ABSTRACT
Background
Immunosuppressive therapy (IST) is standard first‐line treatment for severe aplastic anaemia (AA) in patients ineligible for allogeneic transplantation. Thrombopoietin receptor agonists (TPO‐RAs) are increasingly added to IST to improve haematologic recovery, but long‐term safety remains uncertain.
Methods
We conducted a PRISMA‐guided systematic review and meta‐analysis. MEDLINE, EMBASE and CENTRAL were searched from inception to April 2025. Randomised controlled trials and observational studies comparing TPO‐RA plus IST with IST alone were analysed separately using random‐effects models. The primary outcome was overall haematologic response at 6 months; secondary outcomes included response at 3 and 12 months, complete response, survival, relapse and clonal evolution.
Results
Twenty studies (2 randomised and 18 observational) were included. In randomised trials, TPO‐RA plus IST showed a non‐significant trend towards higher overall response at 6 months (OR 2.01; 95% CI 0.76–5.28), while complete response was significantly higher at 3 and 6 months. Observational studies consistently demonstrated higher overall and complete response rates. No significant differences were observed in survival, relapse or clonal evolution.
Conclusion
Limited randomised evidence does not demonstrate statistically significant benefit across all outcomes, while observational data suggest potential haematologic advantages. Further high‐quality trials are required to clarify the effectiveness and long‐term safety of adding a TPO‐RA to IST in AA.
Trial Registration
The authors have confirmed clinical trial registration is not needed for this submission
Keywords: aplastic anaemia, haematologic response, immunosuppressive therapy, meta‐analysis, thrombopoietin receptor agonists
1. Introduction
Aplastic anaemia (AA) is characterised by immune‐mediated failure of the bone marrow, resulting in insufficient production of haematopoietic cells [1]. Immunosuppressive therapy (IST) is the first line of treatment for patients with severe AA who are not candidates for allogeneic HSC transplantation (HSCT) [1, 2, 3]. IST is usually composed of anti‐thymocyte globulin (ATG) in combination with cyclosporine [4]. Despite IST being shown to result in haematologic responses in the majority of patients (50%–70%) [5], non‐response or suboptimal response is not uncommon. Furthermore, clonal evolution to myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) may occur following treatment for AA even after a response to IST [5, 6]. However, clonal evolution has also been reported in untreated patients, and in some cases may reflect initial diagnostic uncertainty, with AA later reclassified as MDS.
Thrombopoietin (TPO) is a primary haematopoietic cytokine, responsible for megakaryopoiesis and platelet production. TPO also has an important role in the control of survival, proliferation and differentiation of multipotent HSCs through interaction with its receptor (TPO‐R) [3, 4].
Thrombopoietin receptor agonists (TPO‐RA) are small molecules or peptide mimetics that exert their effects by binding to and activating TPO‐R, thereby stimulating HSCs [6, 7]. Recent studies have explored incorporating TPO‐RA along with IST for acquired AA treatment, with the aim of improving haematologic response rates and potentially influencing long‐term outcomes, such as survival [8, 9]. In the clinical management of AA, eltrombopag, avatrombopag and romiplostim have been used, with eltrombopag being the most extensively investigated in this context [10, 11]. While early results suggest that combination of TPO‐RA with IST may lead to better haematologic recovery, longer‐term response rates and safety profiles, including the risk of clonal evolution and other toxicities, remain areas that require further monitoring [6, 8, 12]. This review aims to provide an overview of available evidence and generate pooled estimates of the effect and safety of this combination therapy, with particular attention to haematologic response, survival, clonal evolution and toxicity.
2. Methods and Materials
This review followed PRISMA guidelines and was registered with PROSPERO (CRD42022367033).
2.1. Participants, Intervention, Comparison and Outcomes
Participants included patients diagnosed with acquired AA. The review encompassed patients of any age, and included both treatment‐naïve patients and those with relapsed or refractory AA, while excluding individuals with inherited bone marrow failure syndromes. The intervention being studied involved any regimen that included a TPO‐RA in addition to IST; examples included eltrombopag, avatrombopag, hetrombopag and romiplostim. The comparison involved the use of cyclosporine, either alone or in combination with ATG.
