Romiplostim in the management of severe aplastic anemia: a comprehensive clinical review

Abstract

Severe aplastic anemia (SAA) is a rare bone marrow failure disorder with high morbidity and mortality, particularly in patients ineligible for hematopoietic stem cell transplantation. While immunosuppressive therapy (IST) remains standard first-line treatment, a significant proportion of patients fail to respond or relapse. Thrombopoietin receptor agonists (TPO-RAs) have emerged as promising therapeutic options to enhance hematopoiesis. Among them, romiplostim has shown increasing efficacy across multiple treatment settings. To comprehensively review the clinical efficacy, safety, and optimal use of romiplostim in the treatment of SAA, based on data from clinical trials, real-world studies, and pediatric case series. A systematic literature search was conducted in PubMed, Web of Science, and Scopus through March 2026 using keywords related to “romiplostim” and “severe aplastic anemia.” Studies included prospective trials, retrospective cohorts, and mechanistic studies reporting hematologic response, transfusion independence, and adverse events in SAA patients treated with romiplostim. Romiplostim demonstrated consistent efficacy across pediatric and adult populations in 19 studies involving more than 390 patients with severe aplastic anemia. Hematologic response rates ranged from 41% to 95%, with trilineage recovery observed in up to 55% of patients. High-dose regimens (10–20 µg/kg/week) and early initiation were associated with superior outcomes, particularly in eltrombopag-refractory cases. Long-term use was well tolerated, with low rates of clonal evolution or serious toxicity. Romiplostim is an effective and safe therapeutic option in SAA, particularly in patients who are refractory to or intolerant of standard therapies. Its integration into frontline and salvage regimens offers the potential for durable trilineage responses and transfusion independence. Further studies are needed to define its role in combination strategies and optimal dosing and duration of therapy.

Introduction

Severe aplastic anemia (SAA) is a rare and life-threatening bone marrow failure disorder marked by pancytopenia and a profoundly hypocellular marrow. Most acquired cases are immune-mediated, driven by autoreactive T cells that target hematopoietic stem and progenitor cells (HSPCs), resulting in compromised hematopoiesis. For patients who are not candidates for hematopoietic stem cell transplantation (HSCT), the standard first-line treatment remains immunosuppressive therapy (IST) with Antithymocyte globulin (ATG) and cyclosporine (CSA). However, relapses and treatment failure are particularly frequent among older adults or those with underlying comorbidities [1].

To improve hematologic outcomes, thrombopoietin receptor agonists (TPO-RAs) have emerged as adjunctive and salvage therapies in SAA. Eltrombopag, an oral small-molecule TPO-RA, was the first to demonstrate efficacy in both treatment-naïve and refractory SAA. It enhances multilineage hematopoiesis and is now part of standard first-line regimens in many treatment guidelines [2]. Despite this, some patients remain refractory or develop intolerance to eltrombopag, necessitating alternative TPO-RAs with distinct mechanisms and better safety profiles.

Romiplostim, a peptibody that mimics endogenous thrombopoietin and binds the extracellular domain of the TPOR (c-MPL), has shown promise in this context. Initially approved for chronic immune thrombocytopenia, romiplostim has gained attention in SAA due to its favorable tolerability and potential to expand not only megakaryocytic but also erythroid and myeloid lineages. Unlike eltrombopag, which also acts as an iron chelator and enters cells through a different binding site, romiplostim more closely recapitulates physiological TPOR signaling. Early-phase trials and real-world studies have shown encouraging response rates and transfusion independence, including in patients who have failed prior IST or TPO-RA therapy [3].

Given the growing body of evidence and the evolving role of romiplostim in SAA management, this review aims to comprehensively evaluate its clinical efficacy, safety, and potential indications across various treatment settings. We synthesize data from interventional trials, retrospective studies, pediatric case series, and mechanistic research to define the therapeutic utility of romiplostim in both newly diagnosed and relapsed/refractory SAA, with special attention to its role in eltrombopag-refractory disease and long-term outcomes.

Patients and methods

This review was conducted through a systematic literature search using the PubMed, Web of Science, and Scopus database up to March 2026. The search strategy combined the terms “romiplostim” AND “aplastic anemia” AND (“severe” OR “SAA”) and was limited to studies published in English. Additional filters were applied to include clinical trials, observational studies, case series, and case reports. Titles and abstracts were screened to identify relevant studies involving pediatric and adult patients with SAA treated with romiplostim, either as first-line therapy or in the relapsed/refractory setting. Reference lists of selected articles were also manually reviewed to capture any additional pertinent studies.

