Recombinant human thrombopoietin safety and efficacy in pediatric allogeneic hematopoietic stem cell transplantation: A cohort study

Abstract

BACKGROUND

The safety and efficacy of recombinant human thrombopoietin (rhTPO) administered after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children (0-9 years old) and adolescents (10-17 years old) with hematological disorders remain unclear.

AIM

To evaluate the safety and efficacy of rhTPO administered before platelet (PLT) engraftment in pediatric patients with hematological disorders undergoing HSCT, and to investigate its effects on the incidence of graft-vs-host disease (GVHD) and other transplant-related outcomes.

METHODS

This study enrolled 79 pediatric patients with hematological disorders who received rhTPO after allo-HSCT. The safety and tolerability of rhTPO were evaluated and compared in children (n = 36) and adolescents (n = 43) with hematological disorders. We also investigated the effects of rhTPO administration on the incidence of GVHD and other transplant-related outcomes. Additionally, we examined the efficacy of rhTPO after allo-HSCT in children and adolescents.

RESULTS

All of the children and adolescents underwent hematopoietic reconstruction. The median time to PLT engraftment was 16 days for all patients, with 14 (range, 11-24) days in the 0- to 9-year-old group and 16 (range, 11-41) days in the 10- to 17-year-old group; the difference was statistically significant (P < 0.05). The median time to neutrophil engraftment was 12 days in both groups. The median recovery times for PLT counts of ≥ 20 × 10⁹/L and ≥ 50 × 10⁹/L in the 0- to 9-year-old group were 10 (range, 2-20) and 11 (range, 2-20) days, respectively, and those for the 10- to 17-year-old group were 9 (range, 4-23) and 12 (range, 5-34) days, respectively. Children exhibited significantly shorter time to PLT engraftment (14 days vs 16 days) and shorter recovery time to PLT count ≥ 100 × 10⁹/L (16 days vs 18 days) (P < 0.05) than adolescents. The incidence of acute GVHD in all patients was 53.2%, with a higher incidence in children (61.1%) than in adolescents (46.5%). The incidence of chronic GVHD showed little difference between the two age groups, with an overall incidence of 10.1%. No adverse events, other than bleeding, were observed in either age group. The incidence of bleeding was 20.3%. The median follow-up time for all survivors was 573 days (range: 42-1803 days) after transplantation. At the final follow-up, 3 patients in the 0- to 9-year-old group died; however, none of these deaths were attributed to allo-HSCT or the use of rhTPO. All patients survived in the 10- to 17-year-old group.

CONCLUSION

rhTPO was not associated with any significant safety issues and was well tolerated by pediatric and adolescent patients with hematologic diseases who underwent allo-HSCT. Our results suggested that rhTPO may benefit allo-HSCT in children and adolescents by improving PLT recovery.

Key Words: Recombinant human thrombopoietin; Pediatric hematologic disorders; Allogeneic hematopoietic stem cell transplantation; Platelet engraftment; Graft-vs-host disease

Core Tip: This study evaluated the safety and efficacy of recombinant human thrombopoietin (rhTPO) in pediatric patients (0-17 years) undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). Results show that rhTPO is well tolerated and improves platelet (PLT) recovery, with shorter PLT engraftment times in children (0-9 years) compared to adolescents (10-17 years). The incidence of acute graft-vs-host disease was higher in children but less severe. No severe adverse events related to rhTPO were observed, supporting its safety and utility in pediatric allo-HSCT. This study provides foundational insights for further research in larger pediatric cohorts.

INTRODUCTION

Hematopoietic stem cell transplantation (HSCT) is a curative treatment for many hematological disorders, including aplastic anemia, myelodysplastic syndrome, and leukemia. HSCT is categorized into autologous HSCT and allogeneic HSCT (allo-HSCT). Particularly, allo-HSCT has shown substantial advantages in treating refractory or rapidly progressing hematological malignancies by replacing the damaged hematopoietic system and providing a graft-vs-leukemia effect[1]. However, allo-HSCT poses notable challenges, such as the risk of graft-vs-host disease (GVHD) and delayed immune reconstitution[2].