The primary outcome was haematologic response at 6 months. An ORR was considered as either a complete response (CR) or a partial response (PR). A CR included normalised haemoglobin, platelet and neutrophil levels, alongside transfusion independence, consistent with recent clinical definitions. A PR was characterised by improvements in blood counts that did not meet criteria for CR but indicate haematopoietic recovery.
Secondary outcomes included haematologic response at 3 and 12 months, CR, overall survival (OS), relapse and clonal evolution (cytogenetic abnormalities, MDS or AML). Because hazard ratios (HRs) were infrequently provided and survival data were not consistently reported in a form that allowed reliable reconstruction from Kaplan–Meier curves, risk ratios were calculated based on the number of participants alive at the longest reported follow‐up.
2.1.1. Search Strategy
MEDLINE, EMBASE and CENTRAL were searched from inception to 3 April 2025 using MeSH terms and keywords (Tables S1–S4).
2.1.2. Study Eligibility
Eligible study types included randomised controlled trials (RCTs), non‐randomised studies of interventions (NRSIs) and observational studies, as long‐term safety data were expected to be limited in RCTs alone. Titles and abstracts of all retrieved studies were compiled in EndNote X9 for citation management and duplicate removal. Subsequently, the records were imported into Covidence, an online systematic review management tool, where we conducted screening for titles and abstracts. Screening of titles and abstracts, followed by full‐text review, was performed independently by two reviewers against the inclusion criteria. Any disagreements between the first two reviewers were discussed and resolved by a third independent reviewer. After completing the full‐text screening, the information extracted from the studies included the author, year and journal of publication, study design, setting, dates, source of participants, inclusion/exclusion criteria, length of follow‐up, sample size, age, dose and duration of treatment, prior treatment history (i.e. treatment‐naïve vs. refractory/relapsed disease), efficacy outcomes and rates of clonal evolution, relapse and survival.
2.2. Assessment of the Risk of Bias
RCTs were assessed using the Cochrane Risk of Bias tool. Other study designs were evaluated using the Risk of Bias in Non‐randomised Studies of Interventions (ROBINS‐I) tool [13, 14]. The assessments were performed independently by two reviewers, with a third reviewer resolving any discrepancies (Table S5). Assessment of publication bias was conducted through visual inspection of funnel plots for symmetry, complemented by statistical evaluations using Egger's regression test and Begg's rank correlation test for small‐study effects [15, 16].
2.2.1. Statistical Analysis
Heterogeneity between studies was assessed using the I 2 statistic: 0% indicates no observed heterogeneity, while values above 50% suggest substantial heterogeneity. The meta‐analysis was performed using a random‐effects model to account for variability in study outcomes. The restricted maximum likelihood (REML) method was used to estimate overall pooled effect sizes as odds ratios (ORs) with 95% confidence intervals (CIs). Results were stratified a priori by study design (RCT vs. observational). Subgroup analyses were conducted based on age (< 18 vs. ≥ 18 years) and follow‐up duration (< 2 vs. ≥ 2 years).
3. Results
3.1. Study Selection and Characteristics
After removing duplicates, 1197 studies were screened, and 141 were selected for full‐text review. Following this review, 118 studies were excluded (Figure 1), leaving 23 studies that met the inclusion criteria. Of these, three were excluded due to poor methodological quality. Ultimately, 20 studies published between 2015 and April 2025 were included in the meta‐analysis [6, 7, 8, 9, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32]. Among them, two were RCTs [8, 26].
FIGURE 1.
Flow diagram of the literature search.