Studies included in this review met the following criteria: (1) they involved patients with confirmed diagnosis of severe aplastic anemia; (2) romiplostim was used as part of the treatment strategy, either as monotherapy or in combination with IST; and (3) clinical outcomes such as hematologic response, transfusion requirements, adverse events, or clonal evolution were reported. Both prospective and retrospective designs were included, encompassing pediatric and adult populations, as well as patients with coexisting conditions such as hepatitis-associated AA or prior liver transplantation.

Data were extracted and synthesized from 19 studies comprising randomized phase 2/3 trials, single-center cohorts, national registry analyses, and case reports. Treatment settings ranged from newly diagnosed and IST-naïve patients to heavily pretreated and multi-TPO-RA-refractory cases. Outcome measures across studies included overall response rate (ORR), complete hematologic response (CHR), trilineage hematologic recovery, time to response, transfusion independence, durability of response, and safety parameters including adverse events and clonal cytogenetic evolution.

Figure 1 a total of 112 records were identified through PubMed searching. After removal of duplicates (n = 18), 94 unique records were screened by title and abstract. Of these, 55 were excluded. Thirty-nine full-text articles were assessed for eligibility, and 20 were excluded (five not romiplostim-based, four non-SAA or irrelevant outcomes, three review articles without original data, and eight with insufficient outcome details). In total, 19 studies were included in the qualitative synthesis, comprising prospective trials, retrospective cohorts, and pediatric case series published between 2019 and 2026.

Fig. 1.

PRISMA 2020 flow diagram of study selection

Results

This review includes data from 19 studies encompassing more than 390 patients with severe aplastic anemia (SAA) treated with romiplostim. The studies comprised four prospective interventional trials, ten retrospective cohort studies, and five pediatric case series or reports, involving both treatment-naïve and relapsed/refractory patients, including those who had failed prior immunosuppressive therapy and thrombopoietin receptor agonists such as eltrombopag. Romiplostim was administered at varying doses, ranging from 1 to 20 µg/kg/week, either as monotherapy or in combination with IST.

First-line and IST-Naïve settings

For newly diagnosed adults, romiplostim has been used in combination with standard IST. In a single-center retrospective study by Dhingra et al., 12 patients received romiplostim (5–10 µg/kg/week) with ATG and CsA. At six months, the overall response rate (ORR) was 66.7%, including 25% complete hematologic responses (CHR). Improvements were noted across all hematologic parameters, with neutrophil and platelet counts doubling from baseline. Though two patients died of infectious complications, the regimen was generally tolerated, suggesting that the addition of romiplostim to IST may enhance early hematologic recovery [4].

Building on these findings, three multi-center phase 2/3 trials in Asia evaluated romiplostim as part of first-line therapy in SAA patients. Lee et al. evaluated romiplostim combined with rabbit ATG and CsA in 17 IST-naïve adult patients. At week 27, the ORR was 76.5% (13/17), including 35.3% CHR and 41.2% partial response. This response rate exceeded historical rates (~ 50% at 6 months) for IST alone. No transformation to acute myeloid leukemia or myelodysplastic syndrome (MDS) was observed up to week 27 [5].

Another phase 2/3 study by Lee et al. investigated romiplostim plus CsA (without ATG) in 24 IST-naïve adult patients who were ineligible for or intolerant to ATG. The ORR at week 27 was 41.7% (10/24). Response rates were higher in patients with non-severe AA (57.1%) and SAA (46.2%) compared to very severe AA (0%). Notably, one patient (4.2%) developed MDS that was considered possibly related to romiplostim [6].

In a two-year interim analysis of these combined phase 2/3 trials, continued romiplostim therapy led to further improvement in response rates. The overall 2-year ORR for the combined cohort was 78.8%, with 93.3% ORR in the ATG-containing regimen and 66.7% in the CsA-only regimen. Four patients who were non-responders at 6 months achieved late responses with prolonged romiplostim beyond 6 months, demonstrating the presence of late responders. From week 27 through 2 years, no additional cases of clonal evolution or new cytogenetic abnormalities were observed. Some patients who achieved partial or complete responses by 6 months were able to sustain their remission even after discontinuation of romiplostim therapy in the second year [7].