In pediatric patients, allo-HSCT is essential for the treatment of severe hematologic disorders[3]. The number of children and adolescents undergoing allo-HSCT continues to increase annually, reflecting its increasing importance in pediatric hematology[3]. At some centers, hundreds of pediatric patients with hematological diseases undergo allo-HSCT annually for severe aplastic anemia[4], thalassemia[5], and acute leukemia[3]. Despite its therapeutic benefits, allo-HSCT in children and adolescents is associated with unique challenges due to the ongoing development of their immune systems and higher susceptibility to complications[6,7].

A major complication of allo-HSCT in children and adolescents is delayed platelet (PLT) engraftment, in which PLT production remains insufficient, resulting in prolonged thrombocytopenia[8]. This condition increases the risk of bleeding, necessitates frequent PLT transfusions, and complicates posttransplant care. Although PLT transfusions are the standard treatment for thrombocytopenia, they are associated with risks, such as transfusion reactions, inefficacy, transfusion-related infections, and blood resource shortages[8,9]. Therefore, improving PLT engraftment after HSCT is critical in clinical research.

Thrombopoietin (TPO), a key cytokine that regulates megakaryocyte proliferation and maturation and PLT production, has emerged as a therapeutic agent for enhancing PLT recovery after HSCT. Recombinant human TPO (rhTPO) has shown promising results in improving PLT recovery in patients who underwent HSCT. However, the use of rhTPO in children and adolescents undergoing HSCT remains underexplored[10].

This study evaluated the safety and efficacy of rhTPO administered before PLT engraftment in pediatric patients with hematological disorders who underwent HSCT. We also investigated the effects of rhTPO administration on the incidence of GVHD and other transplant-related outcomes.

MATERIALS AND METHODS

Patient inclusion criteria

This study included patients with hematological diseases who underwent HSCT at the People’s Hospital of the Xinjiang Uygur Autonomous Region (Urumqi, China) between March 2019 and June 2022 in Xinjiang Uygur Autonomous Region. The diagnostic criteria for aplastic anemia were based on the current literature. The eligibility criteria were as follows: (1) Diagnosis of hematological disease; (2) Age < 18 years; (3) Voluntary participation in allo-HSCT; and (4) No TPO administration before transplantation. The exclusion criteria were as follows: (1) Exceeded values of serum urea nitrogen, creatinine, transaminase, and bilirubin (> 2.5 times the upper limit of normal subjects); (2) Cardiac insufficiency based on the New York Heart Association classification (> 2 grades); (3) Recent active bleeding; and (4) Poor compliance. In this study, the patients were divided into children (0-9 years old) and adolescents (10-17 years old)[11].

This study was approved by the Ethics Committee of the People’s Hospital of Xinjiang Uygur Autonomous Region (Approval No. XJS2018080701). All experimental procedures were performed in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from the parents of all patients.

Treatment protocol

Patients received subcutaneous injections of rhTPO (3SBio Group, Shenyang, China) at 300 U/kg/day on posttransplant days 3-6. During treatment, the administration of rhTPO was stopped when the PLT counts were high (PLT count ≥ 60 × 10⁹/L) for two consecutive evaluations (not on the same day), with the exclusion of the transient impacts of PLT transfusions.

A conditioning regimen was given based on the underlying disease, as follows: Thiotepa-busulfan-fludarabine + antithymocyte globulin (ATG) for patients with T-cell lymphoblastic lymphoma; fludarabine/cyclophosphamide (CY) + ATG for patients with Fanconi anemia; busulfan/CY + ATG, modified busulfan/CY + ATG or fludarabine/CY + ATG for patients with aplastic anemia: Busulfan/CY + ATG, modified busulfan/CY + ATG or thiotepa-busulfan-fludarabine + ATG for patients with leukemia, according to the proliferative degree of the bone marrow; and busulfan/CY + ATG for patients with PLT dysfunction.

