Abstract
Hetrombopag, a novel thrombopoietin receptor agonist (TPO-RA), has demonstrated efficacy in adult patients with aplastic anemia (AA), but its role in pediatric AA patients remains unknown. This study evaluated the safety, pharmacokinetic (PK) profile, and preliminary efficacy of hetrombopag in pediatric AA. This pilot study enrolled pediatric patients with AA who were ineligible for hematopoietic stem cell transplantation. Patients received hetrombopag in combination with immunosuppressive therapy. Safety, PK parameters, and hematologic response (HR) rates at 3 and 6 months were analyzed. A total of 21 pediatric patients were enrolled, including six patients aged 1–5 years, nine patients aged 6–11 years, and six patients aged 12–17 years. Among them, 18 patients had severe AA and 3 had non-severe AA. The most common treatment-related adverse events were transaminase increased (33.3%) and blood bilirubin increased (14.3%). PK analysis revealed age-dependent variability, with the 6–11-year cohort exhibiting the highest inter-individual variability and excessive plasma drug exposure. Among patients with SAA, as defined by the Chinese guideline criteria, the HR rate at 3 months was 55.6% (10/18; 95% CI: 21.5–69.2), and the complete response (CR) rate was 5.6% (1/18; 95% CI: 0.1–27.3). By 6 months, the HR rate had increased to 72.2% (13/18; 95% CI: 46.5–90.3), and the CR rate to 22.2% (4/18; 95% CI: 6.4–47.6). Hetrombopag, in combination with IST, demonstrated a favorable safety profile, preliminary efficacy, and age-dependent PK variability in pediatric AA. These findings support further investigation into individualized dosing strategies to optimize therapeutic outcomes in this population. The trial was registered prospectively at the Chinese Clinical Trial Registry (ChiCTR2300068312) on February 14, 2023.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1007/s00277-026-07088-9.
Keywords: Aplastic anemia, Pediatric hematology, Thrombopoietin receptor agonist, Hetrombopag, Pharmacokinetics
Introduction
Aplastic anemia (AA) is a rare and potentially life-threatening bone marrow failure disorder characterized by pancytopenia due to impaired hematopoiesis [1]. Based on severity, AA is classified as severe aplastic anemia (SAA), very severe aplastic anemia (VSAA), or non-severe aplastic anemia (NSAA) [2]. Epidemiological studies indicate a higher incidence of AA in Asian populations compared to Western countries [3]. Current treatment strategies for AA primarily include hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) [4, 5]. HSCT remains the preferred curative approach for SAA [4]; however, its widespread clinical application is limited by donor availability and the risks of graft-versus-host disease and severe infections [6]. For patients without a suitable donor, IST represents the standard first-line therapy [7]. However, IST is associated with substantial limitations, including a relapse rate of approximately 40% and primary treatment resistance in nearly 30% of patients [8]. These therapeutic gaps highlight the urgent need for novel treatment options for patients who are ineligible for HSCT or refractory to IST. Furthermore, NSAA presents with a highly heterogeneous clinical course, ranging from indolent to progressive disease [9]. The optimal therapeutic approach for early-stage NSAA remains unclear, necessitating further investigation into alternative treatment strategies [10].
In recent years, thrombopoietin receptor agonists (TPO-RAs) have emerged as a promising therapeutic strategy for AA, demonstrating significant potential in enhancing hematologic recovery [11]. These agents function by binding to the TPO receptor on hematopoietic stem and progenitor cells, thereby activating key intracellular signaling pathways, including STAT, PI3K, and ERK [12]. This activation promotes hematopoietic stem cell proliferation and differentiation while stimulating platelet production [13]. Multiple studies have shown that the combination of TPO-RAs with IST can substantially improve response rates in patients with SAA, enhance hematopoietic function, and maintain a favorable safety profile [14–17]. Consequently, IST in combination with TPO-RAs is increasingly recognized as an effective first-line treatment option for patients with SAA who are ineligible for HSCT [11].
Hetrombopag is a novel, non-peptide small-molecule TPO-RA [18]. A phase II study in adult patients with SAA refractory to IST showed that hetrombopag effectively improved hematologic responses (HR) while maintaining a favorable safety profile [19]. Based on these findings, the Chinese National Medical Products Administration (NMPA) has approved hetrombopag for the treatment of adult SAA patients unresponsive to IST [18]. Furthermore, a prospective study indicated that the combination of hetrombopag with IST as a first-line treatment significantly enhanced HR rates and shortened response time compared to IST alone [16]. Despite these advances, the efficacy, safety, and pharmacokinetics (PK) of hetrombopag in pediatric AA patients remain unexplored. This study aims to evaluate the safety profile, PK characteristics and preliminary efficacy of hetrombopag in pediatric AA.
Methods
Study design and patients
This pilot study was conducted at the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Patients were required to be younger than 18 years and either ineligible for or unwilling to undergo HSCT. Patients had to fulfill at least two of the following hematologic parameters: hemoglobin concentration < 100 g/L, platelet count < 100 × 10⁹/L, or absolute neutrophil count (ANC) < 1.5 × 10⁹/L. If only two hematopoietic lineages were affected, thrombocytopenia was mandatory for inclusion. Participants were also required to have no prior exposure to TPO-RAs within one week before enrollment and an Eastern Cooperative Oncology Group performance status (ECOG PS) score of ≤ 2. Exclusion criteria encompassed patients with primary myelodysplastic syndrome, primary paroxysmal nocturnal hemoglobinuria, leukemia, or congenital bone marrow failure syndromes, including Fanconi anemia and dyskeratosis congenita. In this study, SAA was defined as bone marrow cellularity between 25 and 50% with residual hematopoietic cells comprising less than 30%, or overall marrow cellularity below 25%, accompanied by at least two of the following peripheral blood criteria: (1) ANC < 0.5 × 10⁹/L; (2) platelet count < 20 × 10⁹/L; and (3) reticulocyte count < 20 × 10⁹/L or corrected reticulocyte percentage < 1%.