Pediatric settings

In the pediatric setting, Bordbar et al. conducted a single-arm trial of 19 children (median age 6 years) with untreated severe or transfusion-dependent non-severe AA. Patients received romiplostim (titrated up to 20 µg/kg/week) alongside horse ATG and CsA. At week 27, the ORR was 89.5%, with 47.4% achieving trilineage response and 15.8% achieving CHR. By week 40, ORR remained high at 86.7%, and CHR improved to 20.0%. Six of eight initially transfusion-dependent patients (75%) became transfusion-independent by week 27. No serious adverse events, bone marrow fibrosis, or clonal evolution were observed during the follow-up period [8].

In a 2024 observational and interventional pilot study by Sharathkumar et al., romiplostim was used with or without IST in 10 pediatric and young adult patients, including nine with SAA and one with myelodysplastic syndrome. Romiplostim was initiated at 5 µg/kg/week, titrated up to 20 µg/kg/week based on platelet response. At week 24, the cumulative incidence of CHR was 70.4% [9]. No clonal evolution, marrow fibrosis, or treatment-related mortality was reported during a median follow-up of 10.9 months.

Al-Huniti et al. described three children treated upfront with romiplostim for acquired bone marrow failure syndromes, including two with SAA. Administered at a median dose of 10 µg/kg/week, all patients achieved trilineage hematopoietic recovery within 13 to 16 weeks, and responses were maintained for a median of 2.8 years following treatment discontinuation [10]. Similarly, Yoshinari et al. described a pediatric case of severe hepatitis-associated aplastic anemia treated with romiplostim plus IST after living-donor liver transplantation. The patient achieved rapid trilineage recovery without liver-related complications or thrombosis [11].

Relapsed/Refractory settings

In the relapsed/refractory setting, romiplostim has shown consistent benefit. A phase II/III open-label trial conducted in Japan and Korea evaluated 31 patients with IST-refractory SAA treated with romiplostim (initially 10 µg/kg/week, titrated up to 20 µg/kg). By week 27, 84% had responded in at least one lineage, and by week 53, 81% sustained their response. Trilineage recovery was observed in 39%, and 73% of initially transfusion-dependent patients achieved transfusion independence. Treatment was generally tolerated, with no discontinuations due to adverse events [12].

Supporting these findings, Lee et al. conducted a dose-finding phase II trial in 35 patients with refractory SAA. Platelet response at week 9 was highest (70%) in the 10 µg/kg/week cohort. During long-term follow-up, 55% achieved sustained platelet response, with many also showing erythroid and neutrophil recovery. These results helped establish 10 µg/kg/week as a clinically effective starting dose [13].

An extension of the previous phase II/III study by Mitani et al. evaluated 27 patients for up to 3.5 years. Hematologic responses were observed in 84% at 52 weeks and 95% at 104 weeks, with all patients achieving transfusion independence by week 156. Trilineage response occurred in 55%. Some patients maintained durable responses after discontinuing romiplostim, while a small subset experienced secondary loss of response. Romiplostim was generally tolerated long-term, with only one grade 3 adverse event and one patient showing clonal expansion [14].

To further elucidate predictors of response in the refractory setting, Jang et al. performed an integrated secondary analysis of 66 patients from the phase 2 and phase 2/3 trials. They found that shorter disease duration (P = 0.040), higher baseline reticulocyte count (P < 0.001), and higher baseline platelet count (P < 0.001) were significant predictors of response to romiplostim at 27 weeks. Specifically, a baseline reticulocyte count cutoff of 30.77 × 10⁹/L predicted response with 82.9% sensitivity and 73.1% specificity [15].

In a retrospective study, Ramanan et al. evaluated 28 adults with refractory SAA who had failed IST and eltrombopag. Romiplostim was given at a fixed dose of 250 µg weekly, often with danazol, cyclosporine, or thalidomide. By week 10, 85.7% (24/28) achieved hematologic response with significant improvements in platelets, hemoglobin, and leukocytes [16].

Romiplostim has also demonstrated efficacy in patients previously treated with eltrombopag. Ise et al. reported 70% hematologic response in 10 patients who had failed high-dose eltrombopag [17]. Sato et al. described 18 patients refractory or intolerant to eltrombopag, with 72% achieving a hematologic response and 50% showing trilineage improvement. All patients who failed to respond had initiated romiplostim more than three years after diagnosis, emphasizing the importance of early intervention [18].

