Hetrombopag Add to Porcine ATG and Cyclosporine for Aplastic Anemia: Early Outcomes of a Prospective Pilot Study

Idiopathic aplastic anemia is a primary bone marrow failure disease that manifests with pancytopenia. The pathogenesis involves T cell-mediated autoimmunity. Currently, the studies from NIH and EBMT both showed that eltrombopag in combination with standard IST had efficacy in treatment-naïve severe or very severe aplastic anemia, and significantly improved the rapidity and strength of hematologic response. To now, standard IST combined with eltrombopag is recommended as a first-line regimen for severe aplastic anemia patients who are ineligible for HSCT.

Hetrombopag is also an oral non-peptide TPO-RA and was approved for refractory SAA by CFDA in June 2021. The structure of hetrombopag is similar to eltrombopag. The vitro and vivo experimental studies have demonstrated that hetrombopag can promote the proliferation and differentiation of hematopoietic stem cells. And the strength of stimulation was superior to eltrombopag. Hetrombopag was shown to have efficacy in aplastic anemia patients with refractory to standard IST in an open-label, nonrandomized, prospective study, and the overall response was about 40%. Here, we report a single-center prospective pilot study of 32 patients with aplastic anemia treated with porcine ATG and cyclosporine plus hetrombopag between August and December 2021. And patients were compared retrospectively with matched aplastic anemia patients previously treated with p-ATG and CsA alone between 2017 and 2019 in our department. Matching was performed in a 1:3 ratio using the nearest neighbor in SPSS software with a caliper width of 0.20. Patients were matched by age and disease severity (non-VSAA and VSAA) (32 patients treated with IST plus hetrombopag and 96 historical controls). Patients received hetrombopag orally at the dose of 15mg daily, as 2.5mg tablets, starting from day+1 of IST.

The median age of 32 patients in the hetrombopag group was 44 years (range from 13 to 69 years), with 17 male and 15 female. The median follow-up time was 260 days (range: from 181 to 343 days) in the hetrombopag group. No patients experienced death within 3 months after IST in the hetrombopag group. Eight (8.3%) patients died within 3 months in the control group, with seven VSAA and one SAA. The leading death causes were hemorrhage and infection.

The overall hematologic response rate (OR) at 3 months was 46.9% (15/32) in the hetrombopag group and 37.5% (36/96) in the control group (P-value = 0.350). The complete hematologic response rate (CR) at 3 months was 21.9% (7/32) in the hetrombopag group, which was significantly higher than 5.2% (5/96) in the control group (P-value = 0.005). At 6 months, the overall response was 68.7% (22/32) in the hetrombopag group and 50.0% (48/96) in the control group (P-value = 0.066). The complete response rate was 34.4% (11/32) in the hetrombopag group, which was significantly higher than 14.6% (14/96) in the control group (P-value = 0.015).

The median time to first response was 56 days in the hetrombopag group and 77 days in the control group (P-value = 0.000). The median time from partial response to complete response was 58 days in the hetrombopag group and 96 days in the control group. The median time to complete response was 96 days in the hetrombopag group and 214 days in the control group (P-value = 0.019). The median time to platelet counts above 100×10⁹/L was 88 days in the hetrombopag group and 207 days in the control group. No patients discontinued hetrombopag due to adverse events. There was no clonal evolution and no death by the last follow-up time point in the hetrombopag group.

In conclusion, standard IST combined with hetrombopag had efficacy in aplastic anemia and significantly improved the rapidity and strength of hematologic response.

No relevant conflicts of interest to declare.