Hetrombopag Added to Cyclosporine as the First‐Line Treatment for Patients With Non‐Severe Aplastic Anemia: A Phase 2 Multicenter Trial

ABSTRACT

Non‐severe aplastic anemia (NSAA) is a heterogeneous bone marrow failure syndrome with limited standardized treatment options. Cyclosporine A (CsA) monotherapy often yields suboptimal responses, highlighting an unmet clinical need for more effective therapies. Thrombopoietin receptor agonists (TPO‐RAs) have shown satisfying outcomes in severe aplastic anemia (SAA), but data on their frontline use in NSAA remain scarce. We enrolled 54 adults with newly diagnosed NSAA, including 25 with transfusion‐dependent NSAA (TD‐NSAA) in the prospective, single‐arm Phase 2 trial (NCT05660785) to evaluate the efficacy and safety of hetrombopag, an oral TPO‐RA, in combination with CsA. At 24 weeks, the overall response rate (ORR) was 81.5% (44/54), comprising 72.2% partial responses and 9.3% complete responses (CRs). Notably, CR and robust partial response (robust PR) were achieved in 46.3% (25/54) of patients. In the TD‐NSAA subgroup, the ORR was even higher at 88.0% (22/25) with substantial improvements in hematologic parameters and quality of life. Extending treatment from 16 to 24 weeks increased the CR and robust PR rate from 24.0% to 44.0%. The median time to achieve an initial response was 6, and 14 weeks for robust PR. Adverse events occurred in 35% of patients, predominantly Grade 1 or 2 and were manageable. Importantly, no clonal progression to myelodysplastic syndrome or leukemia was observed. These findings support hetrombopag plus CsA as a potential first‐line therapeutic intervention for NSAA, especially in TD‐NSAA patients.

1. Introduction

Non‐severe aplastic anemia (NSAA) is a heterogeneous bone marrow failure disorder characterized by varying degrees and combinations of cytopenias [1, 2]. However, the precise criteria for initiating treatment remain unclear, and standardized recommendations for clinical evaluation are largely lacking. Thus, management is primarily based on individual centers' expertise. Although patients with NSAA may initially present with relatively mild or moderate cytopenias, a subset, particularly those who are transfusion‐dependent (TD‐NSAA), can experience progressive marrow failure, increased morbidity, and reduced quality of life [3, 4, 5].

Cyclosporine A (CsA) is a commonly used first‐line immunosuppressive therapy for NSAA, but its efficacy is limited, especially in TD‐NSAA, with response rates ranging from 40% to 60% [6, 7, 8]. The use of antithymocyte globulin (ATG) in combination with CsA can improve outcomes, yet ATG is associated with significant toxicity, higher cost, and limited accessibility in some regions [1, 9]. Consequently, there remains an unmet clinical need for more effective and tolerable frontline therapies for NSAA, particularly in patients requiring regular transfusions.

Thrombopoietin receptor agonists (TPO‐RAs), such as eltrombopag, have demonstrated efficacy in acquired aplastic anemia, particularly in patients who are refractory to immunosuppressive therapy [10, 11, 12]. Hetrombopag, an oral non‐peptide TPO‐RA approved in China for SAA, has shown promising hematologic responses with a favorable safety profile [13, 14]. Nonetheless, limited data are available regarding its use as part of first‐line therapy for NSAA.

In this prospective, single‐arm Phase 2 study, we investigated the efficacy and safety of hetrombopag in combination with CsA as initial therapy for adult patients with newly diagnosed NSAA, with a focus on transfusion‐dependent individuals. We aimed to evaluate hematologic responses, time to response, quality of life improvement, and clonal evolution over a 24‐week treatment period. This study seeks to provide evidence for a potential new standard of care in NSAA management and to address the therapeutic gap in patients for whom current options are suboptimal.

