Welcome to PracticeUpdate! We hope you are enjoying temporary access to this content.
Please register today for a free account and gain full access
to all of our expert-selected content.
Already Have An Account? Log in Now
Determinants of Clonal Evolution in Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria
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.
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.
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.
Disclosure statements are available on the authors' profiles:
Clinical and Molecular Determinants of Clonal Evolution in Aplastic Anemia and Paroxysmal Nocturnal HemoglobinuriaJ. Clin. Oncol 2022 Sep 02;[EPub Ahead of Print], C Gurnari, S Pagliuca, PH Prata, JE Galimard, LFB Catto, L Larcher, M Sebert, V Allain, BJ Patel, A Durmaz, AL Pinto, MCB Inacio, L Hernandez, N Dhedin, S Caillat-Zucman, E Clappier, F Sicre de Fontbrune, MT Voso, V Visconte, R Peffault de Latour, J Soulier, RT Calado, G Socié, JP Maciejewski
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
story of the week
Germline Predisposition Variants Occur in Patients of All Ages With MDS
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.