Table 1 summarises the characteristics of included studies. The studies enrolled diverse populations, including both adults and children, severe and non‐severe AA, and treatment‐naïve and relapsed/refractory disease, with sample sizes ranging from 25 to 416 participants. Median participant ages ranged from 6.5 to 68 years, and follow‐up duration varied from 12 to more than 48 months. Eltrombopag was used in 16 (80%) of the studies, along with two studies utilising avatrombopag, one study using hetrombopag, and one study involving an unspecified TPO‐RA.
TABLE 1.
Characteristics of the included studies.
| Author | Severity | Population | Study design | Age group | Sample size | Intervention (N) | Control (N) | Intervention treatment | Control treatment | Gender (M/F) intervention | Gender (M/F) control | Median age (range) intervention (years) | Median age (range) control (years) | Median follow‐up (range) intervention (months) | Median follow‐up (range) control (months) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Wang et al. [17] | SAA | NA | Observational study | ≥ 18 years | 88 | 40 | 48 | rhTPO + IST | IST | 18/22 | 27/21 | 36 (16–66) | 32 (16–68) | 36.5 (6–52) | 18 (6–48) |
| Assi et al. [7] | SAA | Naïve | Observational study | ≥ 18 years | 38 | 21 | 17 | EPAG + hATG + CsA | hATG + CsA | 11/10 | 8/9 | 60 (19–84) | 53 (24–80) | 21 (3–49) | — |
| Fang et al. [9] | SAA | Naïve | Observational study | < 18 years | 57 | 18 | 39 | EPAG + pATG + CsA | pATG + CsA | 10/8 | 21/18 | 6.5 (1.2–12.5) | 7 (1.6–13.5) | 31 (19–40) | 69 (41–103) |
| Lesmana et al. [18] | SAA | Both | Observational study | < 18 years | 25 | 9 | 16 | EPAG + hATG + CsA | hATG + CsA | 2/7 | 12/4 | 11 (4–18) | 11.5 (1–17) | 15 (11–36) | 86 (4–132) |
| Groarke et al. [19] | SAA | Naïve | Observational study | < 18 years | 127 | 40 | 87 | EPAG + hATG + CsA | hATG + CsA | 23/17 | 51/36 | 13 (3–17) | 11 (2–17) | 47 | 80 |
| Jie et al. [20] | SAA | Naïve | Observational study | < 18 years | 42 | 14 | 28 | EPAG + rATG + CsA | rATG + CsA | 8/6 | 14/15 | 7 (2–15.5) | 8 (4–14) | 28 (25–32) | 28.5 (1–88) |
| de Latour et al. [8] | SAA | Naïve | Randomised controlled trial | ≥ 15 years | 197 | 96 | 101 | EPAG + hATG + CsA | hATG + CsA | 56/40 | 52/49 | 55 (16–77) | 52 (15–81) | 23 (19–24) | 24 (23–24) |
| Jin et al. [21] | SAA | Naïve | Observational study | ≥ 18 years | 121 | 54 | 67 | EPAG + rATG + CsA | rATG + CsA | 28/26 | 30/37 | 39 (18–74) | 40 (18–66) | 14 (1–79) | 16 (1–79) |
| Patel et al. [6] | SAA | NA | Observational study | Unlimited | 280 | 178 | 102 | EPAG + hATG + CsA | hATG + CsA | — | — | — | — | 48.7 (2.8–99.2) | 87.8 (2.9–190.8) |
| Zaimoku et al. [22] | SAA | Naïve | Observational study | Unlimited | 416 | 176 | 240 | EPAG + hATG + CsA | hATG + CsA | 87/89 | 141/99 | 32 (3–82) | 30 (2–82) | — | — |
| Zhao et al. [23] | SAA | Naïve | Observational study | < 18 years | 60 | 15 | 45 | EPAG + r/pATG + CsA | r/pATG + CsA | 10/5 | 26/19 | 13 (4–18) | 13 (7–17) | 19 (7–34) | 74 (1–119) |
