Increasing the dose of recombinant human thrombopoietin can enhance platelet engraftment after allogeneic haematopoietic stem cell transplantation: A NICHE cohort study

Successful platelet engraftment is crucial for assessing the reconstitution of the megakaryocyte lineage following allogeneic haematopoietic stem cell transplantation (allo-HSCT). 5%–37% of patients may experience delayed platelet engraftment or secondary thrombocytopenia, leading to an increased non-relapse mortality rate and a significant reduction in overall survival.¹ Multiple clinical studies have shown that the role of recombinant human thrombopoietin (rhTPO) in promoting platelet production in patients after transplantation for aplastic anaemia and myelodysplastic syndrome is significant and safe.^2-5 Furthermore, considering the unique dietary requirements of transplant patients and the gastrointestinal mucosal damage caused by preconditioning, we believe that the rhTPO injection has significant value for transplant patients compared to oral TPO-RA. The aforementioned studies mostly used a dose of 15 000 U/d of rhTPO for patient treatment, lacking in-depth discussion of the dosage of rhTPO. In this regard, we believe that designing an exploratory clinical study on the dosage of rhTPO is necessary, which may help to improve the treatment regimen of rhTPO.

We conducted a real-world observational study based on the NICHE cohort. Grouping was determined based on inclusion and exclusion criteria, with patients fully informed and their preferences respected. The study included 57 allo-HSCT patients (February–June 2023) receiving rhTPO from day 1 post-transplant. Patients are categorized into the experimental group (22 500 U/d) and the control group (15 000 U/d) based on the different dosages of rhTPO, to evaluate its efficacy and safety in promoting platelet engraftment following allo-HSCT and to further discuss whether this could benefit the overall care of patients.

Clinical characteristics are described in Table 1. Patients in both groups receiving rhTPO treatment had comparable clinical baseline information. There were no statistically significant differences between the two groups in terms of age, gender, height, weight, the composition of the primary diseases and pretransplant disease status (p > 0.05 for all comparisons). Additionally, in the analysis of transplant-related characteristics—such as transplant type, donor–recipient gender, donor age, conditioning regimen and the number of nucleated cells infused—no significant differences were observed between the two groups.

The dosage of 22 500 U/d of rhTPO is as safe as the 15 000 U/d dosage (Table S1). Five cases of bleeding events occurring after transplantation in both groups, mainly manifested as haemorrhagic cystitis. Each group had one thrombotic event, one case of left upper arm intermuscular venous thrombosis in the control group and one case of right upper arm PICC thrombosis in the experimental group. Compared with the control group, patients in the experimental group exhibited significantly fewer adverse events (46.7% vs. 76.7%, p = 0.013), mainly manifested as infectious diseases, and showed no significant difference in toxicity grading (Table S2).

Efficacy assessment indicated that the median platelet engraftment time for patients in the experimental group treated with 22 500 U/d rhTPO was 12 days, which is significantly better than that of the control group patients (z = 4.142, p = 0.042) (Figure 1A) and superior to the median time for promoting platelet engraftment after transplantation reported previously^{3, 4} with the control dose of rhTPO. It also shows a better effect in promoting platelet engraftment compared to eltrombopag.^{6, 7} Considering that prolonged rhTPO use may cause antibodies leading to secondary thrombocytopenia,^{8, 9} we extended the follow-up for patients and observed that the effect of rhTPO in promoting platelet engraftment is stable and sustained (Table S3). Analysing the time when patients achieved a platelet count of 30 × 10⁹/L, the experimental group showed a significantly faster recovery compared to the control group, with times of 13 (12 ~ 17) days and 16 (13 ~ 22) days, respectively, p = 0.047 (Figure 1C). Although statistical support is lacking once platelet levels reach 50 × 10⁹/L, this result suggests that high-dose rhTPO may be more sensitive in promoting the increase of low-level platelet, which may be related to changes in endogenous TPO levels as platelet reconstruction recovers.^10-12 The secondary failure of platelet engraftment (SFPR) in the experimental group was not significantly different from that in the control group, with rates of 14.8% versus 23.3% (z = 0.662, p = 0.416) (Table S4), we believe that increasing the therapeutic dosage of rhTPO can significantly promote rapid and stable platelet engraftment after allo-HSCT.

The recovery and reconstruction of haematopoietic and immune functions after allo-HSCT is a complex process, and a comprehensive assessment of the patient's post-transplant condition is necessary. The treatment group showed no inferiority to the control group in terms of myeloid lineage reconstruction speed, and even had an advantage (11 days vs. 12.5 days, z = 4.534, p = 0.033) (Figure 1B), with no difference observed in the duration of G-CSF usage (Table S4). All patients in both the experimental and control groups survived 1 year after transplantation, with 1-year relapse-free survival rates of 96.3% and 93.3%, respectively, showing no significant difference (p = 0.606). GVHD is the most common immune rejection reaction in transplant patients. In this study, the experimental group showed a lower cumulative incidence of moderate to severe aGVHD (14.8% vs. 40.0%, p = 0.043) (Figure 1D). Although this difference was not observed in cGVHD (Figure 1E), the latter is consistent with other previous reports.^{4, 12} There were no significant advantages or disadvantages between the two groups regarding post-transplant infection issues. In the cytomegalovirus analysis, there were 10 cases in the experimental group and seven in the control group. Similarly, no difference was observed in Epstein–Barr virus occurrence between the groups (2 vs. 7 cases). The analysis indicates that increasing the therapeutic dose of rhTPO does not affect the overall survival or transplant-related complications and may even reduce moderate to severe aGVHD while enhancing platelet engraftment.

Overall, this study is the first to confirm an observational cohort study that increasing the dose of rhTPO will benefit the overall care of patients. It helps to promote rapid and stable platelet engraftment after allo-HSCT, with a lower occurrence of moderate to severe aGVHD, and may even offer advantages in myeloid reconstruction without affecting transplant outcomes. This provides some evidence to support the improvement of clinical treatment plans. In addition, further multicentre, prospective, randomized controlled studies are needed to enhance the level of evidence.

ELJ designed the study; DF analysed the data and wrote the manuscript; QLM modified the article; QZL collected data and processed it; with assistance from HYG, YGC, XC, RLZ, WHZ, DLY, JLW, YH, AMP, SZF and MZH contributed to the enrolment of subjects; all authors approved the final draft of the manuscript. The authors declare no competing interests.

This work was supported by the National Natural Science Foundation of China (82070192, 82170217), the National Key Research and Development Program of China (2023YFC2508902), the Fundamental Research Funds for the Central Universities (3332023058), and the Tianjin Natural Science Foundation (23JCZXJC00220).

The authors declare no competing financial interests.

This project received approval from the IHCAMS Clinical Research Academic Committee and the IHCAMS Ethics Committee (IIT2021007-EC-1).

All patients provided informed consent for clinical information for scientific research at the time of first admission.

All cases were included in the National Longitudinal Cohort of Hematological Diseases (NICHE, NCT04645199).