Introduction Non-severe aplastic anemia (NSAA) shows varied treatment responses and outcomes. While clonal mutations' role in disease management is increasingly studied, their clinical significance remains unclear. For patients with inherited bone marrow failure (IBMFs-associated genes, even with HSCT, customized conditioning is crucial - differing from standard AA care. Additionally, Few studies have specifically examined clonal hematopoiesis in NSAA.

We performed WES on 87 NSAA patients to identify disease-specific mutational patterns and their clinical prognostic implications.

Methods We retrospectively analyzed data from NSAA patients newly diagnosed at the First Affiliated Hospital of Zhejiang Chinese Medical University (2018-2024). The institutional review board waived informed consent for this retrospective study (Chinese Clinical Trial Registry #ChiCTR2100054992). We curated germline genetic mutations in 189 IBMFS-associated genes from WES performed. Diagnosis followed Camitta criteria and 2024 British Journal of Haematology guidelines, with NSAA subclassified as transfusion-dependent (TD-NSAA) or non-transfusion-dependent (NTD-NSAA). Event-free survival (EFS) was measured as the time from AA diagnosis until the occurrence of any event (12-month nonresponse, death, relapse, any additional AA treatment, transformation to PNH, or malignant clonal evolution.

Results For the 87 patients with NSAA, the median age was 29 years (range: 9–74 years), with a median follow-up period of 58.5 months. Upon receiving the initial treatment, 20 patients achieved CR, 29 achieved PR, and 37 showed NR.

The influence on clinical outcomes of the four most frequently mutated genes in patients with NSAA—CSMD1, PIGA, PIGA, and BCOR/L1—was assessed. No significant differences in treatment efficacy or EFS were observed between CSMD1-mutated and wild-type patients. In NSAA patients, PIGA mutations were associated with significantly better treatment response than wild-type (P < 0.01), but no difference in EFS was observed. FAT1mutations were associated with reduced treatment efficacy compared to wild-type (P = 0.0302). Additionally, FAT1-mutated patients had significantly worse EFS than wild-type patients (P = 0.0102). Conversely, no significant differences in treatment efficacy were found between patients harboring BCOR/L1 mutations and those with the wild-type genotype (P > 0.05). Nonetheless, individuals with BCOR/L1 mutations demonstrated significantly reduced EFS relative to those with the wild-type genotype (P = 0.0390).

Patients harboring BCOR/L1 mutations exhibited poorer treatment outcomes than those with wild-type BCOR/L1, which contrasts with the results of previous studies. Further analysis revealed that patients with NSAA with wild-type BCOR/L1 in our study frequently possessed germline mutations related to IBMFs in genes such as BLM, CTCI, GPIBA, ATM, PIGT, NBN, ANKRD26, UBE2T, and TINF2. Patients with germline mutations assosiated with IBMFs exhibited a significantly poorer response to IST than those without (F = 6.65, P = 0.02). Among patients with NSAA with BCOR/L1 somatic mutations, those with concurrent germline mutations (n = 7) exhibited a significantly poorer treatment response than those without germline defects (F = 5.833, P = 0.05).

Conclusion Overall, this study highlights the poor prognosis of immunosuppressive therapy in patients with bone marrow failure-related germline mutations and concomitant BCOR/L1 mutations, providing insights into optimizing personalized treatment for individuals with NSAA.

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2025
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