All patients underwent bone marrow and peripheral blood SCT. The donor received 5 μg/kg recombinant granulocyte colony-stimulating factor subcutaneously once a day for 5 days from day 4 of preconditioning to mobilize the SCs. Bone marrow SCs were collected on the fourth day after SC mobilization, and peripheral blood SCs were collected on the fifth day. All the collected SCs were injected into the recipients on the day of collection. The ideal counts for mononuclear and CD34⁺ cells were (6-8) × 10⁸/kg and (1-3) × 10⁶/kg, respectively. If the target count was not reached, additional peripheral blood SCs were collected on day 6, and the recipient received these cells on the same day. GVHD prophylaxis was administered to all patients using methotrexate, mycophenolate morphenate, and cyclosporine.

A multidrug regimen was administered to prevent complications after allo-HSCT. Chloramphenicol and acyclovir eye drops were administered to prevent ocular infection. For oral infections, a solution of nystatin and sodium bicarbonate was used as mouth rinse. Cotrimoxazole was administered to prevent Pneumocystis jirovecii infection. Antifungal prophylaxis was administered with caspofungin or voriconazole. Acyclovir was administered to prevent viral infections; in cases of viral activation, the treatment was switched to ganciclovir. Alprostadil was used to prevent hepatic sinusoidal obstruction syndrome, and a combination of reduced glutathione and tiopronin was used to protect the liver and reduce transaminase levels.

Observation indicators and follow-up

The presence of an absolute neutrophil count > 0.5 × 10⁹/L for three consecutive days was regarded as neutrophil engraftment. PLT engraftment was defined as a PLT count > 20 × 10⁹/L for seven consecutive days without PLT transfusion. Follow-ups were conducted through outpatient or inpatient re-examinations and telephone communications. The final follow-up was conducted on August 5, 2024. Indicators, including PLT engraftment time, PLT transfusion dose, PLT recovery times (PLT count ≥ 20 × 10⁹/L, ≥ 50 × 10⁹/L, ≥ 100 × 10⁹/L), neutrophil engraftment time, occurrences of GVHD, infections, delayed PLT engraftment, secondary failure of PLT recovery, transplantation-related complications, and bleeding, were recorded during the follow-up. Disease recurrence and survival data were also obtained. Acute GVHD (aGVHD) and chronic GVHD (cGVHD) were diagnosed based on their standard criteria[12,13].

Statistical analyses

Continuous variables that were not normally distributed are presented as medians and ranges. χ² and Fisher’s exact probability tests were used to evaluate differences in categorical variables. The Mann-Whitney U test was used for continuous variables and GVHD grade comparisons. Analyses were performed using R software (version 4.1.0), and P < 0.05 indicated statistical significance.

RESULTS

Patient characteristics

Seventy-nine patients with transplant-eligible hematological diseases who met the inclusion criteria were enrolled, and all patients underwent their first transplantation. Of these, 36 were in the 0- to 9-year-old group, and 43 were in the 10- to 17-year-old group. The cohort included 8 patients with Fanconi anemia, 50 with aplastic anemia, 19 with leukemia, 1 with T-cell lymphoblastic lymphoma, and 1 with PLT dysfunction. The median age of the 79 patients was 10 years (range, 4-16 years). There were 39 males (49.4%) and 40 females (50.6%). Twenty-one patients underwent matched sibling donor HSCT, and 58 underwent haploidentical-HSCT. No statistically significant differences were observed between the two age groups in disease diagnosis, sex, transplantation type, donor type, matched HLA sites, or donor-recipient sex (Table 1).

Table 1 Characteristics of hematologic diseases patients in different age groups, n (%).