| Shinn et al. [24] | SAA | Naïve | Observational study | ≥ 18 years | 82 | 48 | 34 | EPAG + hATG + CsA | hATG + CsA | 25/23 | 18/16 | 54 (20–80) | 39.5 (18–76) | 18 (0.8–70) | 49 (0.4–93) |
| Yang et al. [25] | All | Both | Observational study | ≥ 18 years | 128 | 32 | 96 | HPAG + pATG + CsA | pATG + CsA | 17/15 | 52/44 | 44 (13–69) | 45 (7–70) | 366 days (295–449) | > 12 months |
| Wang et al. [32] | SAA | Refractory | Non‐randomised interventional study | Unlimited | 45 | 20 | 25 | EPAG + CsA | CsA + hATG | — | — | 21 (7–47) | 25.5 (8–65) | 12 | 12 |
| Goronkova et al. [26] | SAA | Naïve | Randomised controlled trial | < 18 years | 98 | 49 | 49 | EPAG + hATG + CsA | hATG + CsA | 35/14 | 30/19 | 10.5 (2–17.7) | 8.7 (2.1–16.8) | 26 (1–55) | 3–6 months |
| Li et al. [27] | SAA | Naïve | Observational study | Unlimited | 371 | 130 | 241 | EPAG + rATG + CsA | r/pATG + CsA | 73/57 | 140/101 | — | — | 27 (7–73) | 30 (14–75) |
| Yang et al. [28] | SAA | Naïve | Observational study | < 18 years | 115 | 66 | 49 | EPAG + rATG + CsA | r/pATG + CsA | 38/28 | 22/27 | 5.59 (1.47–16.29) | 6.2 (2.27–13.88) | 34 (18–51) | 71 (53–103) |
| Zhang et al. [29] | NSAA | Naïve | Observational study | ≥ 60 years | 52 | 26 | 26 | AVA + CsA | CsA | 13/13 | 11/15 | 68 (60–80) | 65 (60–74) | 10 (6–31) | 14 (6–36) |
| Yokota et al. [30] | SAA | Naïve | Observational study | 15–64 years | 101 | 20 | 81 | EPAG + r/pATG + CsA | r/pATG + CsA | 14/6 | 42/39 | 53 (18–65) | 52 (15–65) | 29 (4.6–60.4) | 64 (7.4–153.1) |
| Li et al. [31] | SAA | Naïve | Observational study | Unlimited | 126 | 42 | 84 | AVA + ATG + CsA | ATG + CsA | 24/18 | 46/38 | 31.5 (20.25–54.75) | 33 (19.75–52.25) | 14 (12.2–25.7) | 20 (12.2–25.9) |
Abbreviations: AVA = avatrombopag; EPAG = eltrombopag; HPAG = hetrombopag; NA = not reported; rhTPO = recombinant human thrombopoietin; SAA = severe aplastic anaemia.
3.2. Haematological Response
3.2.1. Overall Response Rate
When restricted to the two available RCTs, pooled analysis showed a non‐significant trend in overall response rate (ORR) with TPO‐RA plus IST at 6 months (OR 2.01; 95% CI 0.76–5.28) (Figure 2) and a statistically significant increase at 3 months (OR 2.49; 95% CI 1.29–4.82) (Figure 3). Only one randomised controlled trial reported 12‐month ORR, with no statistically significant difference between groups (OR 1.28; 95% CI 0.58–2.83).
FIGURE 2.
Overall response rate (ORR) at 6 months; odds ratios (ORs) with 95% confidence intervals (CIs) are shown for TPO‐RA plus IST compared with IST alone.
FIGURE 3.
Overall response rate (ORR) at 3 months; odds ratios (ORs) with 95% confidence intervals (CIs) are shown for TPO‐RA plus IST compared with IST alone.
In observational studies, TPO‐RA plus IST was associated with higher pooled ORR across all time points, including 6 months (OR 2.18; 95% CI 1.77–2.69; 16 studies) (Figure 2), 3 months (OR 1.80; 95% CI 1.42–2.28; 11 studies) (Figure 3) and 12 months (OR 1.57; 95% CI 1.03–2.40; 10 studies).
