and after IST across age, disease severity, and hematological response. Among the 237 patients, somatic mutations were detected in 53 patients (22%) at baseline and 97 (41%) after IST. Distinct patterns of mutational dynamics were observed under IST, with newly acquired mutations defined as Pattern 2 being most common. High-risk mutations such as ASXL1 expanded persistently, whereas favorable clones like BCOR and PIGA often contracted or remained stable. Older age was associated with heavier mutational burden, and disease severity was associated with greater increase in mutations. Cytogenetic abnormalities were observed in 18 of 357 patients (5%) and rose to 37 (10%) post-treatment. PNH clones were present in 20% of patients at baseline and remained relatively stable during follow-up, 15 patients progressed to PNH syndrome. Six patients evolved to myeloid neoplasms, including myelodysplastic syndromes and chronic myelomonocytic leukemia. These findings highlight the importance of long-term molecular surveillance (ClinicalTrials.gov number, NCT04645199).