Variables	Total (n = 79)	0- to 9-year-old group (n = 36)	10- to 17-year-old group (n = 43)	P value
Age, years, median (range)	10 (4-16)	8 (4-9)	12 (10-16)	< 0.001
Disease diagnosis				0.307
Fanconi anemia	8 (10.1)	3 (8.3)	5 (11.6)
Aplastic anemia	50 (63.3)	27 (75.0)	23 (53.5)
Leukemia	19 (24.1)	6 (16.7)	13 (30.2)
T-cell lymphoblastic lymphoma	1 (1.3)	0	1 (2.3)
Platelet dysfunction	1 (1.3)	0	1 (2.3)
Sex				0.210
Male	39 (49.4)	15 (41.7)	24 (55.8)
Female	40 (50.6)	21 (58.3)	19 (44.2)
BMI, kg/m2, median (range)	16.5 (12.3-26.3)	15.6 (12.3-22.3)	17.1 (12.7-26.3)	0.004
Transplantation type				0.771
MSD-HSCT	21 (26.6)	9 (25.0)	12 (27.9)
Haplo-HSCT	58 (73.4)	27 (75.0)	31 (72.1)
Donor type				0.076
Siblings	50 (63.3)	19 (52.8)	31 (72.1)
Parents	29 (36.7)	17 (47.2)	12 (27.9)
Donor-recipient sex				0.477
Male to male	29 (36.7)	11 (30.6)	18 (41.9)
Male to female	32 (40.5)	18 (50.0)	14 (32.6)
Female to female	8 (10.1)	3 (8.3)	5 (11.6)
Female to male	10 (12.7)	4 (11.1)	6 (14.0)
HLA-matched				0.352
3/6	20 (25.3)	10 (27.8)	10 (23.3)
5/10	33 (41.8)	15 (41.7)	18 (41.9)
6/10	3 (3.8)	0	3 (7.0)
7/10	1 (1.3)	1 (2.8)	0
6/6	5 (6.3)	1 (2.8)	4 (9.3)
10/10	17 (21.5)	9 (25.0)	8 (18.6)
Mononuclear cell count, 108/kg, median (range)	15.9 (7.0-32.9)	17.0 (7.6-32.9)	14.3 (7.0-29.9)	0.251
CD34+ cell count, 106/kg, median (range)	6.2 (2.0-33.3)	7.3 (2.6-19.7)	5.1 (2.0-33.3)	0.071

BMI: Body mass index; Haplo-HSCT: Haploidentical-hematopoietic stem cell transplantation; HLA: Human leukocyte antigen; MSD-HSCT: Matched sibling donor-hematopoietic stem cell transplantation.

Neutrophil and PLT recovery

No cases of early death or graft failure occurred in either group, and engraftment was successful in all patients. The median time to PLT engraftment was 14 days (range, 11-24 days) in the 0- to 9-year-old group and 16 days (range, 11-41 days) in the 10- to 17-year-old group, with a statistically significant difference (P < 0.05) (Table 2). The median recovery time for PLT count ≥ 20 × 10⁹/L, ≥ 50 × 10⁹/L, and ≥ 100 × 10⁹/L in the 0- to 9-year-old group was 10 (range, 2-20), 11 (range, 2-20), and 16 (range, 3-88) days, respectively, and that in the 10- to 17-year-old group was 9 (range, 4-23), 12 (range, 5-34), and 18 (range, 5-76) days, respectively. The difference in recovery time for PLT count ≥ 100 × 10⁹/L between the two age groups was statistically significant (P < 0.05) (Table 2). PLT transfusion volumes were not significantly different between the two age groups (Table 2). Five cases of delayed PLT engraftment were observed in the 10- to 17-year-old group, and no cases of secondary failure of PLT recovery were observed.

Table 2 Neutrophil and platelet implantation of hematologic diseases in patients in different age groups.

Variables	Total (n = 79)	0- to 9-year-old group (n = 36)	10- to 17-year-old group (n = 43)	P value
Time to neutrophil engraftment, day, median (range)	12 (10-32)	12 (10-20)	12 (10-32)	0.082
Time to platelet engraftment, day, median (range)	16 (11-41)	14 (11-24)	16 (11-41)	0.017
Platelet transfusions, U, median (range)	14 (4-71)	13 (5-40)	15 (4-71)	0.057
Time to platelet recovery, day, median (range)
≥ 20 × 109/L	9 (2-23)	10 (2-20)	9 (4-23)	0.942
≥ 50 × 109/L	11 (2-34)	11 (2-20)	12 (5-34)	0.351
≥ 100 × 109/L	16 (3-88)	16 (3-88)	18 (5-76)	0.037
DPE, n (%)	2 (4.0)	0	5 (11.6)	0.059
SFPR, n (%)	0	0	0

DPE: Delayed platelet engraftment; SFPR: Secondary failure of platelet recovery.