The study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Ethics Committee of the Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College. Written informed consent was obtained from all participants and their legal guardians before study initiation. The trial was registered prospectively at the Chinese Clinical Trial Registry (ChiCTR2300068312).
Procedure
Eligible patients were assigned into treatment cohorts based on age and subsequently received hetrombopag. For patients aged 1–5 years, the initial dose was 0.15 mg/kg/day, with sequential escalation to 0.2 mg/kg/day, 0.25 mg/kg/day, and 0.3 mg/kg/day, each administered for 7 consecutive days before dose escalation. In the 6–11-year age group, the initial dose was 7.5 mg/day, increasing to 10 mg/day, 12.5 mg/day, and 15 mg/day, with each dose level maintained for 7 consecutive days before escalation. For patients aged 12–17 years, treatment commenced at 7.5 mg/day and increased to 15 mg/day after 7 days of continuous therapy. In the 1–5-year cohort, the administered dose was adjusted based on body weight, with a minimum divisible dose of one-quarter of a tablet (0.625 mg). Patients unable to swallow tablets received hetrombopag with a single drop of purified water applied to the tablet surface to facilitate softening before oral administration. In addition to hetrombopag, all patients received IST as per investigator discretion.
PK assessments were performed at both the initial and highest maintenance dose levels. Blood samples (2 mL per collection) were obtained on day 1 (at 2 h and 6 h post-administration) and on day 7 (within 30 min before dosing). Plasma was extracted from collected samples and analyzed using a validated liquid chromatography-tandem mass spectrometry (LC–MS/MS) method to determine drug concentration profiles.
Endpoints
The primary endpoint of this study was to determine the recommended dose of hetrombopag for the treatment of pediatric AA. Key assessments included PK parameters, such as the area under the concentration–time curve from time zero to 24 h (AUC₀₋₂₄), maximum plasma concentration (Cmax), and time to maximum concentration (Tmax), as well as safety outcomes, including the incidence and severity of treatment-related adverse events (TRAEs). Efficacy endpoints included HR and complete response (CR) rates. HR was defined as meeting any of the following criteria: (1) Platelet response: an increase in platelet count of at least 20 × 10⁹/L from baseline or achievement of transfusion independence for 8 weeks in previously transfusion-dependent patients; (2) Neutrophil response: an increase in the ANC of at least two fold from baseline or an increase of more than 0.5 × 10⁹/L; alternatively, for patients dependent on the use of granulocyte colony-stimulating factor (G-CSF) at enrollment, a response was defined as maintaining at least one week without requiring G-CSF administration; and (3) Erythroid response: an increase in hemoglobin concentration of at least 15 g/L from baseline or transfusion independence for at least one week in previously transfusion-dependent patients. CR was defined as fulfilling all three hematologic response criteria simultaneously.
Statistical analysis
This study is an exploratory analysis with no pre-specified hypothesis testing, with a planned minimum enrollment of six patients per age group. Safety analyses were conducted in the safety set (SS), comprising all patients who receive at least one dose of the study drug. Efficacy analyses were performed in the full analysis set (FAS), which includes all patients who receive treatment. Continuous variables were summarized using the median and range, and categorical variables were presented as counts and percentages. HR rates at 3 and 6 months were reported with their corresponding 95% confidence intervals (CIs), calculated using the Clopper-Pearson method. All statistical analyses were conducted using SAS version 9.4 or later and PK parameters were derived using Phoenix WinNonlin 8.1
Results
Baseline characteristics of patients
Between February 2023 and November 2023, 21 pediatric patients with AA were enrolled in the study, all of whom were included in both the FAS and the SS population (Figure S1). Of the enrolled patients, 13 (61.9%) were male and 8 (38.1%) were female. The median age at enrollment was 8 years (range: 3–17 years). The median BMI was 14.6 kg/m2 (range: 13.6–16.2) in patients aged 1–5 years, 16.5 kg/m2 (range: 13.1–23.1) in those aged 6–11 years, and 19.6 kg/m2 (range: 14.9–29.4) in the 12–17-year cohort. At baseline, 15 (71.4%) patients had an ECOG PS of 0, while 6 (28.6%) had an ECOG score of 1. The majority of patients (85.7%, n = 18) were diagnosed with SAA, and 3 (14.3%) had NSAA. Notably, 20 patients (95.2%) were transfusion-dependent before treatment initiation.
In patients with SAA, baseline platelet and hemoglobin values were collected post-enrollment and may have been affected by recent transfusions. The median ANC was 0.67 × 10⁹/L (range: 0.01–16.14), the median reticulocyte count was 19.9 × 10⁹/L (range: 3.3–95.4), the median platelet count was 17.0 × 10⁹/L (range: 2.0–106.0), and the median hemoglobin concentration was 64.5 g/L (range: 33.0–90.0). In patients with NSAA, the median ANC was 0.63 × 10⁹/L (range: 0.58–0.65), the median reticulocyte count was 52.5 × 10⁹/L (range: 32.3–81.5), the median platelet count was 19.0 × 10⁹/L (range: 7.0–23.0), and the median hemoglobin level was 55.0 g/L (range: 48.0–97.0) (Table 1).
Table 1.
