Background Bone marrow failure disease (BMFD) arises from congenital or acquired hematopoietic stem cell dysfunction, characterized by cytopenias of one or more lineages. Although immunotherapy benefits certain subtypes, allogeneic hematopoietic stem cell transplantation (allo-HCT) remains the most effective intervention. Hematopoietic recovery typically occurs within three weeks post-transplant, yet 5–26% of patients experience delayed platelet engraftment (DPE), which elevates severe bleeding risk and compromises long-term survival. To date, no standard treatment and prevention has been recommended for DPE. Besides, BMFD patients are more likely to suffer from DPE due to abnormalities in the bone marrow microenvironment. Therefore, enhancing hematopoietic reconstruction post HCT is clinically critical for BMFD patients.

Objective The study aimed to promote engraftment, reduce the incidence of DPE, and ultimately improve long-term survival in BMFD patients undergoing allo-HCT.

Methods We initiated a prospective, multicenter, randomized controlled clinical trial across China (ClinicalTrials.gov Identifier: NCT05466201). Eligible BMFD patients (age 12-65 years) were randomly assigned (1:1) to eltrombopag group or supportive care group after HCT. Those assigned to eltrombopag group received eltrombopag at the dose of 50 mg/d orally from day +1 post allo-HCT, and the dose will be titrated by 25 mg every 7 days up to 100 mg/d according to the tolerability. The patients assigned to the other group received best supportive care, rather than recombinant human thrombopoietin or thrombopoietin receptor agonists. The primary endpoint was the proportion of platelet engraftment (platelet count > 20×109/L in consecutive 7 days without platelet transfusion in the prior 7 days) on days +35 post allo-HCT. Secondary endpoints included neutrophil engraftment, hematopoietic reconstruction time, and overall survival (OS). The last follow-up in this study was conducted between May 1st and July 31st, 2025.

Results From October 2022 to May 2025, 120 patients were screened. Two died early (<7 days post-HCT) and were excluded, leaving 118 for analysis (59 participants per group). Baseline characteristics were balanced: median ages were 44 (IQR 34–54) and 42 (IQR 26–53) years (p=0.323), with comparable disease distributions (hypoplastic myelodysplastic syndromes, severe aplastic anemia, paroxysmal nocturnal hemoglobinuria, et al.) and donor types (haploidentical: 78.0% vs. 76.3%; matched unrelated: 8.5% vs. 11.9%; matched sibling: 13.6% vs. 11.9%; p=0.814). The median count for CD34+ cells was 5.4 (IQR 3.8-6.4) ×106/kg in the eltrombopag group and 5.0 (IQR 4.0-6.5) ×106/kg in the supportive care group (p=0.648). The incidence of platelet engraftment on days +35 after allo-HCT was 95.0% in the eltrombopag group and 83.1% in the supportive care group (hazard ratio (HR), 1.864; 95% confidence interval, 95% CI, 1.266-2.744; p=0.002). The median time of platelet engraftment was 13 days in eltrombopag group and 15 days in supportive care group, with HR 1.483, 95% CI, 1.004-2.191 (p=0.035). All of the patients achieved neutrophil engraftment before days +35, with an accelerated recovery in eltrombopag group, HR 1.444; 95% CI, 1.002- 2.080 (p=0.047). Eltrombopag significantly improved the OS of BMFD patients post HCT with a 1-year OS of 85.2% vs 67.7%, and a 2-year OS of 79.4% vs 66.0%, HR 0.469, 95% CI, 0.220-0.998, p=0.044. Interestingly, we observed that despite similar pre-transplant serum ferritin levels and comparable post-transplant blood product transfusion, the eltrombopag group exhibited a significantly milder elevation of serum ferritin by days +21 after HCT, 1627.0 (IQR 937.6-2143.7) ng/mL in eltrombopag group vs 2015.4 (IQR 1331.5-3123.7) ng/mL for supportive care group, p=0.0004. Acute/chronic graft versus host disease and CMV/EBV infections did not differ between the two groups. All the treatment-related adverse events were of grade 1 or 2 and transient.

Conclusion Eltrombopag accelerated the hematopoietic engraftment of BMFD patients post allo-HCT, and improved the overall survival of them notably.

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2025
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