Recombinant Human Thrombopoietin Add to IST Combined with Hetrombopag As First-Line Treatment for Naïve Severe Aplastic Anemia: Early Outcomes of a Prospective Study

Idiopathic aplastic anemia is a primary bone marrow failure disease that manifests with pancytopenia. To now, standard IST combined with eltrombopag is recommended as a first-line regimen for severe aplastic anemia patients who are ineligible for HSCT. Several previous studies have shown that IST combined with recombinant human thrombopoietin (rhTPO) or eltrombopag/ hetrombopag can improve the early hematologic response of SAA patients, especially the proportion of good hematologic response (GHR) in the early stage. RhTPO and thrombopoietin receptor agonist (TPO-RA) have different binding sites with thrombopoietin receptor and do not have competitive binding, which may produce a synergistic effect. A retrospective study showed that eltrombopag combined with rhTPO increased the hematologic response rate of IST and improved the quality of hematologic response in SAA with mild adverse effects. Therefore, the combination of TPO-RA and rhTPO in SAA patients undergoing IST treatment may result in faster and higher HR rates. Clinical studies have confirmed that hetrombopag, acts similarly to eltrombopag in SAA, but there are no clinical studies of hetrombopag in combination with rhTPO in SAA.

Here, we report a single-center prospective study of 39 patients with naïve severe aplastic anemia treated with porcine ATG and cyclosporine plus hetrombopag combined with rhTPO between March 2023 and April 2024 and evaluate the early outcome of this treatment regimen. Patients received hetrombopag orally at the dose of 15mg daily, as 2.5mg tablets, starting from day+1 of IST and rhTPO with hypodermic injection for 90 days, starting from day+15 of IST. The primary endpoint was to observe the good hematologic response rate, blood product transfusion, and safety profile of the study regimen at 3 months.

The median age of 39 patients in the hetrombopag group was 42 years (range from 16 to 70 years), with 22 male and 17 female, with 25 SAA and 14 VSAA. The median follow-up time was 220 days (range: from 100 to 458 days) in the hetrombopag group. No patients experienced death within 3 months after this regimen.

The overall hematologic response rate (OR) at 3 months was 75.0% (27/36) in 36 patients who can access the hematologic response. The complete hematologic response rate (CR) at 3 months was 25% (9/36) and the GPR rate was 22.2% (8/36). The overall good hematologic response rate (CR+GPR) was 47.2% (17/36) at 3 months. At 6 months, the overall response was 76.9% (20/26) in 26 patients with accessible response. The complete response rate was 34.6% (9/26) and the GPR rate was 19.2% (5/26) at 6 months. The overall good hematologic response rate (CR+GPR) was 53.8% (14/26) at 6 months.

No patients discontinued hetrombopag and rh-TPO due to adverse events. There was no clonal evolution and no death by the last follow-up time point. But the relapse rate was 5.5% (2/36). The two patients were dependent on the platelet transfusion.

In conclusion, adding rh-TPO to standard IST combined with hetrombopag had efficacy in treatment-naïve severe aplastic anemia and significantly improved the rapidity and strength of hematologic response.