Baseline characteristics of patients
| Variables | All (n = 21) |
|---|---|
| Age (years), median (range) | 8 (3–17) |
| Sex, n (%) | |
| Male | 13 (61.9) |
| Female | 8 (38.1) |
| BMI (kg/m2), median (range) | |
| 1–5 years | 14.6 (13.6–16.2) |
| 6–11 years | 16.5 (13.1–23.1) |
| 12–17 years | 19.6 (14.9–29.4) |
| ECOG PS, n (%) | |
| 0 | 15 (71.4) |
| 1 | 6 (28.6) |
| Severity, n (%) | |
| SAA | 18 (85.7) |
| NSAA | 3 (14.3) |
| Absolute neutrophil count (× 109/L), median (range) | |
| SAA | 0.67 (0.01–16.14) |
| NSAA | 0.63 (0.58–0.65) |
| Reticulocyte count (× 109/L), median (range) | |
| SAA | 19.9 (3.3–95.4) |
| NSAA | 52.5 (32.3–81.5) |
| Platelet count (× 109/L), median (range) | |
| SAA | 17.0 (2.0–106.0) |
| NSAA | 19.0 (7.0–23.0) |
| Hemoglobin (g/L), median (range) | |
| SAA | 64.5 (33.0–90.0) |
| NSAA | 55.0 (48.0–97.0) |
| Transfusion dependence, n (%) | 20 (95.2) |
BMI: body mass index; ECOG PS: Eastern Cooperative Oncology Group performance status; SAA: severe aplastic anemia; NSAA: non-severe aplastic anemia
Safety
Among the 21 patients who received treatment, 12 (57.1%) experienced TRAEs, with one patient (4.8%) developing a grade 3 TRAE. In the 1–5-year cohort, four patients (66.7%) experienced TRAEs, including one case of grade 3 transaminase increased. In the 6–11-year cohort, TRAEs were reported in five patients (55.6%), with no grade 3 or higher events. Similarly, in the 12–17-year cohort, three patients (50.0%) developed TRAEs, none of which were grade 3 or higher. The most frequently reported TRAEs were transaminase increased (33.3%) and blood bilirubin increased (14.3%) (Table 2). No treatment-related deaths or adverse events leading to discontinuation were recorded.
Table 2.
TRAE
| Events, n (%) | 1–5 (n = 6) | 6–11 (n = 9) | 12–17 (n = 6) | All (n = 21) | ||||
|---|---|---|---|---|---|---|---|---|
| Any grade | Grade 3 | Any grade | Grade 3 | Any grade | Grade 3 | Any grade | Grade 3 | |
| With any TRAE | 4 (66.7) | 1 (16.7) | 5 (55.6) | 0 | 3 (50.0) | 0 | 12 (57.1) | 1 (4.8) |
| Transaminase increased | 2 (33.3) | 1 (16.7) | 2 (22.2) | 0 | 3 (50.0) | 0 | 7 (33.3) | 1 (4.8) |
| Blood bilirubin increased | 2 (33.3) | 0 | 1 (11.1) | 0 | 0 | 0 | 3 (14.3) | 0 |
| Nausea | 0 | 0 | 1 (11.1) | 0 | 1 (16.7) | 0 | 2 (9.5) | 0 |
| Hypokalemia | 0 | 0 | 1 (11.1) | 0 | 0 | 0 | 1 (4.8) | 0 |
| Hyperuricemia | 0 | 0 | 0 | 0 | 1 (16.7) | 0 | 1 (4.8) | 0 |
| Vomiting | 0 | 0 | 0 | 0 | 1 (16.7) | 0 | 1 (4.8) | 0 |
| Upper respiratory tract infection | 0 | 0 | 1 (11.1) | 0 | 0 | 0 | 1 (4.8) | 0 |
| Renal impairment | 0 | 0 | 0 | 0 | 1 (16.7) | 0 | 1 (4.8) | 0 |
| Gastrointestinal inflammation | 0 | 0 | 0 | 0 | 1 (16.7) | 0 | 1 (4.8) | 0 |
| Blood lactate dehydrogenase increased | 1 (16.7) | 0 | 0 | 0 | 0 | 0 | 1 (4.8) | 0 |
TRAE: treatment-related adverse event
Pharmacokinetics
All enrolled patients underwent PK assessments. In the 1–5-year cohort, the highest administered dose of hetrombopag was 0.3 mg/kg/day, yielding a median plasma concentration of 163.4 ng/mL (range: 7.2–262.7). In the 6–11-year cohort, at the highest administered dose of 15 mg/day, the median plasma concentration was 366.0 ng/mL (range: 120.4–1340.8), with similar values observed among SAA patients. In the 12–17-year cohort, also receiving a maximum dose of 15 mg/day, the median plasma concentration was 90.3 ng/mL (range: 25.4–342.3) (Table S1).
At the initial dose level, the geometric mean AUC₀₋₂₄ was 1,289.8 ng·h/mL (geometric coefficient of variation [GeoCV%]: 109.2) in the 1–5-year cohort, 905.8 ng·h/mL (GeoCV%: 78.0) in the 6–11-year cohort, and 3,010.7 ng·h/mL (GeoCV%: 78.8) in the 12–17-year cohort. The geometric mean Cmax was 69.7 ng/mL (GeoCV%: 104.4) in the 1–5-year cohort, 50.6 ng/mL (GeoCV%: 54.1) in the 6–11-year cohort, and 141.6 ng/mL (GeoCV%: 74.7) in the 12–17-year cohort. The median Tmax was 3.5 h (range: 3.0–5.0), 4.5 h (range: 4.0–6.0), and 5.0 h (range: 4.0–13.0) in the respective age cohorts.