High-dose romiplostim (20 µg/kg/week) has shown particular utility in heavily pretreated populations. Lin et al. observed a 72.7% response rate in 11 patients who had failed IST and at least two TPO-RAs. Most responses occurred within one month, and over half achieved CHR [19]. In another study of eltrombopag-refractory patients, Hosokawa et al. reported a 76% response rate, with four patients achieving trilineage hematologic recovery [20]. Conversely, a French registry study using lower romiplostim doses (median 9.4 µg/kg) reported a response rate of only 7.1%, highlighting the importance of adequate dosing and treatment duration [21].

An overview of the major clinical studies of romiplostim in SAA, including patient populations, dosing, outcomes, and safety findings, is provided in Table 1.

Table 1.

Summary of Romiplostim Studies in Severe Aplastic Anemia (SAA)

Study	Population (Age Group)	Treatment Combination	Romiplostim Dose	Follow-up / Timepoint	Hematologic Response	Safety Notes
First-line / IST-naïve
Lee et al. (2025) [5]	IST-naïve adults (n = 17)	+ ATG + CsA	10 to 20 µg/kg/week	Week 27	ORR 76.5%; CHR 35.3%	No MDS/AML; manageable AEs
Lee et al. (2025) [6]	IST-naïve adults (n = 24)	+ CsA	10 to 20 µg/kg/week	Week 27	ORR 41.7%	1 case of MDS (4.2%)
Dhingra et al. (2023) [4]	Newly diagnosed adults (n = 12)	+ ATG + CsA	5 to 10 µg/kg/week	6 months	ORR 66.7%; CHR 25%	2 deaths; generally tolerated
Yamazaki et al. (2022) [22]	IST-naïve adults (n = 17)	+ ATG + CsA	10 µg/kg/week	Week 27	ORR 76.5%; CHR 35%	No clonal evolution reported
Hosokawa et al. (2024) [7]	IST-naïve adults (n = 36)	+ ATG + CsA or + CsA	10 µg/kg/week	2 years	2-year ORR 78.8%	No clonal evolution reported
Bordbar et al. (2026) [8]	IST-naïve pediatric (n = 19)	+ ATG + CsA	10 to 20 µg/kg/week	Week 27 and Week 40	ORR 89.5% at Week 27; CHR 20% at Week 40	No clonal evolution; well tolerated
Al-Huniti et al. (2021) [10]	Pediatric AA/MDS (n = 3)	Upfront monotherapy	5 to 10 µg/kg/week	Median 2.8 years	100% trilineage response	No AEs; sustained response
Yoshinari et al. (2021) [11]	Post-LDLT pediatric HAA (n = 1)	+ IST	Not specified	N/A	Trilineage recovery	No liver toxicity
Relapsed / Refractory
Jang et al. (2021) [12]	IST-refractory adults (n = 31)	Monotherapy	10 to 20 µg/kg/week	Week 53	84% response; 39% trilineage	No discontinuations; mild AEs
Lee et al. (2019) [13]	Refractory adults (n = 35)	Monotherapy	1 to 10 µg/kg/week	Week 9	70% platelet response at 10 µg/kg	Minimal AEs; 1 unrelated death
Mitani et al. (2024) [14]	Refractory adults (n = 27)	Monotherapy	Median 15.9 µg/kg/week	Week 104	95% response; 55% trilineage	1 clonal expansion
Ramanan et al. (2025) [16]	Refractory adults (n = 28)	Monotherapy / mixed	250 µg fixed dose	Week 10	85.7% response	4 discontinuations; no severe AEs
Jang et al. (2025) [15]	Refractory adults (n = 66)	Monotherapy	1 to 20 µg/kg/week	Week 27 and Week 53	ORR 75.6% at Week 53	N/A; focus on predictors
Eltrombopag-refractory
Ise et al. (2020) [17]	EPAG-refractory (n = 10)	Monotherapy	Up to 20 µg/kg/week	Variable	70% response	Mild liver enzyme elevation
Sato et al. (2025) [18]	EPAG-refractory/intolerant (n = 18)	Monotherapy	Not specified	Variable	72% response; 50% trilineage	Earlier initiation associated with better response
Lin et al. (2024) [19]	Multi-TPO-RA failure (n = 11)	Monotherapy	20 µg/kg/week	Variable	72.7% response; CHR 54.5%	1 relapse after discontinuation
Hosokawa et al. (2020) [20]	EPAG-refractory (n = 21)	Monotherapy	Up to 20 µg/kg/week	Variable	76% response; 4 trilineage responses	No clonal evolution reported
Zhao et al. (2019) [21]	Refractory AA (n = 14)	Monotherapy	Median 9.4 µg/kg/week	Variable	Trilineage response 7.1%	Low efficacy; 3 deaths
Sharathkumar et al. (2024) [9]	Pediatric/young adult (n = 10)	Mixed	5 to 20 µg/kg/week	Week 24	CHR 70.4%	No clonal evolution reported

