Predictors, genetic characteristics, and long-term outcomes of patients with SAA who clonally evolved after immunosuppressive therapy (IST) were assessed. SAA patients were treated with IST from 1989-2020. Clonal evolution was categorized as “high-risk” (overt myeloid neoplasm [meeting WHO criteria for dysplasia, MPN or acute leukemia] or isolated chromosome-7 abnormality/complex karyotype without dysplasia or overt myeloid neoplasia) or “low-risk” (non-7 or non-complex chromosome abnormalities without morphological evidence of dysplasia or myeloid neoplasia). Univariate and multivariate analysis using Fine-Gray competing risk regression model determined predictors. Long-term outcomes included relapse, overall survival (OS) and hematopoietic stem cell transplant (HSCT). Somatic mutations in myeloid cancer genes were assessed in evolvers and in 407 patients 6 months after IST. Of 663 SAA patients, 95 developed clonal evolution. Pre-treatment age >48 years and ANC > 0.87 × 109/L were strong predictors of high-risk evolution. OS was 37% in high-risk clonal evolution by 5 years compared to 94% in low-risk. High-risk patients who underwent HSCT had improved OS. Eltrombopag did not increase high-risk evolution. Splicing factors and RUNX1 somatic variants were detected exclusively at high-risk evolution; DNMT3A, BCOR/L1 and ASXL1 were present in both. RUNX1, splicing factors and ASXL1 somatic mutations detected at 6 months after IST predicted high-risk evolution.
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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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Funding for this study was provided by the intramural research program of the National Heart, Lung, and Blood Institute. NSY and CED receive research funding from Novartis via a CRADA. This study was presented as an oral abstract at the American Society of Hematology annual meeting 2021. Graphic artist credit to Alan Hoofring, NIH Medical Arts Department.
NSY and CED receive funding from a Collaborative Research and Development Agreements between NIH and Novartis. No other authors have relevant conflicts of interest.
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Groarke, E.M., Patel, B.A., Shalhoub, R. et al. Predictors of clonal evolution and myeloid neoplasia following immunosuppressive therapy in severe aplastic anemia. Leukemia (2022). https://doi.org/10.1038/s41375-022-01636-8