Editor’s Note: The optimal treatment for transfusion-dependent non-severe aplastic anemia (TD-NSAA) remains uncertain. While UK guidelines recommend intensified immunosuppressive therapy (IST) as a first-line treatment for TD-NSAA, the associated costs and risks are relatively high. A recent study conducted by Professor Guangsheng He’s team at Jiangsu Provincial People’s Hospital, presented at the 65th American Society of Hematology (ASH) Annual Meeting, explored the effectiveness of Hetrombopag combined with Cyclosporine A (CsA) in treating TD-NSAA. The study provides crucial insights for clinical consideration. Here is a summary.

Objective:

The therapeutic approach for transfusion-dependent non-severe aplastic anemia (TD-NSAA) is undetermined. Though the British guideline recommended intensive immunosuppressive therapy (IST) as front-line therapy for TD-NSAA (Killick SB, et al. British Journal of Haematology. 2016; 172(2): 187-207), the cost and risk were relatively high. Hetrombopag is a thrombopoietin receptor agonist approved for IST-refractory severe aplastic anemia (SAA) by the China Food and Drug Administration in 2021 (Peng G, et al. Ther Adv Hematol. 2022; 13: 20406207221085197). This study aimed to evaluate the efficacy of hetrombopag plus cyclosporine A (CsA) for TD-NSAA.

Methods:

24 eligible patients receiving hetrombopag plus CsA from September 2021 to July 2023 were collected by prospective registration (ChiCTR2100045895) in the Chinese Eastern Collaboration Group of Anemia (CECGA). A historical cohort (n=79) receiving CsA alone from December 2013 to January 2017 in the CECGA was used as a comparator (Table 1). Primary endpoint was overall response at 24 weeks, defined as hematologic response in ≥ 1 lineage. Secondary endpoints were overall response at 12 and 48 weeks, complete response at 48 weeks, overall survival, transformation to SAA and treatment-related adverse events.

Results:

At 24 weeks, the overall response rate was 74% in hetrombopag plus CsA cohort and 16% in CsA cohort (odds ratio [OR]: 14.7; 95% confidence interval [CI]: 4.1 ~ 52.4; p＜0.001). The overall response rates at 12 and 48 weeks were also significantly higher in hetrombopag plus CsA cohort than those in CsA cohort (43% vs 8%, OR: 9.1, 95% CI: 2.7 ~ 31.1, p＜0.001; 85% vs 30%, OR: 13.0, 95% CI: 2.5 ~ 66.2, p = 0.001, respectively). At 48 weeks, the complete response rate was 23% in hetrombopag plus CsA cohort and 2% in CsA cohort (OR: 13.8; 95% CI: 1.3 ~ 146.8; p = 0.029). The median time to initial response was 11.6 [95% CI: 2.9~20.3] weeks in hetrombopag plus CsA cohort, significantly shorter than that in CsA cohort (hazard ratio: 5.0; 95% CI: 2.1 ~ 12.1; p＜0.0001) (Figure 1). The median time to erythroid, platelet and neutrophil responses in hetrombopag plus CsA cohort were 20.6 [95% CI: 9.1 ~ 32.0], 16.4 [95% CI: 3.0 ~ 29.9] and 23.0 [95% CI: 10.6 ~ 35.4] weeks, respectively. The 1-year survival rates in hetrombopag plus CsA cohort and in CsA cohort were similar (90% vs 94%; hazard ratio: 1.9; 95% CI: 0.2 ~ 15; p = 0.5). The percentage of patients transforming to SAA was 8% in hetrombopag plus CsA cohort and 34% in CsA cohort (OR: 0.2; 95% CI: 0.0 ~ 0.8; p = 0.018). Treatment-related hepatic or renal injury occurred in 7 patients (29%) in hetrombopag plus CsA cohort with only one ≥ Grade 3; all gained remission after dose reduction or discontinuation. Multivariate analysis of clinical parameters of all patients from both cohorts revealed that adding hetrombopag to therapy was strongly correlated with response (OR: 43; 95% CI: 4 ~ 528; p = 0.003), as was lower lymphocyte count (OR: 0.5; 95% CI: 0.3 ~ 0.8; p = 0.011).

Conclusion:

The combination of hetrombopag with CsA improved the rate, rapidity, and strength of hematologic response among patients with TD-NSAA, and lowered their risks of transforming to SAA.

Researchers’ Comments:

Aplastic anemia (AA) is a complex syndrome of bone marrow failure caused by various factors, involving three main mechanisms: “seed,” “bug,” and “soil.” The “seed” refers to hematopoietic stem cells, and targeting this aspect has been challenging until the advent of thrombopoietin receptor agonists (TPO-RAs). Our clinical study indicates that Hetrombopag, a domestically developed TPO-RA, combined with CsA, can effectively address the needs of TD-NSAA patients, shifting the treatment paradigm from mere survival to a better quality of life.

Department of Hematology, Jiangsu Provincial People’s Hospital

Deputy Director, Hematology Department, Nanjing Medical University First Affiliated Hospital

Chief Expert in Hematopoietic Function Failure

Chairman, Anemia Branch of Jiangsu Research Hospital Society

Chairman, Hematologic Disease Prevention and Control Professional Committee of Jiangsu Preventive Medicine Association

Editorial Board Member: Front Immunol, Cell Transplatation, Ann Hematol, Hematol

Editor-in-Chief, Chinese Journal of Practical Internal Medicine

Second Prize of National Medical Science and Technology Progress Award

Chen Jinrong Life Science Talent Award, Suzhou University

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