At the highest dose level, the geometric mean AUC₀₋₂₄ increased to 3,184.5 ng·h/mL (GeoCV%: 123.0) in the 1–5-year cohort, 2,357.2 ng·h/mL (GeoCV%: 97.1) in the 6–11-year cohort, and 9,882.9 ng·h/mL (GeoCV%: 105.6) in the 12–17-year cohort. The geometric mean Cmax was 161.4 ng/mL (GeoCV%: 116.4) in the 1–5-year cohort, 126.2 ng/mL (GeoCV%: 67.9) in the 6–11-year cohort, and 446.3 ng/mL (GeoCV%: 96.7) in the 12–17-year cohort. The median Tmax values at the highest dose level remained consistent with those observed at the initial dose, with values of 3.5 h (range: 3.0–5.0), 4.5 h (range: 4.0–6.0), and 5.0 h (range: 4.0–13.0) across the respective age cohorts (Table 3).
Table 3.
Pharmacokinetic parameters
| Variables | Initial dose | Highest dose | ||||
|---|---|---|---|---|---|---|
| 1–5 (n = 6) | 6–11 (n = 9) | 12–17 (n = 6) | 1–5 (n = 6) | 6–11 (n = 9) | 12–17 (n = 6) | |
| AUC0–24, ng·h/mL | ||||||
| Geomean (GeoCV%) | 1,289.8 (109.2) | 905.8 (78.0) | 3,010.7 (78.8) | 3,184.5 (123.0) | 2,357.2 (97.1) | 9,882.9 (105.6) |
| Median | 1,404.5 | 1,207.7 | 3,727.0 | 3,461.3 | 3,569.2 | 7,703.7 |
| Cmax, ng/mL | ||||||
| Geomean (GeoCV%) | 69.7 (104.4) | 50.6 (54.1) | 141.6 (74.7) | 161.4 (116.4) | 126.2 (67.9) | 446.3 (96.7) |
| Median | 81.7 | 59.1 | 159.4 | 172.9 | 169.0 | 365.6 |
| Tmax, h | ||||||
| Median (range) | 3.5 (3.0–5.0) | 4.5 (4.0–6.0) | 5.0 (4.0–13.0) | 3.5 (3.0–5.0) | 4.5 (4.0–6.0) | 5.0 (4.0–13.0) |
Initial dose: 0.15 mg/kg/day for patients aged 1–5 years, 7.5 mg/day for those aged 6–11 years, and 7.5 mg/day for those aged 12–17 years. Highest dose: 0.3 mg/kg/day for patients aged 1–5 years, and 15 mg/day for those aged 6–11 and 12–17 years
AUC₀₋₂₄: area under the concentration–time curve from time zero to 24 h; GeoCV%: geometric coefficient of variation percentage; Cmax: maximum plasma concentration; Tmax: time to maximum plasma concentration
Efficacy
Among the 21 patients treated with hetrombopag, one patient discontinued treatment before the assessment at 3 months due to a switch to another TPO-RA treatment, and two patients discontinued before the assessment at 6 months to undergo HSCT. The HR rate at 3 months was 95.2% (20/21; 95% CI: 76.2–99.9), while the CR rate was 52.4% (11/21; 95% CI: 29.8–74.3). At 6 months, the HR rate was 81.0% (17/21; 95% CI: 58.1–94.6), while the CR rate remained at 47.6% (10/21; 95% CI: 25.7–70.2). The median time to first hematologic response was 57.0 days (interquartile range [IQR]: 47.0–61.0). At 3 months, response rates were 85.7% for hemoglobin, 71.4% for neutrophils, and 71.4% for platelets, with corresponding rates at 6 months of 66.7%, 76.2%, and 57.1%, respectively (Fig. 1). Red blood cell transfusion independence was achieved by 82.4% (14/17) of previously transfusion-dependent patients at 3 months and 6 months, while platelet transfusion independence was attained by 65.0% (13/20) at 3 months and 55.0% (11/20) at 6 months.
Fig. 1.
Hematologic response rate at (A) month 3 and (B) month 6
Among patients with SAA (n = 18), the HR rate was 94.4% at 3 months and 83.3% at 6 months, while the CR rate remains at 55.6%. In contrast, among the three patients with NSAA, all received treatment for at least 3 months, and two completed 6 months of therapy. At 3 months, the HR rate was 100% (3/3) and the CR rate was 33.3% (1/3). One patient discontinued hetrombopag after 3 months to undergo hematopoietic stem cell transplantation. At 6 months, the HR rate was 66.7% (2/3), and no patients achieved CR. In the 1–5-year group (n = 6), the HR rate remained 100.0% at both 3 and 6 months, while the CR rate were 50.0% and 16.7%. Among the 6–11-year group (n = 9), the HR rate was 88.9% at 3 months and 55.6% at 6 months, with a stable CR rate of 44.4% at both time points. In the 12–17-year cohort (n = 6), the HR rate remained 100.0% at both time points, with the CR rate increasing from 66.7% to 83.3%. Patients with ECOG PS of 0 (n = 15) had HR rates of 93.3% at 3 months and 80.0% at 6 months, while CR rates declined from 53.3% to 40.0%. Patients with ECOG PS of 1 (n = 6) exhibited a 100.0% HR rate at 3 months and 83.3% at 6 months, while the CR rate improved from 50.0% to 66.7%. Among male patients (n = 13), the HR rate was 100.0% at 3 months and 84.6% at 6 months, with CR rates increasing from 46.2% to 53.8%. Among female patients (n = 8), the HR rate was 87.5% at 3 months and 75.0% at 6 months, while the CR rate was 62.5% and 37.5%, respectively (Table 4).
