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

Abstract

PURPOSE Secondary myeloid neoplasms (sMNs) remain the most serious long-term complications in patients with aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH). However, sMNs lack specific predictors, dedicated surveillance measures, and early therapeutic interventions. PATIENTS AND METHODS We studied a multicenter, retrospective cohort of 1,008 patients (median follow-up 8.6 years) with AA and PNH to assess clinical and molecular determinants of clonal evolution. RESULTS 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 nontransplanted cases was 11.6%. In severe AA, older age at presentation and lack of response to immunosuppressive therapy were independently associated with increased risk of sMN, whereas untreated patients had the highest risk among nonsevere cases. The elapsed time from AA to sMN was 4.5 years. sMN developed in 94 patients. The 5-year overall survival reached 40% and was independently associated with bone marrow blasts at sMN onset. 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, whereas myeloid driver lesions marked the group with a higher risk. CONCLUSION The risk of sMN in AA is associated with disease severity, lack of response to treatment, and patients' age. sMNs display high-risk morphological, karyotypic, and molecular features. The landscape of acquired somatic mutations is complex and incompletely understood and should be considered with caution in medical management.

Significance of hereditary gene alterations for the pathogenesis of adult bone marrow failure versus myeloid neoplasia

“…1C, D). Conversely, and in line with our previous results [28], the presence of PNH constituted a protective factor for sMN evolution (odds ratio [OR] = 0.29; p = 0.0004). When we studied MN phenotypes specifically, AML cases showed a higher frequency of P/LP variants compared to MDS or MDS/MPN cases (Fig.…”

Anti-Thymocyte Globulin (ATG)-Free Nonmyeloablative Haploidentical PBSCT Plus Post-Transplantation Cyclophosphamide Is a Safe and Efficient Treatment Approach for Pediatric Acquired Aplastic Anemia

“…Among the six patients subjected to whole-exome sequencing, the BCORL1 variant in Case 2 was the only molecular determinant identified by sequence analysis from a panel of genes linked to clonal hematopoiesis of indeterminate potential. Carriers of BCORL1 mutation, such as PIGA and BCOR , exhibit a lower risk of progressing to secondary myeloid neoplasms, and thus, this variant could represent a marker of immune selection without being a significant driver of myeloid malignancy [ 37 , 38 ]. We also observed both SAMD9L mutation-associated AA patients (Cases 2 and 9) not only showed evidence of immune-mediated pathophysiology resulting in AA but also presented with significantly shorter telomeres upon presenting with cytopenia.…”

Haemolytic paroxysmal nocturnal haemoglobinuria in patients with myeloid neoplasms: A rare association with specific therapeutic implications

“…5 The presence of small PNH clones (<10%) in patients with myelodysplastic syndrome (MDS) 7,8 is well known, as is the classical PNH evolution to MN (11.6% at 10 years). 9 Conversely, concurrent or secondary diagnosis of haemolytic PNH in patients with MN is extremely rare 1 and is confined to case reports in patients with myeloproliferative neoplasms (MPN). [10][11][12] The purpose of the present work was to describe the disease characteristics and clinical course of patients with a concurrent diagnosis of PNH and MN, without evidence of pre-existing PNH.…”