Efficacy and Safety of Hetrombopag in Promoting Platelet Engraftment after Allogeneic Stem Cell Transplantation: A Prospective, Single-Arm Clinical Trail

Background: Thrombocytopenia is a common complication following allogeneic stem cell transplantation (allo-HSCT), leading to increased transplant-related mortality. Currently, thrombopoietin receptor agonists (TPO-RAs) are used to treat patients with thrombocytopenia. Hetrombopag (HPAG) is a small-molecule TPO-RA that binds to the transmembrane domain of thrombopoietin receptors and has been approved for the treatment of chronic primary immune thrombocytopenia and severe aplastic anemia in China. However, there are few reports on the use of HPAG for treating thrombocytopenia post-HSCT. Thus, we conducted this study to evaluate the efficacy and safety of HPAG in promoting platelet engraftment after allo-HSCT (ChiCTR2200062156, chictr.org).

Experimental Design: Patients aged ≥ 18 years with poor platelet engraftment after allo-HSCT from July 2022 to July 2024 were enrolled in this study. Poor platelet engraftment was defined as a platelet (PLT) count < 20×10⁹/L for 7 consecutive days or dependency on platelet transfusion beyond 28 days post-HSCT. Platelet engraftment was defined as platelet count ≥ 20×10⁹/L for consecutive 7 days without platelet transfusion. These patients were treated with HPAG from day +28 until ether platelet reconstitution, or a count of PLT ≥ 100×10⁹/L, or prolonged thrombocytopenia after more than 8 weeks of medication. The initial dose was 5 mg daily, with a maximum dosage of 10 mg daily. These patients were compared with 65 historical controls (ChiCTR-IPR-16009357, chictr.org).

Results: Forty-eight patients with a median age of 40 years (range, 18-60 years) were enrolled in the study. The last follow-up time was July 23, 2024 with a median follow-up time of 201 days (range, 36-773 days). Twenty-nine patients were male. The diagnoses included 20 patients with acute myeloid leukemia patients, 16 with acute lymphoblastic leukemia, 11 with myelodysplastic syndrome and 1 with chronic myelomonocytic leukemia. Two of the 48 patients received peripheral blood stem cell Transplantation (PBSCT), while other 46 patients underwent umbilical cord blood transplantation (UCBT). Of the 48 patients, 42 were administrated HPAG following the 14 consecutive days of recombinant thrombopoietin (rhTPO) treatment that from day +14 to day +28 after UCBT

The median time of neutrophil engraftment was 17 days (range, 11-36 days) post-HSCT. A total of 54 patients reached platelet-engraftment. The 60-day cumulative incidence rate of platelet engraftment was 91.3% [95% confidence interval (CI): 78.5%-96.6%], and the 120-day cumulative incidence of platelet recovery was 88.4% (95%CI: 74.3%-95.0%). The median unit of platelet transfusion required after 8 weeks of enrollment was 1 U (range, 0-23 units).

We further compared the efficacy of sequential treatment with rhTPO and HPAG in the 42 patients to a historical control group, which included 33 patients treated with rhTPO only from day +14 to day +28 and 32 patients who did not receive rhTPO or TPO-RAs after transplantation. The results showed that the cumulative incidence of platelet engraftment by day +60 in sequential treatment group was significantly higher than in the rhTPO-only group and the control group (90.0% vs. 75.8% vs. 53.1%, P < 0.001). The cumulative incidence of platelet recovery to 50×10⁹/L by day +120 in sequential treatment group showed a similar trend (86.8% vs. 72.7% vs. 53.1%, P < 0.001).

During the observation period, one patient experienced HAPG-related liver damage and another experienced HPAG-related kidney damage. No abnormality was found in the remaining patients.

Conclusions: Compared to rhTPO alone, these results suggested that sequential treatment with rhTPO and HPAG could rapidly promote platelet recovery especially in UCBT.

Keywords: Hetrombopag, rhTPO, Allo-HSCT, UCBT, Platelet engraftment.