Table 4.
Hematologic response rate
| Outcomes | 3 months | 6 months |
|---|---|---|
| All (n = 21) | ||
| HR | 20 (95.2) [76.2–99.9] | 17 (81.0) [58.1–94.6] |
| CR | 11 (52.4) [29.8—74.3] | 10 (47.6) [25.7–70.2] |
| 1–5 (n = 6) | ||
| HR | 6 (100.0) [54.1–100.0] | 6 (100.0) [54.1–100.0] |
| CR | 3 (50.0) [11.8—88.2] | 1 (16.7) [0.4–64.1] |
| 6–11 (n = 9) | ||
| HR | 8 (88.9) [51.8—99.7] | 5 (55.6) [21.2–86.3] |
| CR | 4 (44.4) [13.7–78.8] | 4 (44.4) [13.7–78.8] |
| 12–17 (n = 6) | ||
| HR | 6 (100.0) [54.1–100.0] | 6 (100.0) [54.1–100.0] |
| CR | 4 (66.7) [22.3–95.7] | 5 (83.3) [35.9–99.6] |
| SAA (n = 18) | ||
| HR | 17 (94.4) [72.7–99.9] | 15 (83.3) [58.6–96.4] |
| CR | 10 (55.6) [30.8–78.5] | 10 (55.6) [30.8–78.5] |
| NSAA (n = 3) | ||
| HR | 3 (100.0) [29.2–100.0] | 2 (66.7) [9.4–99.2] |
| CR | 1 (33.3) [0.8–90.6] | 0 (0) [0–70.8] |
| ECOG PS = 0 (n = 15) | ||
| HR | 14 (93.3) [68.1—99.8] | 12 (80.0) [51.9–95.7] |
| CR | 8 (53.3) [26.6—78.7] | 6 (40.0) [16.3–67.7] |
| ECOG PS = 1 (n = 6) | ||
| HR | 6 (100.0) [54.1–100.0] | 5 (83.3) [35.9–99.6] |
| CR | 3 (50.0) [11.8–88.2] | 4 (66.7) [22.3–95.7] |
| Male (n = 13) | ||
| HR | 13 (100.0) [75.3—100.0] | 11 (84.6) [54.6–98.1] |
| CR | 6 (46.2) [19.2—74.9] | 7 (53.8) [25.1–80.8] |
| Female (n = 8) | ||
| HR | 7 (87.5) [47.3–99.7] | 6 (75.0) [34.9–96.8] |
| CR | 5 (62.5) [24.5–91.5] | 3 (37.5) [8.5–75.5] |
Data were presented as n (%) [95%CI]
HR: hematologic response; CR: complete response; SAA: severe aplastic anemia; VSAA: very severe aplastic anemia; NSAA: non-severe aplastic anemia; ECOG PS: Eastern Cooperative Oncology Group performance status
In addition to the primary efficacy assessment, responses were also evaluated according to the Chinese guideline criteria for SAA patients. At 3 months, the overall HR rate was 55.6% (10/18; 95% CI: 21.5–69.2), and the CR rate was 5.6% (1/18; 95% CI: 0.1–27.3). By 6 months, the HR rate increased to 72.2% (13/18; 95% CI: 46.5–90.3), and the CR rate to 22.2% (4/18; 95% CI: 6.4–47.6) (Table S2).
Discussion
To the best of our knowledge, this study is the first to evaluate the PK, safety, and preliminary efficacy of hetrombopag in pediatric patients with AA using a dose-escalation approach. Our findings demonstrate that hetrombopag, in combination with IST, exhibits a favorable safety profile and robust HR rates across different pediatric age groups. At 3 months, the HR rate reached 95.2%, with a CR rate of 52.4%, and these responses remained stable at 6 months. PK analysis revealed inter-individual variability, particularly in the 6–11-year age group, although higher plasma concentrations were observed in some patients, this did not necessarily correlate with superior efficacy, suggesting a need for age-specific dose adjustments. These results provide critical insights into the optimal dosing strategy for hetrombopag and highlight its potential as a potential therapeutic option for pediatric AA.
The PK profile and optimal dosing strategy of TPO-RAs in pediatric patients with AA remain poorly defined [20]. This study represents the first comprehensive PK analysis of hetrombopag in this population, revealing significant age-dependent variations in drug metabolism and exposure levels. Our findings indicate that patients aged 1–5 years, who received weight-based dosing, exhibited PK parameters similar to those in the 12–17-year age group, whereas patients in the 6–11-year age group, who received a fixed high dose, demonstrated substantial inter-individual variability and excessive plasma drug exposure. These results suggest that weight-based dosing should be prioritized for the 6–11-year cohort to minimize PK fluctuations and improve therapeutic predictability. Currently, no established plasma concentration thresholds define the optimal therapeutic range for TPO-RAs in pediatric AA. Our study provides the first insight into the plasma concentration range associated with clinical efficacy, suggesting that a target concentration between 100–300 ng/mL may be beneficial. Notably, higher plasma concentrations did not consistently correlate with improved therapeutic responses. This was particularly evident in three patients within the 6–11-year group, who exhibited abnormally high plasma concentrations (1340.8 ng/mL, 905.2 ng/mL, and 1054.9 ng/mL, respectively) yet demonstrated poor clinical responses. Among these patients, one failed to achieve any HR after three months of treatment, while the other two attained only partial responses (PR). Due to inadequate efficacy, one patient ultimately underwent HSCT, while another was switched to an alternative TPO-RA. These findings emphasize the importance of individualized dosing strategies, particularly in children aged 6–11 years, who appear most susceptible to irregular drug metabolism and suboptimal response patterns. Given the variability in plasma drug exposure and the observed disconnect between higher concentrations and clinical efficacy, routine therapeutic drug monitoring may be beneficial in guiding personalized dosing adjustments. However, given the small sample size of this study, these preliminary conclusions require validation in larger, prospective clinical trials to better elucidate the relationship between plasma drug concentration, therapeutic response, and long-term outcomes.
