Efficacy and Safety of Hematopoietic Stem Cell Transplantation Vs. Immunosuppressive Therapy in Patients with Hepatitis-Associated Aplastic Anemia: A Single-Center Cohort Study and Meta-Analysis
Authors: Hong Yaonan , Li Yuzhu , Liu Qi , Dong Huijie , Liu Wenbin , Hu Huijin , Shen Yingying , Lin Shengyun , Liu Shan , Wu Dijiong 
Published: November 2021

Abstract
Hepatitis-associated aplastic anemia (HAAA) refers to aplastic anemia (AA) in which pancytopenia appears within 6 months after an acute attack of hepatitis. The incidence of HAAA in the Far East and West accounts for 4-10% and 2-5%, respectively, in all AA cases. HAAA frequently occurs in young men, with a median age of 19 (6-56) years, and the two-month mortality after the onset of HAAA can reach 78-88% if the disease was leaved untreated. To date, the underlying pathogenesis is not yet clarified, and no specific correlation has been established between HAAA and chemical toxicants, neither radiation. Based on available studies, the hyper-activation of T lymphocytes and abnormal humoral immunity were confirmed in HAAA, and a large number of infiltrated lymphocytes are also noted in liver at the early stage of the disease, which resulting in liver dysfunction. Some viruses, including hepatitis A, hepatitis B, hepatitis C, parvovirus B19, human herpesvirus (HHV), and Epstein-Barr virus were correlated to the development of HAAA. However, the clinical results of the serological tests for hepatitis-associated viruses of most patients are negative, i.e., serologically negative HAAA.
The frontline treatments are agreed to be allogeneic hematopoietic stem cell transplantation (allo-HSCT) or immunosuppressive therapy (IST). Because of the relatively scattered clinical data, compared to other acquired AA, the basis of treatment decision-making is insufficient. Some studies speculated that both IST and HSCT are effective, while others believe that transplantation should be the first choice if suitable donors are available. Therefore, we conducted a retrospective study and meta-analysis for better understanding and choice of the treatment.
Our retrospective cohort study enrolled 18 HAAA patients, including 12 males and 6 females. A total of 12 (66.7%) patients received IST treatment, in which 4(33.33%) achieved completed remission (CR), 1(8.33%) partial remission (PR), and 7(58.33%) no response (NR), with a total effective rate of 41.7%. 6 patients (33.3%) received HSCT treatment, in which, 2 achieved CR, 1 PR, and 3 NR, with an effective rate of 50% (Table 1). The one-year overall survival (OS) rate of the IST group was significantly higher than that of the HSCT group (P&lt;0.05) (Figure A). In further, we also conducted a meta-analysis which encompassed 6 studies and encompassing 345 cases. The results showed that the pooled mortality of IST and HSCT on HAAA was RR=1.16(95% CI: 0.63-2.13) (Figure B) and the difference was not statistically significant; the pooled one-year overall survival rate was RR=0.95(95% CI: 0.84-1.08)(Figure C), and the difference was not statistically significant; the pooled effective rate was RR=0.68(95% CI: 0.49-0.95)(Figure D), indicating that the efficacy of HSCT group was significantly higher than that of IST. The subgroup analysis showed that the pooled RR of the group &lt;16-years-old was 0.61(95% CI: 0.41-0.95); the pooled RR of the group &gt;16-years-old was 0.86 (95% CI: 0.50-1.46)(Figure E). The effective rate of ATG/ALG combined with CSA was 51.35%, and that of CSA alone was 46.7%. Compared to the HSCT group, the efficacy of ATG/ALG + CSA group (RR=0.73, 95% CI: 0.51-1.04) was better than that of CSA alone (RR=0.59, 95% CI: 0.32-1.09) (Figure F). The result of comparing ATG/ALG + CSA with CSA showed that the pooled RR was 1.35(95% CI: 0.70, 2.59) (Figure G), and the difference was not significant. This phenomenon could be attributed to the small number of articles included and insufficient sample size after subgroup analysis according to the IST treatment. We speculated that ATG/ALG combined with CSA has advantages in the treatment of HAAA compared to CSA alone.
In summary, HSCT is more effective than IST in the treatment of HAAA, especially for patients &lt;16-years-old, who should receive HSCT at the earliest. ATG/ALG combined with CSA can also be an idea option of IST treatment, but not single CsA. For patients &gt;16-years-old, there is no significant difference in the efficacy between the HSCT and ATG/ALG + CsA strategies.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.