2. Methods

2.1. Patients

Data from patients newly diagnosed with acquired NSAA between January 2023 and May 2024 were prospectively collected. Patients were eligible if they met the following criteria: (1) aged ≥ 18 years; (2) newly diagnosed with AA [1] but not fulfilling the criteria for severe AA (SAA) or very severe AA (VSAA); (3) had a platelet counts (PLT) < 50 × 10⁹/L on at least two consecutive occasions, with an interval of more than one week between measurements. Inherited bone marrow failure was ruled out through analysis of congenital hematologic diseases‐associated genes (Table S1).

Transfusion dependence was defined as requiring ≥ 4 units of red blood cells or ≥ 2 units of platelet transfusion per month for at least two consecutive months, or having hemoglobin (HGB) < 60 g/L (or < 70 g/L in patients with cardiovascular disease), or a platelet count < 10 × 10⁹/L (or < 20 × 10⁹/L in patients with recurrent bleeding episodes) [10, 15, 16].

Exclusion criteria included: (1) prior treatment with immunosuppressive therapy or any TPO‐RA more than 4 weeks before enrollment, (2) treatment with TPO‐RA within 1 week before enrollment, (3) inherited bone marrow failure syndromes, (4) bone marrow fibrosis of grade ≥ 2, (5) presence of a hemolytic paroxysmal nocturnal hemoglobinuria (PNH) clone, (6) clonal karyotypic abnormalities (excluding del(20q), +8, and −Y) [17], (7) history of radiotherapy or chemotherapy for solid malignancies, (8) cytopenias due to non‐hematologic disorders, (9) history of thromboembolic events such as acute coronary syndrome or stroke, and (10) pregnancy or lactation.

This prospective study was a Phase 2, single‐arm study, approved by the ethics committee of the Institute of Hematology & Blood Diseases Hospital (approval number: IIT2022049‐EC‐2) and registered on ClinicalTrials.gov (NCT05660785). All eligible patients were thoroughly informed about the study and provided written informed consent.

2.2. Treatment Regimen

CsA was administered orally at a dose of 3–5 mg/kg/day. The dose was adjusted according to plasma CsA concentration to maintain a trough plasma concentration of 100–200 ng/mL. The initial dose of hetrombopag was 15 mg once daily. If the platelet count exceeded 200 × 10⁹/L, the dose was reduced by 2.5 mg, with complete blood counts monitored at least once weekly. If the platelet count remained ≥ 200 × 10⁹/L on two consecutive occasions, the previous dose level is resumed. In cases where one result shows platelet count ≥ 200 × 10⁹/L and the other < 200 × 10⁹/L, the current dose is maintained. In the event of a grade ≥ 2 elevation in serum creatinine, CsA treatment was suspended. If a grade ≥ 3 elevation in alanine aminotransferase (ALT) or bilirubin occurred, both CsA and hetrombopag were discontinued. Transfusions were allowed for supportive care accordingly.

2.3. Endpoint

The primary endpoint was the ORR at 24 weeks, including CR and partial response (PR). CR was defined as a PLT > 100 × 10⁹/L, HGB > 120 g/L for males (≥ 110 g/L for females), and absolute neutrophil count (ANC) > 1.5 × 10⁹/L. PR was defined as meeting any one of the following criteria: (1) double the baseline count or back to the normal count of one or two cell lines, (2) independence from red blood cell and platelet transfusions sustained for more than 8 weeks, or (3) an increase above 30 × 10⁹/L in PLT or 30 g/L in HGB or 0.5 × 10⁹/L in ANC [1, 5, 18].

The secondary endpoints included the ORR at 16 weeks, robust partial response (robust PR) rates at both 16 and 24 weeks, time to hematologic response, life quality improvement, and toxic effects at 24 weeks. Robust PR include near CR (meeting the criteria for PR, and HGB ≥ 120 g/L for males, ≥ 110 g/L for females; PLT ≥ 100 × 10⁹/L and ANC ≥ 1.0 × 10⁹/L), very good partial response (VGPR; meeting the criteria for PR, and HGB ≥ 100 g/L, PLT ≥ 80 × 10⁹/L, and ANC ≥ 1.0 × 10⁹/L), meaningful response (MPR; meeting the criteria for PR, and HGB ≥ 100 g/L, PLT ≥ 50 × 10⁹/L, and ANC ≥ 1.0 × 10⁹/L). An inferior partial response (inferior PR) is defined as meeting the criteria for PR without fulfilling the criteria for any robust response category. Time to response was defined as the duration from initial treatment to the first documented overall response. Adverse events (AEs) are graded and documented according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

