Aplastic anemia (AA) is a bone marrow failure disorder characterized by pancytopenia. Currently, immunosuppressive therapy (IST) using cyclosporine (CsA) with or without anti-thymoglobulin (ATG) are the standard first-line management for AA patients not eligible for allogeneic stem cell transplantation. Several studies identified the influencing factors on IST response and survival, however, there are still a considerable number of patients suffering from poor prognosis even if they have achieved workable treatment, which encourage us to further identify additional prognosis / response predictor. The whole-exome sequencing (WES) is an accurate molecular technique to rule out congenital hematopoietic failures in young patients with pancytopenia. Up to date, several reports showed a relatively higher FANC heterozygous germline mutation rate was found in AA/MDS patients than general population, which may contribute to hematopoietic failure and confer congenital susceptibility to myeloid malignancies. Mostly, immunosuppressive therapy (IST) rescues hematopoiesis stem cell from cytotoxic T lymphocyte mediated bone marrow failure, but may exert limited effect in reconstruct gene deficit induced hematopoietic dysfunction. At present, few study focus on exploring the impact of FANC mutation on the response of AA to IST treatment, as well as its long-term prognosis. Herein, we respectively reviewed the AA patients who have the WES result in our cohort.

A total of 61 patients aged ≤40 years old diagnosed with AA and underwent WES analysis were enrolled in this study, and result showed unexpected high FANC heterozygous germline mutations in our cohort (28/61, 45.9%) (Fig. A). Patients with FANC mutations have a significantly lower absolute reticulocyte count, and CD34+ % in bone marrow, and also lower 3, 6, and 9-month IST response than that without mutation, which were 0% vs. 25% (P=0.017), 26.3% vs. 42.1% (P=0.495), and 29.4% vs. 72.2% (P=0.011), especially in anti-thymocyte globulin combined with Cyclosporin A (ATG + CsA) group, which were 0% vs.33.4% (P=0.143), 25% vs.83.3% (P=0.103), and 25% vs. 100% (P=0.003), respectively (Fig. B-E). While the efficiencies of patients received HSCT were all 100% at 3rd, 6th, and 9th months evaluation. The overall survival (OS) didn't have a difference based on FANC status as well as treatment strategy (IST vs. HSCT), only one patient in the FANCmut group transformed into acute myeloid leukemia (AML) 49 months after the failure of CsA single treatment and died due to severe infection (Fig F, G). The event-free survival (EFS) in the FANCwt group was better than that in the FANCmut group (P=0.016) (Fig H), and also showed in patients received ATG + CsA treatment (P=0.045) (Fig I). We further explored the possible factors that may affect the EFS, and the FANC mutation was found to be the only predictor associated with poorer EFS [odds ratio (OR)=5.576, 95% confidence interval (CI): 1.169-26.590, P=0.031] in patients received IST (Fig J).

In summary, WES based detection of FANC heterozygous germline mutations may have a great meaning in predicting IST response of acquired AA. For patients younger than 40-year-old without FANC germline mutation, ATG + CsA can exert a curative effect that was comparable to HSCT, while for cases with FANC mutation, HSCT may be a better choice. FANC germline mutation can negatively impact the IST response for Chinese patients with AA.

No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.

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