Abbreviations: AA aplastic anemia, AE adverse event, AML acute myeloid leukemia, ATG antithymocyte globulin, CHR complete hematologic response, CsA cyclosporine A, EPAG eltrombopag, HAA hepatitis-associated aplastic anemia, IST immunosuppressive therapy, LDLT living donor liver transplantation, MDS myelodysplastic syndrome, N/A not available, ORR overall response rate, TPO-RA thrombopoietin receptor agonist

Discussion

The accumulated evidence across prospective trials, retrospective cohorts, and pediatric case series confirms that romiplostim is an effective and well-tolerated treatment for severe aplastic anemia. Its clinical utility spans multiple therapeutic settings: as upfront therapy in combination with IST, as monotherapy in relapsed or refractory disease, and as a salvage agent in patients who failed or were intolerant to eltrombopag. Across studies, romiplostim consistently induced hematologic responses, often in multiple lineages, with a substantial proportion of patients achieving transfusion independence. Durable trilineage recoveries have been observed in both pediatric and adult patients, highlighting the potential for romiplostim to restore bone marrow function in SAA.

In newly diagnosed patients, particularly when combined with IST, romiplostim appears to accelerate hematologic recovery. The addition of romiplostim to standard ATG and CsA protocols produced response rates that exceeded historical outcomes with IST alone [3]. In the Lee 2025 Phase 2/3 trial, romiplostim combined with rabbit ATG + CsA achieved a 76.5% overall response rate at 27 weeks, including rapid attainment of transfusion independence, compared with the 50–60% responses typically observed with IST without TPO-RA support [5]. Long-term data reinforce these benefits: the Hosokawa 2024 two-year interim follow-up of the 531-003/004 studies reported an overall response rate of 78.8%, with survival exceeding 90%, stable hematologic parameters, and the emergence of “late responders” who benefited from prolonged romiplostim therapy beyond the initial six months [7]. Collectively, these findings extend romiplostim’s role beyond salvage therapy, positioning it as a compelling first-line adjunct to IST that not only accelerates hematologic recovery but also deepens and sustains long-term responses [7, 22]. Importantly, in pediatric populations, romiplostim also appears to offer safe and sustained responses. The recent study by Bordbar et al. demonstrated an 89.5% ORR at week 27 in IST-naïve children treated with romiplostim, horse ATG, and CsA, with some children maintaining trilineage recovery for years after discontinuation [8–10].

Romiplostim’s performance in the relapsed/refractory setting is perhaps even more compelling. Multiple trials and long-term extensions report response rates above 70%, even in patients who had failed IST and remained transfusion dependent [12–14]. The trilineage recovery observed in over a third of patients is particularly notable, suggesting romiplostim’s capacity to stimulate multilineage hematopoiesis an essential goal in aplastic anemia treatment. Moreover, its long-term safety profile, with minimal discontinuations and low rates of clonal evolution, is favorable when compared to other agents [12, 14]. Real-world data from Ramanan et al. demonstrated an 85.7% hematologic response rate in with fixed dose of romiplostim at 250 µg weekly. The treatment was generally well tolerated, reinforcing its practical utility in routine and resource-limited settings [16].

Dosing appears to be a critical determinant of romiplostim efficacy. Studies initiating therapy at or escalating to 10–20 µg/kg/week achieved markedly higher response rates than those using lower doses [13, 19, 20]. The disappointing results from the French registry study, which employed a median dose of only 9.4 µg/kg, reinforce the importance of adequate dosing and early titration [21]. This finding is especially relevant in eltrombopag-refractory cases, where high-dose romiplostim (up to 20 µg/kg/week) elicited hematologic responses in over 70% of patients [17, 19, 20].