2.4. Statistical Analysis

We followed Simon's two‐stage “optimal” design method [19]. Thus, the null and alternative hypotheses were a response probability of 70%, with a minimum acceptable ORR set at 50%. With a one‐sided significance level (α) of 0.05, the sample size calculation was performed using NCSS PASS 15 software (LLC, Kaysville, UT, USA, ncss.com/software/pass), indicating that a total of 43 patients will be enrolled across both stages to ensure a statistical power of no less than 80%.

In the first stage, 15 patients were enrolled. If eight or fewer patients achieved a hematologic response, the treatment would be considered ineffective, and the trial was terminated. If more than eight patients responded, the trial would proceed to the second stage with an additional 28 patients. If 26 or fewer of the total 43 patients achieved a hematologic response at 24 weeks, the efficacy of the combination therapy would be considered unsatisfactory. Considering an anticipated dropout rate of 20%, the total sample size was set at 54 patients. Summary statistics were used to describe the characteristics of the patients, baseline variables, and treatment responses. Data analysis was performed with the use of GraphPad Prism 8.0 and R (4.2.1).

3. Results

3.1. Characteristics of the Patients

A total of 54 patients were screened and enrolled in this study. Two patients discontinued treatment at Weeks 14 and 18, respectively (Figure 1). The median age at treatment initiation was 36 years (range, 18–68 years), and 31 patients (57.4%) were male. At baseline, one patient presented with an abnormal karyotype (+8). Genetic mutations were positively detected in nine patients: four with BOCR mutations, and one each with mutations in DNMT3A, ASXL1, HLA‐B, SBDS, and PIGA. The patient harboring the SBDS mutation was a 41‐year‐old woman with normal development and no history of diabetes or other comorbidities, who had presented with anemia and thrombocytopenia for 8 months. She was diagnosed with TD‐NSAA, without a PNH clone but with a cytogenetic abnormality (+8). The SBDS mutation was identified as a heterozygous splicing mutation with a variant allele frequency (VAF) of 35.4%. In addition, six patients were found to have a PNH clone.

FIGURE 1.

Trial profile. A total of 54 patients were enrolled and allocated to receive hetrombopag and CsA. Two of them were lost to follow‐up.

Twenty‐five patients were transfusion‐dependent. In this subgroup, the median age was 41 years (range, 20–68 years), and 13 patients (52.0%) were male. Among them, 21 patients (84.0%) required platelet transfusions, and 14 patients (56.0%) were dependent on red blood cell transfusions. At baseline, none of these patients exhibited an abnormal karyotype. Genetic analysis revealed one patient with a PIGA mutation, one with a SBDS mutation, two with BCOR mutations, and one with an HLA‐B mutation. PNH clone was identified in six patients. Baseline demographic and clinical characteristics of the patients are summarized in Table 1.

TABLE 1.

Baseline characteristics for the intention‐to‐treat population.

	TD‐NSAA (N = 25)	NTD‐NSAA (N = 29)	Total (N = 54)
Age (years, range)	41 (20, 68)	33 (19, 63)	36 (19, 68)
Male (n, %)	13 (52.0)	18 (62.1)	31 (57.4)
HGB (g/L, range)	60 (39, 91)	93 (62127)	75 (39127)
NEU (×109/L, range)	0.9 (0.5, 2.2)	1.2 (0.5, 2.8)	1.1 (0.5, 2.8)
PLT (×109/L, range)	12.5 (10, 30)	28 (14, 46)	21 (1, 46)
ARC (×109/L, range)	63.3 (30.7, 132.8)	63.6 (27.8, 126.8)	63.3 (27.8, 132.8)
EPO (mIU/mL, range)	760.0 (158.5, 3658.3)	625.0 (60.1, 949.7)	758.0 (60.1, 3658.3)
Marrow cellularity
< 5% (n, %)	4 (16.0)	7 (24.1)	11 (20.4)
5%–10% (n, %)	4 (16.0)	4 (13.8)	8 (14.8)
Megakaryocyte count	11 (2, 21)	9 (1, 25)	10 (1, 25)
PNH clone (n, %)	6 (24.0)	0 (0.0)	6 (11.1)