3.2.2. Complete Response Rate
In randomised trials, TPO‐RA plus IST was associated with a significantly higher complete response rate (CRR) at 6 months (OR 2.02; 95% CI 1.18–3.45) (Figure 4) and at 3 months (OR 2.76; 95% CI 1.45–5.25) (Figure 5), but not at 12 months (OR 1.59; 95% CI 0.73–3.47) (Figure 6).
FIGURE 4.
Complete response rate (CRR) at 6 months; odds ratios (ORs) with 95% confidence intervals (CIs) are shown for TPO‐RA plus IST compared with IST alone.
FIGURE 5.
Complete response rate (CRR) at 3 months; odds ratios (ORs) with 95% confidence intervals (CIs) are shown for TPO‐RA plus IST compared with IST alone.
FIGURE 6.
Complete response rate (CRR) at 12 months; odds ratios (ORs) with 95% confidence intervals (CIs) are shown for TPO‐RA plus IST compared with IST alone.
Observational studies consistently demonstrated higher CRR with combination therapy at 3 months (OR 3.08; 95% CI 2.06–4.61; 11 studies), 6 months (OR 3.12; 95% CI 2.46–3.96; 16 studies) and 12 months (OR 1.64; 95% CI 1.06–2.54; 8 studies).
3.3. Relapse Rate
Across the two RCTs, there was no statistically significant difference in relapse risk between TPO‐RA plus IST and IST alone (pooled OR 1.83; 95% CI 0.94–3.58).
Similarly, observational studies showed no significant difference in relapse rates between treatment groups (pooled OR 0.64; 95% CI 0.33–1.24; 11 studies) (Figure 7).
FIGURE 7.
Relapse rate; odds ratios (ORs) with 95% confidence intervals (CIs) are shown for TPO‐RA plus IST compared with IST alone.
3.4. Clonal Evolution Rate
In RCTs, there was no statistically significant difference in the risk of clonal evolution between TPO‐RA plus IST and IST alone (pooled OR 1.03; 95% CI 0.18–5.70). Similarly, observational studies showed no significant difference between treatment groups (pooled OR 1.16; 95% CI 0.71–1.91; 10 studies) (Figure 8).
FIGURE 8.
Clonal evolution rate: odds ratios (ORs) with 95% confidence intervals (CIs) are shown for TPO‐RA plus IST compared with IST alone.
3.5. Survival Outcomes
There was no statistically significant difference in OS between TPO‐RA plus IST and IST alone in randomised trials (pooled RR 1.37; 95% CI 0.64–2.93). Similarly, observational studies showed no significant difference in OS with the addition of a TPO‐RA (pooled RR 1.24; 95% CI 0.85–1.82; 13 studies) (Figure 9).
FIGURE 9.
Overall survival (OS); risk ratios (RRs) with 95% confidence intervals (CIs) are shown for TPO‐RA plus IST compared with IST alone.
3.6. Subgroup Analysis
Subgroup analyses of observational studies, stratified by age and follow‐up duration, are summarised in Table 2. ORRs were consistently higher in adults than in paediatric patients, with statistically significant pooled estimates observed in adults at 3, 6 and 12 months, whereas estimates in paediatric cohorts were smaller and not consistently statistically significant.
TABLE 2.
Subgroup analysis of outcomes by age and study design.
