Introduction: Patients with severe thalassemia undergoing haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HSCT) are at substantial risk of delayed platelet engraftment, with reported incidence rates ranging from 5% to 38%. This complication increases the risk of hemorrhage, compromises overall survival, and adds to the healthcare burdens. Hetrombopag, a next-generation oral non-peptide thrombopoietin receptor agonist, promotes megakaryocyte differentiation by activating the TPO-R/c-MPL–JAK–STAT signaling pathway. This study aims to evaluate the effectiveness and safety of hetrombopag in promoting platelet engraftment following haplo-HSCT.

Methods: This prospective observational study enrolled patients with a confirmed diagnosed of severe thalassemia based on genetic testing, transfusion history, and complete blood counts. Eligible participants were over 2 years old, consented to undergo haploidentical transplantation, and were deemed by the transplant team to have no contraindications. Patients were block-randomized into different groups, each managed by a separate physician. Graft-versus-host disease prophylaxis included cyclophosphamide at a total dose of 100 mg/kg (divided into two doses on day +3 and +4), methotrexate at 10 mg/m² (administered on days +1, +2, +5, and +6), and cyclosporine A at 4 mg/kg/day starting from day +6. The infused mononuclear cell dose ranged from 10 to 25 ×10⁸/kg, and the CD34⁺ peripheral blood stem cell dose ranged from 5 to 20 ×10⁶/kg. Hetrombopag was initiated on day +6 post-transplant at a dose of 5 mg for patients aged ≥10 years and 2.5 mg for those <10 years. From day +10, the dose was increased to 7.5 mg and continued until platelet counts reached ≥100 × 10⁹/L. Fresh apheresis platelet concentrates (one therapeutic dose) were transfused when platelet counts were ≤10 ×10⁹/L, or 11–50 ×10⁹/L in the presence of active bleeding. The primary outcomes were time to platelet engraftment and the number of platelet transfusion units. Platelet engraftment was defined as a sustained peripheral platelet count ≥20 ×10⁹/L for at least seven consecutive days without transfusion. The first day this threshold was met was recorded as the day of engraftment.

Results：Between January 1, 2023, and July 17, 2025 (ClinicalTrials.gov ID: NCT07003269), 33 patients received hetrombopag post-haplo-HSCT. Two died shortly after transplantation and were excluded, leaving 31 patients for analysis. The mean age was 9 ± 4 years (range: 4–19), with 17 females and 14 males. The mean number of platelet transfusions was 55 ± 29 U (range: 12–132), and the mean time to platelet engraftment was 17 ± 7 days (range: 9–43). Group A (n=16) and Group B (n=15) showed no significant differences in age or sex. The mean transfusion volume was significantly higher in Group A (68 ± 32 U) than in Group B (42 ± 20 U) (P = 0.01). In Group A, 72 U accounted for 31.3% (5/16); 24 U, 36 U, 48 U, and 108 U each for 12.5% (2/16); 60 U, 96U and 132 U each for 6.3% (1/16). In Group B, 24 U accounted for 33.3% (5/15); 60 U for 26.7% (4/15); 36U and 48U each for 13.3%(2/15); 12 U and 84 U each for 6.6% (1/15). Both deaths occurred in Group A. The mean CD34⁺ cell dose was 18.57 ± 4.94 × 10⁶/kg (range: 10.89–28.01) in Group A and 16.32 ± 6.52 × 10⁶/kg (range: 5.00–23.62) in Group B (P = 0.75). The average time to platelet engraftment also showed no significant difference (17 ± 6 days [range: 10–27] vs. 17 ± 9 days [range: 9–43]). No significant correlation was observed between CD34⁺ cell dose and engraftment time or transfusion volume (P > 0.05). As latest follow-up, post-transplant survival was 93.9% (31/33). No thrombotic events or severe hepatic or renal dysfunction occurred. Bone pain was the most common adverse event, with 35.5% (11/31) reporting Grade 1 and 6.5% (2/31) Grade 2 events per CTCAE 5.0 criteria. No major bleeding events were observed.

Conclusions：In patients with severe thalassemia receiving hetrombopag following haplo-HSCT, the mean platelet transfusion volume was 55 ± 29 U, and the mean time to platelet engraftment was 17 ± 7 days. A significant difference in transfusion volume between groups may have introduced bias in post-transplant outcome analysis. These findings suggest that relying solely on platelet engraftment time as a measure of engraftment efficacy may be inadequate and potentially limiting.

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2025
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