Note: Data were represented by median.

Abbreviations: ARC, absolute reticulocyte count; EPO, erythropoietin; HGB, hemoglobin; NEU, neutrophil; NTD‐NSAA, non‐transfusion‐dependent aplastic anemia; PLT, platelet; PNH, paroxysmal nocturnal hemoglobinuria; TD‐NSAA, transfusion‐dependent aplastic anemia.

3.2. Response

The ORR for patients treated with hetrombopag plus CsA was 81.5% (44/54) at Week 16 and 81.5% (44/54) at Week 24, comprising 72.2% PR and 9.3% CR (Figure 2A,B). The median time to achieve a hematologic response was 6 weeks (range, 2–22 weeks) (Figure 2C,D). In addition, the CR and robust PR rate was 31.5% (17/54) at Week 16 and increased to 46.3% (25/54) by Week 24. The median time to reach CR or robust PR was 14 weeks (range, 2–24 weeks).

FIGURE 2.

Efficacy assessments. (A, B) Hematological response for total group, TD‐NSAA group and NTD‐NSAA group at Week 16 (A) and Week 24 (B). (C) The overall response rate for total group at different time points. (D) The cumulative incidence of hematological response in the TD‐NSAA and NTD‐NSAA group. (E) Remission quality stratification for TD‐NSAA group at Weeks 8, 16, and 24. (F) Remission quality stratification for NTD‐NSAA group at Weeks 8, 16, and 24. [Color figure can be viewed at wileyonlinelibrary.com]

In the TD‐NSAA cohort, the ORR was 88.0% (22/25) at both Weeks 16 and 24, comprising 76.0% of PR and 12.0% of CR (Figure 2A,B). The median time to reach hematological response was only 6 weeks (range, 2–20 weeks) (Figure 2D). The CR and robust PR rate increased from 24.0% at Week 16 to 44.0% at Week 24 (Figure 2E), with a median time to CR or robust PR of 17 weeks (range, 2–24 weeks).

In transfusion‐independent patients, the ORR was 75.9% (22/29) at Week 16 and Week 24. The median time to first response was also only 6 weeks, range from 2 to 22 weeks (Figure 2D). The CR and robust PR rate rose from 37.9% at Week 16 to 48.3% at Week 24 (Figure 2F), with a median time to robust response of 14 weeks (range, 6–24 weeks).

The platelet, HGB, and neutrophil counts showed significant improvement following treatment (Figure 3). Overall, the median HGB level increased from 75 g/L at baseline to 105 g/L by Week 16 and 107 g/L by Week 24. The median platelet count rose from 21 × 10⁹/L to 49.5 × 10⁹/L at Week 16 and to 50 × 10⁹/L at Week 24. The median neutrophil count increased from 1.08 × 10⁹/L to 1.52 × 10⁹/L at Week 16 and to 1.62 × 10⁹/L at Week 24. In the TD‐NSAA subgroup, the median HGB level increased from 60 to 95 g/L at Week 16 and to 105 g/L at Week 24. The median platelet count increased from 12.5 × 10⁹/L to 39 × 10⁹/L by Week 16 and remained at 40 × 10⁹/L by Week 24. The median neutrophil count rose from 0.91 × 10⁹/L to 1.37 × 10⁹/L by Week 16 and to 1.67 × 10⁹/L by Week 24. For transfusion‐independent patients, the median HGB increased from 93 to 108 g/L by Week 16 and to 114 g/L by Week 24. The median platelet rose from 28 × 10⁹/L to 54 × 10⁹/L by Week 16 and to 50.5 × 10⁹/L by Week 24. The median neutrophil count increased from 1.20 × 10⁹/L to 1.75 × 10⁹/L by Week 16 and to 1.53 × 10⁹/L by Week 24.

