Researchers identified predictive factors for secondary myeloid neoplasms (sMNs) in patients with aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH), in a study reported in the Journal of Clinical Oncology.

“Our results show that AA progression to sMN has unique molecular characteristics with the distinction of different subgroups characterized by discrete cytogenetic and molecular features,” the researchers wrote in their report.

Although sMNs represent a serious complication of AA and PNH, information has been limited regarding factors associated with sMNs. In this multicenter, retrospective study, the researchers evaluated possible factors related to clonal evolution with AA and PNH.

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The researchers evaluated baseline characteristics and genomic features, analyzed through next-generation sequencing, to identify possible predictors of risks of late clonal complications. The study population included 817 patients with AA, 107 patients with PNH, and 75 patients with AA/PNH overlap.

The researchers focused their analyses on patients who did not undergo hematopoietic stem cell transplantation (HSCT). This is because by a median follow-up time of 8.2 years, no patients who had undergone upfront HSCT had shown late clonal complications.

In the evaluated population, with a median follow-up of 8.6 years, there was a 10-year overall survival (OS) rate of 76.4%. The 10-year cumulative incidence of sMN in these patients was 11.6%. A nonsignificant trend of a higher risk of malignant progression was reported in patients with AA (12.8%) and AA/PNH (13.1%), versus PNH (3.4%; P =.06). The 10-year OS rates for each group were 72.1% with AA, 88.8% with AA/PNH, and 95.2% with classic PNH (P <.001).

In patients with AA, disease severity appeared to influence OS. Nonsevere disease was associated with a better OS than severe disease was (P <.001), even with a similar rate of sMN progression as seen with severe disease (P =.86).

Some factors in patients with severe AA showed independent associations with sMN risk, including having an older age at presentation and having a partial or no response to immunosuppressive therapy. With nonsevere AA, being untreated posed the greatest risk of sMN.

Development of sMN occurred in 94 patients. Following a diagnosis of sMN, patients had a 5-year OS of 40%, after a median follow-up of 4.7 years. Bone marrow (BM) blast ≥5% was an independent factor for survival after sMN diagnosis (hazard ratio, 3.64, 95% CI, 1.82-7.30; P <.001). Among sMNs, myelodysplastic syndrome was diagnosed in 75% cases of evolution.

Analyses of molecular patterns suggested there were 4 cytogenetic groups of sMNs, characterized by complex karyotype, del(7/7p), normal karyotype, or other cytogenetic alterations. Overall, clonal dynamics over time in patients with AA suggested that PIGA variants and human leukocyte antigen aberrations were less frequent by the time of sMN progression, while myeloid lesions were more frequent. Among patients with AA, carriers of variants of PIGA and BCOR/L1 showed reduced risk of sMN progression, compared with having myeloid driver mutations.

“Our results call for a close monitoring of patients with AA with classical BM smear examination and cytogenetics,” the researchers wrote in their report.

Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Gurnari C, Pagliuca S, Prata PH, et al. Clinical and molecular determinants of clonal evolution in aplastic anemia and paroxysmal nocturnal hemoglobinuria. J Clin Oncol. 2023;41(1):132-142. doi:10.1200/JCO.22.00710