The median and median change (median [Q1, Q3]) in PLT count after rhTPO treatment from baseline (PLT count at the beginning of rhTPO administration) in patients in different age groups are presented in Figure 1. After 23 and 16 days of treatment, PLT counts reached maximum values of 137 (58, 214) × 10⁹/L and 111 (46, 199) × 10⁹/L in the 0- to 9-year-old and 10- to 17-year-old groups, respectively. PLT counts began to increase after 2 days in both age groups, with a slow increase in the 0- to 9-year-old group and a decrease in the 10- to 17-year-old group beginning after 16 days of rhTPO treatment (Figure 1).

Figure 1 Median and median change of platelet after recombinant human thrombopoietin treatment from baseline in patients with hematological diseases in different age groups. A: Median platelet (PLT) over time; B: Median change of PLT from baseline. Data shown are median (Q1, Q3). Numbers under abscissa indicate time (day) after treatment with recombinant human thrombopoietin (rhTPO).

Transplant-related complications

Among the 79 patients, the incidence of aGVHD was 53.2% (42/79), with rates of 34.2% (27/79) for grades I-II and 19.0% (15/79) for grades III-IV. The incidence of aGVHD in the 0-9-year-old group and 10-17-year-old groups was 61.1% (22/36) and 46.5% (20/43), respectively, with no significant difference (P = 0.195) (Table 3). The differences in grades I and II-IV between the two groups were not statistically significant (P = 0.100). The incidence of cGVHD was 8.3% (3/36) in the 0- to 9-year-old group and 11.6% (5/43) in the 10- to 17-year-old group. In the 0- to 9-year-old group, 11 patients experienced cytomegalovirus (CMV) reactivation, with two cases progressing to CMV enteritis and 3 patients developing Epstein-Barr virus (EBV) reactivation. In the 10- to 17-year-old group, CMV reactivation was observed in 11 patients, with 1 case of CMV enteritis, and EBV reactivation occurred in 1 patient (Table 3).

Table 3 Transplantation-related complications of hematologic diseases in patients in different age groups, n (%).

Variables	Total (n = 79)	0- to 9-year-old group (n = 36)	10- to 17-year-old group (n = 43)	P value
aGVHD	42 (53.2)	22 (61.1)	20 (46.5)	0.195
I	16 (20.3)	11 (30.6)	5 (11.6)	0.1001
II	11 (13.9)	4 (11.1)	7 (16.3)
III	10 (12.7)	5 (13.9)	5 (11.6)
IV	5 (6.3)	2 (5.6)	3 (7.0)
cGVHD	8 (10.1)	3 (8.3)	5 (11.6)	0.721
Virus reactivation
CMV	22 (27.8)	11 (30.6)	11 (25.6)	0.623
EBV	4 (5.1)	3 (8.3)	1 (2.3)	0.326

¹The difference of I and II-IV between the two groups.

aGVHD: Acute graft-vs-host disease; cGVHD: Chronic graft-vs-host disease; CMV: Cytomegalovirus; EBV: Epstein-Barr virus.

Safety assessment and survival

The median duration of rhTPO treatment was 16 (range, 6-40 days) and 17 days (range, 6-76 days) for patients in the 0- to 9-year-old and 10- to 17-year-old groups, respectively. No adverse events, other than bleeding, were observed (Table 4). The incidence of bleeding was 19.4% (7/36) in the 0- to 9-year-old group and 20.9% (9/43) in the 10- to 17-year-old group, with no statistical difference between the two groups. The median follow-up period for all survivors was 573 days (range: 42-1803 days) posttransplantation. At the final follow-up on September 13, 2024, 3 patients in the 0- to 9-year-old group died, although none of the deaths were attributed to allo-HSCT or rhTPO. All patients survived in the 10- to 17-year-old group.