FIGURE 3.

Hemoglobin, neutrophil, and platelet counts by analysis period. Graphs show median (IQR). [Color figure can be viewed at wileyonlinelibrary.com]

3.3. Clinical Improvement

Following treatment with hetrombopag and cyclosporine, erythropoietin (EPO) levels were assessed in 35 patients and serum ferritin levels in 40 patients. The median EPO level decreased significantly from 714.5 ng/mL (range, 60.6–3432 ng/mL) to 156.5 ng/mL (range, 12.74–1876 ng/mL). Similarly, serum ferritin levels declined from a median of 257.0 ng/mL (range, 5.6–950 ng/mL) to 143.8 ng/mL (range, 12.7–683 ng/mL) (Figure 4A,B).

FIGURE 4.

Hematologic index and life quality changes. (A) The erythropoietin (EPO) level at baseline and Week 24. (B) The ferritin level at baseline and Week 24. (C) The SF‐36 score at baseline and Week 24 in the TD‐NSAA group. (D) The SF‐36 score at baseline and Week 24 in the NTD‐NSAA group. [Color figure can be viewed at wileyonlinelibrary.com]

Quality of life was assessed using the 36‐Item Short Form Health Survey (SF‐36). Significant improvements were observed in physical functioning, mental health, role‐emotional, and role‐physical domains after treatment, with especially pronounced benefits seen in transfusion‐dependent patients (Figure 4C,D).

3.4. Safety and Clonal Evolution

Overall, 19 patients experienced AEs of any grade during treatment (Table 2), including two patients with Grade 3 AEs (upper abdominal pain and elevated ALT, respectively), and 17 patients with Grade 1 or 2 AEs. The most commonly reported AEs of any grade were hyperuricemia, increased blood bilirubin, and elevated ALT. In addition, there was no significant difference in the incidence of AEs between the transfusion‐dependent patients and the non‐transfusion‐dependent patients.

TABLE 2.

Treatment‐related adverse events in the intention‐to‐treat population.

Total	TD‐NSAA (N = 25)		NTD‐NSAA (N = 29)		Total (N = 54)
	Any grade, n (%)	Grade ≥ 3, n (%)	Any grade, n (%)	Grade ≥ 3, n (%)	Any grade, n (%)	Grade ≥ 3, n (%)
Upper abdominal pain	1 (4.0)	1 (4.0)	0	0	1 (1.9)	1 (1.9)
Diarrhea	0	0	1 (3.4)	0	1 (1.9)	0
Gingival hypertrophy	3 (12.0)	0	1 (3.4)	0	4 (7.4)	0
Hypertrichosis	1 (4.0)	0	3 (10.3)	0	4 (7.4)	0
Headache	0	0	1 (3.4)	0	1 (1.9)	0
Hands tremble	1 (4.0)	0	0	0	1 (1.9)	0
Hypertension	0	0	2 (6.9)	0	2 (3.7)	0
Myalgia	1 (4.0)	0	0	0	1 (1.9)	0
Increased alanine aminotransferase	1 (4.0)	0	7 (24.1)	0	8 (14.8)	0
Increased gamma‐glutamyltransferase	1 (4.0)	0	5 (17.2)	1 (3.4)	6 (11.1)	1 (1.9)
Increased blood bilirubin	6 (24.0)	0	6 (20.7)	0	12 (22.2)	0
Abnormal renal function	2 (8.0)	0	0	0	2 (3.7)	0
Hyperuricaemia	8 (32.0)	0	9 (31.0)	0	17 (31.5)	0

A PNH clone was considered present if the proportion of GPI‐deficient neutrophils or monocyte exceeded 1% [20, 21, 22]. At baseline, 6 of 54 patients had detectable PNH clones; all were transfusion‐dependent and responded to hetrombopag. In these patients, the size of the PNH clone either plateaued or showed a slight increase over time, and no cases of hemolytic PNH were observed. In addition, two patients without a detectable PNH clone at baseline had 1.1% and 1.0% PNH neutrophils, respectively, at the 24‐week primary end point.