The time since diagnosis also emerged as a predictor of response. Jang et al. demonstrated that shorter disease duration and higher baseline reticulocyte counts are significant predictors of hematologic response at 27 weeks [15]. Similarly, In Sato et al.‘s cohort, all patients who initiated romiplostim more than three years after diagnosis failed to respond [18]. This underscores the importance of early intervention, possibly due to progressive stem cell attrition or marrow fibrosis in later stages. These insights should inform clinical decision-making, particularly in patients with long-standing disease or multiple prior treatment failures.

Importantly, romiplostim demonstrated efficacy even in patients who failed eltrombopag, suggesting non-cross resistance between the two TPO-RAs. This finding is clinically significant given the increasing use of eltrombopag in first-line therapy. The ability to switch to romiplostim following eltrombopag failure expands therapeutic options for this challenging patient population and avoids the need for more toxic interventions [17–20].

Mechanistically, romiplostim appears to promote hematopoiesis through pathways that mimic endogenous thrombopoietin more closely than eltrombopag. A recent in vitro study demonstrated that romiplostim robustly expanded human CD34⁺CD38⁻ hematopoietic stem and progenitor cells (HSPCs), activating TPOR signaling cascades such as RHOA, EIF2, and mitochondrial regulatory pathways. These signaling patterns were distinct from those of eltrombopag, which, due to its iron-chelating properties, also induced transferrin receptor (TFRC) expression-potentially counteracting proliferative effects [23].

Romiplostim’s capacity to expand primitive HSPCs aligns well with its observed clinical activity, including late responders and durable remissions. Moreover, its lack of intracellular iron chelation may offer a safer option in patients at risk for hepatic dysfunction or those with elevated liver iron, as seen in transfusion-dependent populations. These mechanistic distinctions may also explain why romiplostim appears better tolerated over extended durations [23].

Safety remains a critical consideration in long-term treatment of SAA. Romiplostim has shown a consistently favorable safety profile, with low rates of grade ≥ 3 toxicity. However, it is crucial to recognize that the risk of clonal evolution is not entirely absent. While many studies have reported no cases of clonal evolution, this must be interpreted cautiously due to heterogeneous follow-up durations and small sample sizes. Notably, Lee et al. reported one case of transformation to MDS among 24 patients treated with romiplostim and CsA, which was considered possibly related to the treatment [6]. Mitani et al. also noted one instance of clonal expansion during long-term follow-up [14]. The biological plausibility of TPO-RAs stimulating the expansion of pre-existing abnormal clones in the hypocellular marrow remains a concern. Therefore, “no reported cases” in certain cohorts should not be conflated with an “absence of risk.” Routine and rigorous monitoring, including regular peripheral blood smears, bone marrow aspirates, and cytogenetic evaluations, is highly recommended for all SAA patients receiving long-term TPO-RA therapy to detect early signs of clonal evolution.

Despite these positive findings, several areas warrant further research. Optimal treatment duration remains undefined, and the potential for tapering or discontinuing therapy in responders should be prospectively studied. Additionally, romiplostim’s role in combination with other agents, beyond standard IST such as in patients with PNH clones or hypoplastic MDS, is an area of active investigation.

Finally, the accessibility and cost-effectiveness of romiplostim compared to other TPO-RAs will influence its adoption across health systems. Given its parenteral administration and high-dose requirements in some patients, strategies to optimize use and minimize burden will be critical. Future head-to-head trials with eltrombopag or novel agents may help define its comparative role more precisely.

Conclusion

Romiplostim has become a valuable addition to the therapeutic landscape of severe aplastic anemia. Its consistent efficacy, tolerability, and potential for durable trilineage recovery support its use in both upfront and salvage settings. When appropriately dosed and initiated early, romiplostim offers a meaningful chance for transfusion independence and long-term hematologic remission in patients with SAA.

Author contributions

M.F.M.S. and A.N. conceived the study and designed the review. M.F.M.S. and A.N. conducted the literature search, data extraction, and primary manuscript drafting. A.K., H.A., H.Z., A.A., and M.A. contributed to data interpretation, critical appraisal, and revision of specific sections. M.J. provided senior oversight and critical revision for intellectual content. All authors reviewed and approved the final manuscript.

Funding

No specific funding was received for this work.

Data availability

All data generated or analyzed during this study are included in this published article. Further details are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable. This article is a narrative review of published literature and does not involve any new human participants or animal experiments.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.