CsA+EPAG/HPAG+Romiplostim N01 in the Treatment of Newly-diagnosed SAA/TD-NSAA

Cyclosporine, Eltrombopag or Hetrombopag, and Romiplostim N01 in the Treatment of Newly-diagnosed Transfusion-dependent Non-severe Aplastic Anemia/ Severe Aplastic Anemia

This study aimed to explore the efficacy and safety of cyclosporine (CsA) combined with eltrombopag (EPAG)/hetrombopag (HPAG) and romiplostim N01 in the treatment of newly-diagnosed transfusion-dependent aplastic anemia (TD-NSAA) and severe aplastic anemia (SAA)

For SAA/TD-NSAA patients without HLA-matched donors and those over 40 years old, the first choice is immunosuppressive therapy (IST) + cyclosporine A (CsA) combined with thrombopoietin receptor agonists (TPO-RAs).

TPO-RAs could bind to the thrombopoietin (TPO) receptor, causing conformational changes in the TPO receptor and activating the JAK2/STAT5 pathway, thereby increasing the proliferation of megakaryocyte progenitor cells and platelet production. Previous studies have shown that compared with IST alone, the combination of IST and eltrombopag (EPAG)/hetrombopag (HPAG) as the first-line treatment for SAA can increase the overall response rate (ORR) to 60%-70%.

However, ATG treatment requires hospitalization and has significant toxic effects, leading to a high risk of complications in the elderly or patients with poor health. Therefore, in recent years, treatment regimens without ATG have also been gradually explored. The results of the SOAR trial showed that in newly diagnosed SAA patients, the overall hematological response rate after 6 months of CsA + EPAG was 46%.

In a phase II/III study for refractory AA, romiplostim monotherapy achieved an ORR of 84% at week 27. Although both romiplostim and eltrombopag/hyrtiopeg activate the TPO receptor (c-Mpl), there are differences and complementarities in their molecular mechanisms. Romiplostim is a peptide mimetic that binds to the extracellular domain of the receptor to mimic endogenous TPO; while eltrombopag and hetrombopag are small molecules that target the transmembrane domain, among which hetrombopag replaces the biphenyl structure to enhance lipophilicity, improve efficacy, and reduce liver toxicity. The binding sites of the two drugs are spatially separated and may produce a synergistic effect through different intensities and dynamics of downstream STAT, PI3K/AKT, and other signaling pathways.

Inclusion Criteria:

1. Age ≥ 18 years old;
2. Diagnosed with aplastic anemia (AA) through routine blood tests, bone marrow puncture, bone marrow biopsy, and exclusion tests, and determined as transfusion-dependent non-severe aplastic anemia (TD-NSAA) or severe aplastic anemia (SAA) according to the Camitta criteria; Platelet < 30×10^9/L;
3. Had no HLA-matched donors or was not suitable for first-line allogeneic hematopoietic stem cell transplantation (HSCT);
4. Not suitable for ATG, due to reasons such as age, complications, and the patient's own wishes;
5. With baseline liver and kidney functions <2 ULN;
6. ECOG score ≤ 2;
7. Signed the informed consent;

Exclusion Criteria:

1. Had other primary or secondary bone marrow failure (BMF) diseases, such as Fanconi anemia, congenital keratinization disorder, etc.;
2. With evidence of clonal hematological bone marrow diseases (MDS, AML) in cytogenetics;
3. PNH clone ≥ 50%;
4. Received HSCT before enrollment;
5. Previously used immunosuppressive treatments such as ATG, CsA, TPO receptor agonists (TPO-RAs);
6. Allergic or intolerant to romiplostim N01, eltrombopag, hetrombopag, or CsA;
7. Pregnant or lactating patients;
8. Severe bleeding or infection that cannot be controlled by standard treatment;
9. History of arterial or venous thrombosis;
10. Complicated with malignant tumors;
11. Participated in other clinical trials within 3 months;
12. Patients considered not suitable to participate in this study by the investigator.