Clonal evolution was defined as the presence of cytogenetic abnormalities on standard metaphase analysis of bone marrow or overt clinical transformation to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) [20]. During treatment, none of the non‐responding participants progressed to SAA by Week 24. Furthermore, no progression to MDS was observed in any patient.

We analyzed the somatic mutation profiles of 37 patients before and after treatment using targeted deep sequencing. At baseline, the sequencing panel covered 450 candidate genes associated with hematologic malignancies and/or bone marrow failure diseases (Table S2). At the primary endpoint, a panel of 267 candidate genes was used to evaluate the overall incidence of somatic mutations and clonal dynamics (Table S3, the posttreatment panel for genetic testing covered key myeloid genes and included all mutations detected at baseline). A VAF threshold of > 0.025 was used to define valid mutations [23, 24]. Among the 37 patients, 9 (24.3%) had detectable mutations at baseline, and eight of them responded to hetrombopag. At the primary endpoint, a total of 12 patients (32.4%) had detectable mutations in related candidate genes, including 4 responders who acquired new mutations. In contrast, mutations present at baseline were no longer detectable in three patients (Figure 5). Overall, the incidence of somatic mutations remained largely comparable before and after treatment (p = 0.606). But the interpretation of longitudinal clonal dynamics should be made with caution because the posttreatment sequencing panel included fewer genes than the baseline panel, which might potentially limit the detection of some newly emerging mutations outside the scope of the second panel.

FIGURE 5.

Acquired somatic mutations in hematological malignancies and AA‐related genes in relation to hetrombopag treatment. Targeted deep sequencing was performed on bone marrow cells from 46 patients. Detection of acquired variants in a panel of genes with somatic mutations associated with myeloid cancer or AA is shown. Each row indicates a specific myeloid cancer or AA gene and each column a patient, with results shown for baseline and primary end point (24‐week). The panel of specific myeloid cancer or AA genes is given in Tables S2 and S3. [Color figure can be viewed at wileyonlinelibrary.com]

4. Discussion

This prospective study demonstrates that the combination of hetrombopag and CsA as first‐line therapy is both highly effective and capable of inducing a rapid hematologic response in patients with NSAA. The median time to response was only 6 weeks, notably shorter than that observed with CsA monotherapy [6, 14]. At 24 weeks, the ORR reached 81.5%, surpassing historical response rates of approximately 50%–60% reported with CsA alone [7, 8], suggesting a synergistic effect when hetrombopag combined with immunosuppression therapy. Importantly, half of patients achieved platelet counts exceeding 50 × 10⁹/L by Week 24, a clinically meaningful threshold associated with reduced bleeding risk [18]. These findings underscore the potential of hetrombopag to accelerate and deepen hematologic recovery in NSAA.

A transfusion‐dependent state poses significant medical and social challenges, including iron overload, diminished quality of life, and reduced social contribution. The treatment choice for TD‐NSAA and SAA has been demonstrated to be similar because patients with TD‐NSAA have a higher likelihood of progressing to SAA and can greatly reduce quality of life [3, 4, 25, 26]. However, the ATG‐based regimen (including ATG, CsA, and hetrombopag) requires inpatient administration and prolonged hospitalization, which significantly increases overall medical expenses. In contrast, the CsA plus hetrombopag regimen can be administered in an outpatient setting or even at home, thereby avoiding the cost of ATG and reducing hospitalization‐related healthcare expenditure.