| Outcome | Time point | Subgroup | Number of studies (n) | Pooled odds ratio (95% CI) |
|---|---|---|---|---|
| Overall response rate | 3 months | Age < 18 years | 5 | 1.67 (1.08–2.59) |
| Age ≥ 18 years | 4 | 2.31 (1.50–3.57) | ||
| 6 months | Age < 18 years | 6 | 1.55 (0.98–2.45) | |
| Age ≥ 18 years | 6 | 2.06 (1.24–3.42) | ||
| 12 months | Age < 18 years | 4 | 0.92 (0.57–1.49) | |
| Age ≥ 18 years | 4 | 2.35 (1.22–4.51) | ||
| Relapse rate | Last follow‐up | Age < 18 years | 4 | 1.37 (0.68–2.78) |
| Age ≥ 18 years | 4 | 0.31 (0.11–0.89) | ||
| Follow‐up < 2 years | 5 | 0.35 (0.13–0.94) | ||
| Follow‐up ≥ 2 years | 6 | 0.84 (0.41–1.73) | ||
| Clonal evolution rate | Last follow‐up | Age < 18 years | 3 | 1.27 (0.43–3.75) |
| Age ≥ 18 years | 5 | 0.93 (0.33–2.63) | ||
| Follow‐up < 2 years | 3 | 0.83 (0.24–2.86) | ||
| Follow‐up ≥ 2 years | 7 | 1.24 (0.72–2.14) |
In observational studies, relapse risk differed by subgroup. Among adults (≥ 18 years), TPO‐RA plus IST was associated with a significantly lower relapse risk (OR 0.31; 95% CI 0.11–0.89), while no statistically significant difference was observed in paediatric cohorts. When stratified by follow‐up duration, relapse risk was lower in studies with < 2 years of follow‐up (OR 0.35; 95% CI 0.13–0.94), but not in studies with ≥ 2 years of follow‐up (OR 0.84; 95% CI 0.41–1.73). Clonal evolution rates did not differ significantly between treatment groups across age subgroups or follow‐up strata.
4. Discussion
This systematic review and meta‐analysis evaluated the effects and safety of TPO‐RA added to IST for acquired AA compared with IST alone. In our analysis of 20 studies (including 2 RCTs and 18 observational studies), randomised data showed a non‐significant trend towards higher haematologic response at 6 months, and a statistically significant improvement at 3 months, with TPO‐RA plus IST. In contrast, observational studies consistently suggested higher overall and CRR at 3, 6 and 12 months with combination therapy, although these findings are susceptible to confounding. Furthermore, OS did not differ significantly between treatment groups. Relapse rates were broadly similar across randomised and observational studies. Clonal evolution events were infrequent, and neither randomised nor observational data demonstrated a statistically significant difference between groups.
Our review extends previous efforts by Zhang et al. [12] and Zhang et al. [33], by incorporating studies published up to April 2025, including multiple TPO‐RA beyond eltrombopag, and examining a wider spectrum of disease severity and outcomes, including relapse and clonal evolution. Because of fundamental differences in risk of bias, treatment assignment and confounding structures, randomised trials were analysed separately from non‐randomised and observational studies, and effect estimates were not pooled across study designs. Regarding study design, analysis revealed differences in pooled estimates. Greater effect sizes in observational studies may reflect selection bias or unmeasured confounding, which are more prevalent in non‐randomised designs [9, 10, 11]. While observational data are valuable for assessing less frequent outcomes and providing a larger overall sample size, results from RCTs are generally considered to provide higher‐quality evidence due to reduced risk of bias.
One of the concerns with the addition of TPO‐RA is their potential impact on the risk of clonal evolution. In our analysis, clonal evolution events were uncommon. Randomised evidence and observational studies did not show a clear difference, and statistical precision was limited. This finding is consistent with evidence from larger observational cohorts [20, 34] and more recent meta‐analyses [33], which likewise have not shown an increase in the risk of clonal evolution with TPO‐RA in AA. Nevertheless, follow‐up duration in most included studies was relatively short, and the limited number of randomised studies means that long‐term safety remains uncertain and requires further investigation.
In age‐stratified analyses restricted to observational studies, relapse risk was significantly lower among adults receiving TPO‐RA plus IST, whereas no statistically significant difference was observed in paediatric populations. When stratified by follow‐up duration, relapse risk was lower in studies with shorter follow‐up, which may reflect differences in follow‐up duration rather than true differences in relapse risk. Longer‐term follow‐up is therefore required to determine whether these early differences persist over time. Analyses of prespecified subgroups by disease severity (severe vs. non‐severe AA) or treatment status (treatment‐naïve vs. relapsed/refractory) could not be performed due to insufficient data.
