Clinical and Molecular Determinants of Clonal Evolution in Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria

This article has been excerpted and reprinted from the Journal of Clinical Oncology.

The risk of secondary myeloid neoplasms in patients with aplastic anemia is associated with disease severity, lack of response to treatment, and patients’ age, according to new research. Jaroslaw P. Maciejewski, MD, PhD of the Cleveland Clinic Department of Translational Hematology and Oncology Research participated in the multinational study.

Secondary myeloid neoplasms remain the most serious long-term complications in patients with non-transplanted acquired aplastic anemia or paroxysmal nocturnal hemoglobinuria (PNH). However, sMNs lack specific predictors, dedicated surveillance measures, and early therapeutic interventions.

Seeking rational diagnostic approaches

To understand how clinical, cytogenetic, and molecular characteristics influence the risk of sMN, the researchers studied a retrospective cohort of 1,008 patients with aplastic anemia anemia or PNH, with a median follow-up of 8.6 years.

Although none of the patients transplanted upfront (n = 117) developed clonal complications (either sMN or secondary PNH), the 10-year cumulative incidence of sMN in non-transplanted cases was 11.6%. In severe aplastic anemia, older age at presentation and lack of response to immunosuppressive therapy were independently associated with increased risk of sMN, while untreated patients had the highest risk among non-severe cases. The elapsed time from aplastic anemia to sMN was 4.5 years. sMN developed in 94 patients. The five-year overall survival reached 40%, and was independently associated with bone marrow blasts at sMN onset.

Analyzing genetic mutations

Myelodysplastic syndrome with high-risk phenotypes, del7/7q, and ASXL1, SETBP1, RUNX1, and RAS pathway gene mutations were the most frequent characteristics. Cross-sectional studies of clonal dynamics from baseline to evolution revealed that PIGA/human leukocyte antigen lesions decreased over time, being replaced by clones with myeloid hits. PIGA and BCOR/L1 mutation carriers had a lower risk of sMN progression, while myeloid driver lesions marked the group with a higher risk.

Generating new insights yet questions remain

sMN presented high-risk morphological, cytogenetic, and molecular features. Cross-sectional analyses revealed an inversion in clonal dynamics: PIGA/human leukocyte antigen mutations, predominant at baseline, were replaced by myeloid drivers at transformation. Lack of response to non-transplant treatments, older age, and myeloid driver mutations at aplastic anemia/PNH onset conferred higher risk of progression.

The landscape of acquired somatic mutations is complex, not thoroughly understood, and should be considered with caution in medical management.

Patients with aplastic anemia or PNH need close, prolonged monitoring with marrow morphology and cytogenetics. Morphological progression to sMN or occurrence of monosomy 7 should prompt clinicians to consider transplantation in eligible patients. Clinicians should carefully interpret the molecular profile with morphological and cytogenetic data for therapeutic decisions.

The full-length article is available at the Journal of Clinical Oncology.