Due to concerns regarding safety, tolerability, and cost, ATG may not be suitable for all patients. The response rate to CsA monotherapy in this population is relatively low, and nonresponders often experience poor quality of life or may succumb to bone marrow failure [7, 8, 27]. In this study, we observed a high hematological response rate of 88.0% in patients with TD‐NSAA, indicating that oral hetrombopag combined with CsA can provide a satisfactory treatment response for transfusion‐dependent aplastic anemia. Moreover, the median time to response was only 6 weeks, leading to reduced transfusion burden and improved quality of life. Notably, approximately 20% of TD‐NSAA patients achieved enhanced response quality with extended hetrombopag treatment from 16 to 24 weeks. These findings suggest that hetrombopag combined with CsA may represent a promising first‐line therapy for TD‐NSAA.

Hetrombopag is an oral non‐peptide TPO‐RA which received its first approval for the treatment of SAA in patients refractory to immunosuppressive therapy [28]. Previous trials showed that hetrombopag was effective, generally well tolerated, and safe for long‐term use in patients with SAA [13]. In this study, approximately 35% of patients experienced AEs, mainly of low grade and primarily attributable to CsA, such as hyperuricaemia and blood bilirubin increased. Only two patients experienced Grade 3 AEs, including upper abdominal pain and increased gamma‐glutamyltransferase. Importantly, no treatment‐related deaths or serious complications were observed. Furthermore, no new safety signals associated with hetrombopag emerged in this study.

Clonal evolution remains a significant concern in the long‐term management of aplastic anemia [5, 23, 24]. Similar to previous reports with eltrombopag‐based regimens [20], no patients progressed to MDS or AML during the 24‐week treatment period in this cohort. Similarly, PNH clones remained stable or only slightly expanded, and no cases of hemolytic PNH were observed. Serial cytogenetic analysis and targeted deep sequencing did not reveal major clonal expansion in most patients. However, these observations should be interpreted with caution. The posttreatment sequencing panel included fewer genes than the baseline panel, which might potentially limit the detection of newly emerging mutations outside the coverage of the second panel. In addition, the relatively short follow‐up period of this study may not be sufficient to fully assess long‐term clonal dynamics or the risk of late malignant transformation.

Although our study shows promising short‐term efficacy and safety of hetrombopag combined with CsA in NSAA, it has several limitations. The single‐arm, open‐label design without a control group limits conclusions about treatment superiority. The short 24‐week follow‐up is insufficient to assess long‐term outcomes such as relapse, clonal evolution, or disease progression. Longer‐term, controlled studies with larger cohorts are needed to confirm these findings.

5. Conclusion

In summary, hetrombopag combined with CsA offers a promising first‐line treatment option for patients with NSAA, demonstrating high efficacy, rapid response, manageable toxicity, and no apparent increase in clonal evolution risk over the short term. These findings warrant further investigation in larger, longer‐term studies and support broader adoption of TPO receptor agonist‐based regimens in frontline therapy for NSAA.

Author Contributions

J.S., J.L., and H.Z. conceived the study and gave final approval of the manuscript. L.Z., R.L., and Q.L. analyzed the results, wrote the manuscript, and made the figures and tables. H.P., Z.G., W.L., L.F., J.Z., X.Y., Z.K., N.N., J.L., J.H., X.Z., M.G., and Y.Z. contributed to the clinical practices and data collection. All authors have read and approved the submitted version.

Funding

This work was supported by grants from the National Key R&D Program of China (2024YFC2510500), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, CIFMS (2023‐I2M‐2‐007 and 2021‐I2M‐2‐073), and the National Natural Science Foundation of China (82270145, 82300162, and 82100145).

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Table S1: Genes related to inherit bone marrow failure.

Table S2: Genes related to hematogical malignancy.

Table S3: Genes related to myeloid tumors.

Zhang L., Li R., Liang Q., et al., “Hetrombopag Added to Cyclosporine as the First‐Line Treatment for Patients With Non‐Severe Aplastic Anemia: A Phase 2 Multicenter Trial,” American Journal of Hematology 101, no. 3 (2026): 467–476, 10.1002/ajh.70183.

Data Availability Statement

No datasets were generated or analyzed during the current study.