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Case Reports
genetic features of SAA patients developing MDS/AML without chromosome 7 abnormalities, arising more than 5 years after IST. In all four patients, we identified molec- ular alterations in genes recurrently mutated in myeloid malignancies: RUNX1, NRAS, NPM1, ASXL1, SETBP1, PHF6.12 Three subjects had at least one RUNX1 variant, for which the reported prevalence is 10% in de novo AML/MDS or therapy related myeloid neoplasm.12 Somatic RUNX1 mutations have also been described in myeloid malignancies arising from inherited marrow fail- ure including Fanconi anemia (20%) and congenital neu- tropenia (64%).13,14 Accelerated telomere attrition corre- lates with monosomy 7 transformation,9 but acquisition of somatic mutations, specifically RUNX1, may be impli- cated in late high risk clonal evolution without chromo- some 7 aberration. Previously, ASXL1 has been associat- ed with higher risk of myeloid malignancy with abnor- mal cytogenetics.8
Whether clonal evolution to MDS/AML is a result of genomic instability present at diagnosis or developing after IST has not been elucidated. We were able to detect somatic variants present in bone marrow samples from 1-2 years prior to clonal evolution but not at initial SAA diagnosis. Given the rare nature of late evolution to myeloid malignancy without chromosomal abnormali- ties, and the current limitations of NGS for de novo dis- covery of MDS/AML variants,15 it is not known if sequen- tial molecular monitoring would be clinically useful for early detection of evolving myeloid malignancy. The util- ity of early interventions designed to prevent develop- ment of myeloid malignancy in high-risk individuals is currently unknown. Approximately 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.
Bhavisha A. Patel,* Jack Ghannam,* Emma M. Groarke,* Meghali Goswami, Laura Dillon, Fernanda Gutierrez- Rodrigues, Olga Rios, Diego Quinones Raffo, Jennifer Lotter, Neal S. Young# and Christopher S. Hourigan#
Hematology Branch, National Heart, Lung, and Blood Institute (NHLBI),Bethesda, MD, USA
*BAP, JG, and EMG contributed equally as co-first authors. #CSH and NSY contributed euqually as co-senior authors
Correspondence:
NEAL S. YOUNG - youngns@nhlbi.nih.gov
doi:10.3324/haematol.2020.263046
Disclosures: Eltrombopag was provided by GlaxoSmithKline and Novartis under a Clinical Trials Agreement with NIH, which included research funding for additional experimental laboratory studies.
Contributions: BAP, EMG, NSY designed the study and performed clinical analyses; JG, MG, LD, DQ performed laboratory studies and analyses; BAP, EMG, NSY, OR, JL provided clinical care; BAP, EMG JG, FGR, CSH and NSY wrote and edited the manuscript.
Funding: this research was supported in part by the Intramural Research Program of the NIH and NHLBI.
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