Combining Intensive Immunosuppressive Therapy with Eltrombopag in the Severe Aplastic Anemia: Mild Aggravation of Hepatic Injury
Authors: Chen Xiaoyu , Qin Chengtao , Zhang Ting , Gong Yuemin , Zhang Yawen , He Guangsheng , Li Jianyong 
Published: December 2024

Immunosuppressive treatment (IST) with Eltrombopag (EPAG) is recommended for adult patients with severe aplastic anemia (SAA) who do not have a suitable hematopoietic stem cell donor. EPAG is primarily metabolized by hepatic Cytochrome P450 (CYP) 1A2 and CYP2C9 isoenzymes and uridine diphosphate-glucuronosyltransferase (UGT) 1A1 and UGT1A3 in vivo, which poses a potential risk of hepatic injury. A higher incidence and more severe hepatic injury were observed in the EPAG group compared to the placebo control group in chronic ITP. Hepatic adverse events have also been reported in single-arm clinical trials of EPAG monotherapy in refractory SAA. The United States Food and Drug Administration added a black box warning for EPAG: EPAG may increase the risk of serious or potentially life-threatening liver toxicity. This study aims to investigate the prevalence and severity of liver injury in real-world SAA patients treated with EPAG in the context of IST.
A prospective analysis was conducted on 145 SAA patients receiving IST with EPAG or not in the Chinese Eastern Collaboration Group of Anemia (CECGA) between October 2014 and September 2023. These patients were divided into the IST+EPAG cohort and the IST alone cohort. The abnormal events of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), and total bilirubin (TBIL) were monitored between the two cohorts monthly for 6 months after IST. They were conducted by the Drug-Induced Liver Injury (DILI) and the Common Terminology Criteria for Adverse Events (CTCAE) 5.0.
The baseline characteristics of the two cohorts were comparable. The occurrence of abnormal ALT, AST, ALP, GGT and TBIL events was observed in the IST+EPAG and IST groups, with the highest incidence occurring within the first month following rabbit anti-human thymocyte immunoglobulin administration. However, these events demonstrated a notable improvement upon treatment with hepatoprotective drugs. The median cumulative time for abnormal ALT, AST, ALP, GGT, and TBIL levels in the two groups were: 1.5 (1-3) vs 2.5 (1-5) weeks, 2 (1-4) vs 2.5 (1-5) weeks, 3 (2-8) vs 4.5 (1-8) weeks, 5 (1-8) vs 4 (1-12) weeks and 4 (1-9) vs 4.5 (1-7) weeks, respectively. No significant difference was observed between the two groups in terms of the incidence of abnormalities or the cumulative duration.
The incidence of acute DILI was slightly higher in the IST+EPAG group in the 1st month, and 2nd month: 10% vs 5% (P = 0.400), 9% vs 8% (P = 1.000). DILI still occurred in the eltrombopag group in the 3rd (7% vs 0%, P = 0.088) and 4th months (2% vs 0%, P = 1.000). According to CTCAE 5.0, grade 3 or 4 adverse events of ALT, AST, and TBIL in the IST+EPAG group and IST group, were 5% vs 3% (P = 0.228), 2% vs 1% (P = 1.000), 2% vs 1% (P = 1.000) at the 1st month, respectively. Only one patient in the IST group still had a grade 3 adverse event of TBIL (0% vs 1%, P = 1.000) in the 2nd month. In patients with severe liver damage, the median ferritin level incidence was 1329.30 (965.50-1926.20) ng/ml. Univariate and multivariate logistic analysis showed that iron burden was positively correlated with severe liver injury events (P = 0.009, P = 0.049).
In the context, there was a slight increase in the incidence and duration of severe hepatic injury events in SAA patients treated with EPAG, but it was not statistically significant. High serum level of ferritin is associated with hepatic injury.