Hetrombopag demonstrated a favorable safety profile in this study, with no treatment-related deaths or adverse events leading to treatment discontinuation. The incidence of TRAEs was comparable across age groups, with transaminase and blood bilirubin increased being the most frequently observed events. Importantly, only one patient experienced a grade 3 TRAE, and no severe hematologic toxicities or life-threatening complications were recorded. These findings align with previous studies on eltrombopag in pediatric SAA, which similarly reported transient hepatic abnormalities as the primary safety concern [21–24]. Notably, no cases of clonal evolution, myelodysplastic syndrome, or leukemia were observed during the study period, a concern frequently associated with IST [25]. Given the reversible nature of hepatic toxicity observed with TPO-RAs, routine liver function monitoring remains essential during treatment. Further long-term follow-up and larger cohort studies are warranted to comprehensively assess the long-term safety and potential risk of clonal evolution associated with TPO-RAs in pediatric AA.
The findings of this study suggest that hetrombopag, in combination with IST, results in high HR rates in pediatric patients with AA. Efficacy assessment based on the Chinese guideline for SAA patients demonstrated that, the HR rate was 55.6% at 3 months and increased to 72.2% at 6 months. CR rates were 5.6% at 3 months and 22.2% at 6 months. These results are broadly consistent with those reported in the registration trial of hetrombopag combined with IST as first-line treatment for adult patients with SAA [26]. These outcomes compare favorably with historical data for IST alone in pediatric severe AA, where reported overall response rate (ORR) and CR rates were approximately 51.9% and 3.7% at 3 months and 57.4% and 11.1% at 6 months, respectively [8]. Moreover, the efficacy observed in our cohort is broadly consistent with that reported for eltrombopag combined with IST in children, which demonstrated an ORR of about 70% and a CR rate of about 30% at 6 months [27], suggesting a class effect of TPO-RAs in enhancing hematologic recovery. The early and sustained improvements in hemoglobin, neutrophils, and platelets indicate that hetrombopag effectively promotes multilineage hematopoiesis. Consistent with prior studies on TPO-RAs, neutrophil recovery appeared particularly robust, which may contribute to a reduced risk of severe infections [28]. Notably, patients aged 6–11 years demonstrated lower response rates than other age groups, mirroring findings from previous studies on eltrombopag, where age influenced treatment outcomes [27]. This discrepancy may also be partially explained by differences in PK, with the 6–11-year cohort exhibiting greater inter-individual variability in plasma drug concentrations, potentially leading to suboptimal dosing in some patients. These findings underscore the importance of individualized dosing strategies to optimize treatment response and improve long-term outcomes.
This study has several limitations. First, the relatively small sample size, inherent to its exploratory pilot design in a setting with limited prior pediatric data, may restrict the generalizability of the findings and contribute to variability in treatment responses across subgroups. Second, the relatively short duration of follow-up precludes comprehensive assessment of long-term responses, durability of remission, and the risk of late-onset adverse events. Accordingly, larger, prospective, multicenter studies with extended follow-up are warranted to validate these findings and further define the long-term safety and efficacy of hetrombopag in pediatric patients with AA.
Conclusion
In conclusion, this study evaluates hetrombopag in pediatric patients with AA, demonstrating a favorable safety profile, preliminary efficacy, and age-dependent PK variability. The findings suggest that hetrombopag, in combination with IST, represents a potential treatment option for pediatric AA patients who are ineligible for HSCT. Larger, multicenter trials with extended follow-up are necessary to validate these findings, refine age-specific dosing strategies, and better characterize the long-term safety and efficacy of hetrombopag in pediatric AA.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
We extend our heartfelt gratitude to every patient and family member who has supported our research. We also thank Hongyi Kou and Xinwei Zhong for statistical checks.
Author contributions
Lixian Chang, Beibei Zhao, and Xiaofan Zhu were responsible for protocol design and development. Lixian Chang and Beibei Zhao contributed to case provision, manuscript drafting, data extraction and analysis, result interpretation, and reference management. Min Ruan, Weiwang Li, Xiaoming Liu, Tianfeng Liu, Li Zhang, Yao Zou, Yumei Chen, Xiaojuan Chen, and Wenyu Yang contributed to data collection and case provision. All authors have read and approved the final manuscript.
Funding
This study was supported by the National Natural Science Foundation of China (82572140) and CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-CandT-B-082).
Data availability
All data supporting the findings of this study are available within the paper and its Supplementary Information.
Declarations
Disclosures
The authors declare no conflicts of interest.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Lixian Chang and Beibei Zhao contributed equally to this work.