Table 4 Bleeding for hematologic diseases patients after recombinant human thrombopoietin treatment in different age groups, n (%).

Variables	Total (n = 79)	0- to 9-year-old group (n = 36)	10- to 17-year-old group (n = 43)	P value
Bleeding	16 (20.3)	7 (19.4)	9 (20.9)	0.870
Bleeding sites				0.891
Gastrointestinal tract	10 (12.7)	5 (13.9)	5 (11.6)
Bladder	3 (3.8)	1 (2. 8)	2 (4.7)
Mucosal and skin	1 (1.3)	0	1 (2.3)
Multiple sites	2 (2.5)	1 (2. 8)	1 (2.3)

rhTPO: Recombinant human thrombopoietin.

DISCUSSION

TPO, a physiological regulator of PLT production, activates numerous anti-apoptotic and cell maturation pathways by binding to the prothrombopoietin receptor c-Mpl. TPO receptors are not only expressed on megakaryocytes and PLTs but also at lower levels in CD34⁺ SCs and progenitor cells[14]. Pramono et al[15] found that TPO induces hematopoiesis and stimulates megakaryocyte growth, maturation, and PLT production through the bone morphogenetic protein 4 signaling pathway in mouse embryonic SCs. TPO has no storage form and directly enters the circulation, where it is cleared by binding to TPO receptors on megakaryocytes or PLTs. The transcription, translation, and release of TPO are not regulated by any substance[16]. Recombinant TPO was produced by culturing, isolating, and purifying Chinese hamster cells that contained a highly expressed human TPO gene. It is similar to natural TPO and is widely used in clinical practice[17].

Hematological diseases are a group of disorders characterized by abnormalities in blood cells or their production. Allo-HCT is an important curative treatment for patients with hematological diseases. However, the use of chemotherapy and radiation therapy during the preconditioning (or conditioning) process before allo-HSCT increases the risk of bleeding, particularly because of thrombocytopenia and coagulation abnormalities, which affect the outcome and prognosis[18]. The early use of rhTPO in patients with hematologic diseases promotes PLT recovery after allo-HSCT, reduces the degree of thrombocytopenia, and limits the risk of bleeding, thereby shortening the duration of thrombocytopenia. Tian et al[19] found that withholding rhTPO after allo-HSCT was associated with poor PLT implantation, an increased risk of bleeding, and longer hospital stay in patients with hematological malignancies. Fu et al[20] reported that patients with severe aplastic anemia who received rhTPO after haploidentical-HSCT had a significantly reduced number of infused PLTs and time of PLT engraftment compared with the group without rhTPO administration. Song et al[4] concluded that among patients with severe aplastic anemia treated with allo-HSCT, the recovery time of PLT count ≥ 50 × 10⁹/L (16.5 days vs 22 days) and ≥ 100 × 10⁹/L (23 days vs 28 days) and PLT transfusion volume (20 U vs 35 U) were lower in the group that received rhTPO than in the group that did not receive PLT. Due to the small number of cases, we were unable to draw conclusions regarding the effectiveness of rhTPO prior to PLT engraftment in pediatric patients with hematologic diseases. In addition, given the limited evidence in children and adolescents, these findings may not be directly comparable. However, compared with the results of Song et al[4] conducted among adults, our study showed that in both groups of children and adolescents, using rhTPO after allo-HSCT resulted in shorter recovery times for PLT counts ≥ 50 × 10⁹/L (11 days vs 16.5 days) and ≥ 100 × 10⁹/L (16 days vs 16.5 days) and lower PLT transfusion volume (14 U vs 20 U). This suggests the utility of rhTPO administration after HSCT in some pediatric patients with hematological diseases. However, it is worth noting that pediatric patients exhibited significantly shorter time to PLT engraftment and shorter recovery time for PLT count ≥ 100 × 10⁹/L than adolescent patients, indicating that rhTPO administration may have more of an advantage on allo-HSCT among pediatric patients with hematologic diseases.