The majority of the included studies tested eltrombopag (representing 80% of the data), in line with its widespread clinical use in AA. This aggregation of evidence, though providing robust evidence for eltrombopag, limits our ability to draw conclusions on the relative effectiveness and safety of other TPO‐RA, such as avatrombopag and romiplostim, when used with IST. Future research should include studies that directly compare these alternative TPO‐RA to inform clinical decision‐making.
Since our 3 April 2025 cut‐off, two additional comparative studies have reported on the use of TPO‐RA in combination with IST in elderly patients with severe AA. In a multicentre prospective study, cyclosporine combined with avatrombopag demonstrated comparable haematologic efficacy but a more favourable safety profile than ATG‐based IST regimens [34]. An observational study in a similar population likewise found that the addition of a TPO‐RA to IST achieved haematologic responses and survival outcomes at least comparable to IST alone, with a trend towards reduced early mortality [35]. Although these studies were published after our predefined cut‐off and were not included in the quantitative synthesis, they extend and reinforce our findings by supporting the potential role of TPO‐RA in older patients who may be less able to tolerate conventional IST.
Several inherent limitations of this systematic review must be considered when interpreting our results. The heterogeneity observed between the included studies is likely due to variations in study setting, patient population (age range, disease severity and history of prior treatment), the specific IST regimens employed, TPO‐RA dosing and duration and differences in outcome definitions. Although a random‐effects model provides more conservative pooled estimates by incorporating between‐study variability, it does not resolve the underlying clinical and methodological heterogeneity. As a result, the generalisability of the pooled findings remains limited. The predominance of observational studies introduces residual confounding and bias, particularly for safety and clonal evolution outcomes. Short and inconsistent follow‐up further restricts assessment of long‐term risks, and variability in adverse‐event reporting limits our ability to synthesise a comprehensive safety profile. Time‐to‐event HRs could not be extracted because both randomised trials reported very few survival events and heavily censored Kaplan–Meier curves without unadjusted HRs, making reconstruction statistically unreliable. As a result, survival was synthesised using risk ratios at the longest follow‐up rather than HRs. Regarding the potential for publication bias, funnel plots for primary outcomes were symmetrical upon visual inspection. Both Egger's regression test and Begg's rank correlation test indicated no significant small‐study effects, suggesting limited evidence of publication bias [15, 16]. However, despite the moderate number of studies included, these findings should be interpreted with caution, given the inherent limitations of these tests and the potential heterogeneity among the studies.
Despite these limitations, this review provides the most up‐to‐date synthesis of evidence on adding TPO‐RA to IST in acquired AA. Overall, randomised data did not demonstrate statistically significant improvements across all outcomes, whereas observational studies suggested more favourable haematologic estimates. Evidence on clonal evolution remains limited; available data did not show a clear increase over the follow‐up periods reported, although the number of randomised studies was small and follow‐up duration was generally short. Further well‐designed trials with longer follow‐up are required to clarify both the effectiveness and long‐term safety of combining TPO‐RA with IST.
Author Contributions
Z.K.M., E.M.W., L.Y., L.C.F. and S.B.T. designed the study. L.Y., Z.K.M. and E.A. conducted the review and analyses. Z.K.M. and E.A. wrote the manuscript. All authors reviewed and approved the final version.
Funding
The authors have nothing to report.
Ethics Statement
The authors have nothing to report.
Consent
The authors have nothing to report.
Conflicts of Interest
The authors declare no conflicts of interest.
Supporting information
Supporting Information
Acknowledgments
Open access publishing facilitated by Monash University, as part of the Wiley ‐ Monash University agreement via the Council of Australian University Librarians.
Data Availability Statement
All data underlying this systematic review are available in the published studies included.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supporting Information
Data Availability Statement
All data underlying this systematic review are available in the published studies included.