References
- 1.Giudice V, Selleri C (2022) Aplastic anemia: pathophysiology. Semin Hematol 59(1):13–20. 10.1053/j.seminhematol.2021.12.002 [DOI] [PubMed] [Google Scholar]
- 2.Young NS (2018) Aplastic anemia. N Engl J Med 379(17):1643–1656. 10.1056/NEJMra1413485 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Kojima S (2017) Why is the incidence of aplastic anemia higher in Asia? Expert Rev Hematol 10(4):277–279. 10.1080/17474086.2017.1302797 [DOI] [PubMed] [Google Scholar]
- 4.Iftikhar R, DeFilipp Z, DeZern AE, Pulsipher MA, Bejanyan N, Burroughs LM, Kharfan-Dabaja MA, Arai S, Kassim A, Nakamura R, Saldana BJD, Aljurf M, Hamadani M, Carpenter PA, Antin JH (2024) Allogeneic hematopoietic cell transplantation for the treatment of severe aplastic anemia: evidence-based guidelines from the American Society for Transplantation and Cellular Therapy. Transplant Cell Ther 30(12):1155–1170. 10.1016/j.jtct.2024.09.017 [DOI] [PubMed] [Google Scholar]
- 5.Kulasekararaj A, Cavenagh J, Dokal I, Foukaneli T, Gandhi S, Garg M, Griffin M, Hillmen P, Ireland R, Killick S, Mansour S, Mufti G, Potter V, Snowden J, Stanworth S, Zuha R, Marsh J, Committee BSH (2024) Guidelines for the diagnosis and management of adult aplastic anaemia: a British Society for Haematology guideline. Br J Haematol 204(3):784–804. 10.1111/bjh.19236 [DOI] [PubMed] [Google Scholar]
- 6.Iftikhar R, Chaudhry QUN, Anwer F, Neupane K, Rafae A, Mahmood SK, Ghafoor T, Shahbaz N, Khan MA, Khattak TA, Shamshad GU, Rehman J, Farhan M, Khan M, Ansar I, Ashraf R, Marsh J, Satti TM, Ahmed P (2021) Allogeneic hematopoietic stem cell transplantation in aplastic anemia: current indications and transplant strategies. Blood Rev 47:100772. 10.1016/j.blre.2020.100772 [DOI] [PubMed] [Google Scholar]
- 7.Patel BA, Townsley DM, Scheinberg P (2022) Immunosuppressive therapy in severe aplastic anemia. Semin Hematol 59(1):21–29. 10.1053/j.seminhematol.2022.01.002 [DOI] [PubMed] [Google Scholar]
- 8.Zhou F, Zhang F, Zhang L, Wu Q, Ma J, Zhao C, Wang L, Jie G, Zhang H, Zhang H, Wang S, Teng Q (2022) A multicentre trial of intensive immunosuppressive therapy combined with umbilical cord blood for the treatment of severe aplastic anaemia. Ann Hematol 101(8):1785–1794. 10.1007/s00277-022-04864-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Zhang Y, He Y, Wang S, Sun J, Jia J, Gong Y, He G, Li J (2023) Transfusion-dependent non-severe aplastic anemia: characteristics and outcomes in the clinic. Front Immunol 14:1197982. 10.3389/fimmu.2023.1197982 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Fattizzo B, Gurnari C, Cassanello G, Bortolotti M, Awada H, Giammarco S, Consonni D, Sica S, Gandhi S, Trikha R, Large J, Salter S, Maciejewski JP, Barcellini W, Kulasekararaj AG (2023) Deciphering treatment patterns in non-severe/moderate aplastic anemia: an international observational study. Leukemia 37(12):2479–2485. 10.1038/s41375-023-02047-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Scheinberg P (2021) Acquired severe aplastic anaemia: how medical therapy evolved in the 20th and 21st centuries. Br J Haematol 194(6):954–969. 10.1111/bjh.17403 [DOI] [PubMed] [Google Scholar]
- 12.Gilreath J, Lo M, Bubalo J (2021) Thrombopoietin receptor agonists (TPO-RAs): drug class considerations for pharmacists. Drugs 81(11):1285–1305. 10.1007/s40265-021-01553-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Ghanima W, Cooper N, Rodeghiero F, Godeau B, Bussel JB (2019) Thrombopoietin receptor agonists: ten years later. Haematologica 104(6):1112–1123. 10.3324/haematol.2018.212845 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Peffault de Latour R, Kulasekararaj A, Iacobelli S, Terwel SR, Cook R, Griffin M, Halkes CJM, Recher C, Barraco F, Forcade E, Vallejo JC, Drexler B, Mear JB, Smith AE, Angelucci E, Raymakers RAP, de Groot MR, Daguindau E, Nur E, Barcellini W, Russell NH, Terriou L, Iori AP, La Rocca U, Sureda A, Sanchez-Ortega S, Xicoy B, Jarque I, Cavenagh J, Sicre de Fontbrune F, Marotta S, Munir T, Tjon JML, Tavitian S, Praire A, Clement L, Rabian F, Marano L, Hill A, Palmisani E, Muus P, Cacace F, Frieri C, van Lint MT, Passweg JR, Marsh JCW, Socie G, Mufti GJ, Dufour C, Risitano AM, Severe Aplastic Anemia Working Party of the European Society for B, Marrow T (2022) Eltrombopag added to immunosuppression in severe aplastic anemia. N Engl J Med 386(1):11–23. 10.1056/NEJMoa2109965 [DOI] [PubMed] [Google Scholar]