GVHD remains a major obstacle in achieving successful allo-HSCT. Our results showed that although the incidence of aGVHD was slightly higher in 0-9-year-olds, it was less severe, with 50% of affected patients having grade I aGVHD compared with 25% of patients aged 10-17 years. The reasons for this may be as follows. First, the immune system of children is not fully developed, and their immune response to donor cells may be more sensitive[21,22], resulting in a slightly higher incidence of aGVHD than in adolescents. However, because children’s immune regulation is relatively weak, their inflammatory response may be less intense than that of adolescents; therefore, aGVHD is milder in severity[23]. Second, tissue antigen expression and immunomodulatory mechanisms in children are different from those in adolescents, rendering children potentially more susceptible to immune-mediated responses but also able to progress more quickly into a “tolerance” state that reduces the severity of aGVHD[23-25]. In addition, donor source and pretreatment regimen before transplantation may affect the incidence and severity of aGVHD[26]. Finally, children have a rapid rate of immune rebuilding after transplantation, which may help alleviate aGVHD symptoms after allo-HSCT.

In our study on children and adolescents, the incidence of aGVHD was higher (53.2%) than that of cGVHD (10.1%). Song et al[4] performed allo-HSCT in 85 adult patients with severe aplastic anemia and found a 34.1% incidence of aGVHD and 22.4% incidence of cGVHD. Severity or disease status before transplantation has not been widely recognized as a contributor to the development of cGVHD. Research has indicated that the immune response following transplantation is more critical in the development of cGVHD than in preexisting disease[27,28]. The difference in cGVHD incidence may indicate that younger age is advantageous in reducing cGVHD after allo-HSCT[29,30]. The immune systems of children are not fully developed, and after receiving HSCT, they may recognize and respond to donor cells differently than adults. In general, young children are at a relatively high risk of developing aGVHD[31], whereas the incidence of cGVHD may be lower in young children than in adults[32]. This may be related to the plasticity and resilience of the immune system in children[33]. Regardless of the GVHD grade, none of the patients discontinued the use of rhTPO, and no pediatric patients died owing to GVHD.

Patients with posttransplantation immunodeficiency are more likely to experience viral reactivation. In our study, the incidence of CMV infection was 30.6% in the 0-9-year-old group and 25.6% in the 10-17-year-old group, rates similar to other studies[34,35]. We observed only four cases (5.1%) of EBV reactivation in all children and adolescents, and none of them had developed EBV-related posttransplant lymphoproliferative disorders by the end of follow-up. Some studies have suggested that younger children have a higher incidence of aGVHD, leading to increased rates of CMV reactivation, whereas adolescents experience different patterns of viral infection because of their more mature immune systems[36]. However, the incidence of CMV and EBV infections did not significantly differ between children and adolescents.

No severe adverse reactions, such as liver or kidney toxicity, allergies, or thrombosis-related complications, were observed in either the pediatric or adolescent groups. In our study, only mild or moderate bleeding events occurred, which resolved independently or with symptomatic treatments. Previous studies explored the safety of rhTPO in pediatric patients after allo-HSCT. Our study achieved results similar to those in adults[20,37-39], indicating that the use of rhTPO is safe in pediatric patients with hematologic diseases, including GVHD and viral infection, after allo-HSCT. These findings support the safety and tolerability of rhTPO for allo-HSCT in children and adolescents who have undergone transplantation. Notably, the limitations of this study include the absence of a control group and the single-center nature of the analysis. Larger and more diverse studies involving multiple centers are warranted to confirm our findings.

CONCLUSION

Our results demonstrated that rhTPO was not associated with any significant safety issues and was well tolerated by pediatric and adolescent patients with hematologic diseases who underwent allo-HSCT. Our results suggest that rhTPO administration may be beneficial in this population. Additionally, our study provides a foundation for further exploration of the efficacy of rhTPO in pediatric patients with hematological diseases using larger sample sizes.