Determinants of Clonal Evolution in Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria

Aplastic anemia (AA) is an acquired bone marrow failure disorder that occurs due to an immune-mediated attack of hematopoietic stem cells (HSCs). The standard of care is HSC transplant (HSCT) for patients who are fit and have suitable donors as well as immunosuppressive therapy (IST) with and without eltrombopag for those who are unfit or do not have suitable donors. Paroxysmal nocturnal hemoglobinuria (PNH) is a type of hemolytic anemia that occurs due to acquired mutations in the PIGA gene, which results in the loss of CD55 and CD59 markers on the cell surface, leading to excessive complement activation. It is quite common to observe a small PNH clone in patients with AA because PIGA-mutant HSC clones may escape the immune attack and expand in the bone marrow, while PIGA wild-type HSCs are being attacked by the auto-reactive cytotoxic T cells. Clonal evolution into a secondary myeloid neoplasm (sMN) is one of the most fearful late complications observed in patients with AA/PNH, and its incidence has been reported to be approximately 15%.^1,2

In a recent volume of the Journal of Clinical Oncology, Gurnari et al published a multicenter retrospective study of 1008 patients with AA and PNH that assessed the determinants of clonal evolution. None of the patients who underwent HSCT upfront experienced clonal evolution. Among nontransplanted patients, the 10-year cumulative incidence of sMN was 11.6%. Patients with AA or AA/PNH overlap tended to have a higher risk of developing sMN than those with classical hemolytic PNH (trend only). In severe AA, advanced age at the time of diagnosis (age, >35 years) and suboptimal response to IST were independently associated with higher risks of developing sMN. Myelodysplastic syndrome (MDS) was the most frequent diagnosis at evolution, and post-AA MDS was characterized by the over-representation of higher R-IPSS scores driven by the high frequency of monosomy 7 or del(7q) and a complex karyotype. A bone marrow blast percentage ≥5% at the time of sMN onset was significantly associated with shorter overall survival. The baseline mutational landscape also predicted progression-free survival (PFS): myeloid driver mutations (eg, ASXL1, RUNX1, SETBP1, etc) conferred the worst PFS, and PIGA or BCOR/L1 mutations conferred the best PFS; however, PFS for the unmutated population was in between, consistent with that reported in a prior study.³ The frequency of PIGA and HLA mutations was decreased, whereas that of myeloid driver mutations was increased dramatically at the time of clonal evolution. The incorporation of serial molecular testing should be considered in addition to the surveillance of morphological evolution and conventional cytogenetics for nontransplanted patients with AA and AA/PNH. Future studies are required to determine the best treatment strategy with new molecular information.

References

1. Babushok DV. A brief, but comprehensive, guide to clonal evolution in aplastic anemia. Hematology Am Soc Hematol Educ Program. 2018;2018(1):457-466. https://ashpublications.org/hematology/article/2018/1/457/277594/A-brief-but-comprehensive-guide-to-clonal
2. Patel BA, Groarke EM, Lotter J, et al. Long-term outcomes in patients with severe aplastic anemia treated with immunosuppression and eltrombopag: a phase 2 study. Blood. 2022;139(1):34-43. https://ashpublications.org/blood/article-abstract/139/1/34/476916/Long-term-outcomes-in-patients-with-severe?redirectedFrom=fulltext
3. Yoshizato T, Dumitriu B, Hosokawa K, et al. Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia. N Engl J Med. 2015;373(1):35-47. https://www.nejm.org/doi/full/10.1056/nejmoa1414799