- 15.Townsley DM, Scheinberg P, Winkler T, Desmond R, Dumitriu B, Rios O, Weinstein B, Valdez J, Lotter J, Feng X, Desierto M, Leuva H, Bevans M, Wu C, Larochelle A, Calvo KR, Dunbar CE, Young NS (2017) Eltrombopag added to standard immunosuppression for aplastic anemia. N Engl J Med 376(16):1540–1550. 10.1056/NEJMoa1613878 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Yang W, Zhao X, Liu X, Xiong Y, Fan H, Zhang L, Li J, Ye L, Zhou K, Li Y, Yang Y, Peng G, Jing L, Zhang F (2023) Hetrombopag plus porcine ATG and cyclosporine for the treatment of aplastic anaemia: early outcomes of a prospective pilot study. Exp Hematol Oncol 12(1):16. 10.1186/s40164-023-00377-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Zhang Y, Li J, Li X, Geng Q, Xie Y, Zhang G, Wei M, Ma Y (2024) Efficacy and safety of immunosuppressive therapy combined with eltrombopag for severe aplastic anemia: a systematic review and meta-analysis. Syst Rev 13(1):101. 10.1186/s13643-024-02515-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Syed YY (2021) Hetrombopag: first approval. Drugs 81(13):1581–1585. 10.1007/s40265-021-01575-1 [DOI] [PubMed] [Google Scholar]
- 19.Peng G, He G, Chang H, Gao S, Liu X, Chen T, Li P, Han B, Miao M, Ge Z, Ge X, Li F, Li Y, Wang S, Wang Y, Shen Y, Zhang T, Zou J, Zhang F (2022) A multicenter phase II study on the efficacy and safety of Hetrombopag in patients with severe aplastic anemia refractory to immunosuppressive therapy. Ther Adv Hematol 13:20406207221085197. 10.1177/20406207221085197 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Zhang W, Chang LX, Zhao BB, Zheng Y, Shan DD, Tang BH, Yang F, Zhou Y, Hao GX, Zhang YH, van den Anker J, Zhu XF, Zhang L, Zhao W (2024) Efficacy, safety, and population pharmacokinetics of Eltrombopag in children with different severities of aplastic anemia. J Clin Pharmacol 64(8):932–943. 10.1002/jcph.2430 [DOI] [PubMed] [Google Scholar]
- 21.Fang M, Song H, Zhang J, Li S, Shen D, Tang Y (2021) Efficacy and safety of immunosuppressive therapy with or without eltrombopag in pediatric patients with acquired aplastic anemia: A Chinese retrospective study. Pediatr Hematol Oncol 38(7):633–646. 10.1080/08880018.2021.1895924 [DOI] [PubMed] [Google Scholar]
- 22.Jie M, Fu L, Li S, He Y, Yao J, Cheng X, Zhang L, Zheng J, Zhang R, Wu R (2021) Efficacy and safety of eltrombopag in the first-line therapy of severe aplastic anemia in children. Pediatr Hematol Oncol 38(7):647–657. 10.1080/08880018.2021.1900475 [DOI] [PubMed] [Google Scholar]
- 23.Su MY, Chang HH, Chou SW, Lu MY, Yang YL, Lin DT, Lin KH, Jou ST (2021) Role of eltrombopag in severe aplastic anemia treatment in children. Pediatr Neonatol 62(6):655–657. 10.1016/j.pedneo.2021.07.002 [DOI] [PubMed] [Google Scholar]
- 24.Goronkova O, Novichkova G, Salimova T, Kalinina I, Baidildina D, Petrova U, Antonova K, Sadovskaya M, Suntsova E, Evseev D, Matveev V, Venyov D, Khachatryan L, Litvinov D, Pshonkin A, Ovsyannikova G, Kotskaya N, Gobadze D, Olshanskaya Y, Popov A, Raykina E, Mironenko O, Voronin K, Purbueva B, Boichenko E, Dinikina Y, Guseynova E, Sherstnev D, Kalinina E, Mezentsev S, Streneva O, Yudina N, Plaksina O, Erega E, Maschan M, Maschan A (2023) Efficacy of combined immunosuppression with or without eltrombopag in children with newly diagnosed aplastic anemia. Blood Adv 7(6):953–962. 10.1182/bloodadvances.2021006716 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Groarke EM, Patel BA, Shalhoub R, Gutierrez-Rodrigues F, Desai P, Leuva H, Zaimoku Y, Paton C, Spitofsky N, Lotter J, Rios O, Childs RW, Young DJ, Dulau-Florea A, Dunbar CE, Calvo KR, Wu CO, Young NS (2022) Predictors of clonal evolution and myeloid neoplasia following immunosuppressive therapy in severe aplastic anemia. Leukemia 36(9):2328–2337. 10.1038/s41375-022-01636-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Zhang F, Zhao X, Chang H, Han B, Gao S, Miao M, Hu J, Lin Y, Liu X, Zhang L, Jin C, Li Y, Lin S, Jia J, Wang Y, Chang C, Ge Z, He G, Xia R, Fu X, Li Y, Liu H, Sun K, Wang S, Xia L, Zhang W, Li R, Xiong J, Zhai W (2024) Hetrombopag added to immunosuppressive therapy in first-line treatment of severe aplastic anemia: A randomized, double-blind, placebo-controlled phase 3 trial. Blood 144(Supplement 1):304–304. 10.1182/blood-2024-206377 [DOI] [Google Scholar]
- 27.Groarke EM, Patel BA, Gutierrez-Rodrigues F, Rios O, Lotter J, Baldoni D, St Pierre A, Shalhoub R, Wu CO, Townsley DM, Young NS (2021) Eltrombopag added to immunosuppression for children with treatment‐naïve severe aplastic anaemia. Br J Haematol 192(3):605–614. 10.1111/bjh.17232 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Marrapodi MM, Mascolo A, Roberti D, Martino MD, Rafaniello C, Riccardi C, Rossi F (2023) The efficacy and the safety of eltrombopag in pediatric patients with severe aplastic anemia: A systematic review. Front Pediatr 11:1149718. 10.3389/fped.2023.1149718 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All data supporting the findings of this study are available within the paper and its Supplementary Information.