Efficacy and safety of ropeginterferon alfa-2b in the treatment of polycythemia vera: a systematic review with single arm meta-analysis

Abstract

Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by increased red blood cell production, with high risk of venous and arterial thrombosis. Mutations in the JAK2 gene, particularly JAK2 V617F, play a central role in its pathogenesis. Ropeginterferon alfa-2b is a novel long-acting interferon showing promise in managing PV through hematologic and molecular control.

This study aimed to evaluate the efficacy and safety of Ropeginterferon alfa-2b in patients with PV based on a systematic review and meta-analysis of available clinical trials.

A systematic search was conducted across PubMed, Cochrane Library, Web of Science, Google Scholar, and Scopus on May 8, 2025. Randomized controlled trials (RCTs) assessing Ropeginterferon alfa-2b in PV were included. The PRISMA guidelines were followed, and the protocol was registered in PROSPERO (CRD420251051466). Quality assessment was performed using RoB 2.0 and ROBINS-I tools. A random-effects model was applied using R software.

Eight studies involving 761 patients were included and only six studies included in single arm meta-analysis with 328 patients. The pooled proportion of complete hematological response at 12 months was 0.63 (95% CI [0.51–0.73]), with high heterogeneity. Reductions in JAK2 V617F allele burden were significant (MD: 26.57, 95% CI [13.49–39.65]). Molecular response was achieved in 25% (95% CI [0.04–0.70]) of patients. The most common adverse events were elevated liver enzymes (AST: 0.28; ALT: 0.32), influenza-like illness (0.11), and anemia (0.09), with unresolved heterogeneity in all outcomes.

Ropeginterferon alfa-2b shows promising efficacy in achieving hematological and molecular responses in patients with PV. However, notable heterogeneity and safety concerns, particularly liver-related adverse effects, warrant further investigation in large-scale trials.

Graphical Abstract

Supplementary Information

The online version contains supplementary material available at 10.1007/s00277-025-06701-7.

Introduction

Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) characterized by increased red blood cell production and associated with substantial morbidity and mortality due to venous and arterial thrombosis [1]. Elevated red blood cell, white blood cell (WBC), and platelet counts result from increased proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow. Symptoms of PV may include night sweats, bone pain, fatigue, pruritus, bleeding, and thrombosis [2].

The pathogenesis of PV involves mutations in the Janus kinase 2 (JAK2) gene. The classical JAK2 V617F mutation and JAK2 exon 12 mutations are present in approximately 96% and 3% of patients, respectively [3, 4], leading to constitutive kinase activity that promotes both hematopoietic cell proliferation and a proinflammatory state [5–8].

According to the 2016 revised World Health Organization (WHO) guidelines, diagnosis of PV requires either all three major criteria or the first two major criteria plus the minor criterion [9, 10]. More recently, the 2022 International Consensus Classification (ICC) has proposed updated diagnostic criteria for myeloid neoplasms that refine and build upon the WHO framework [11, 12].

The major WHO criteria are: Hemoglobin > 16.5 g/dL in men and > 16 g/dL in women, or hematocrit > 49% in men and > 48% in women, or red cell mass > 25% above the predicted mean normal value, Bone marrow biopsy showing hypercellularity for age with trilineage growth (panmyelosis), including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic, mature megakaryocytes and Presence of JAK2 V617F or JAK2 exon 12 mutation.

The minor criterion is: Subnormal serum erythropoietin level.

Treatment options include phlebotomy, hydroxyurea (with or without phlebotomy), interferon-alpha, pegylated interferon-alpha, and ruxolitinib. Other options such as chlorambucil or busulfan may be considered, particularly in patients over 70 years who do not tolerate interferon or hydroxyurea. Low-dose aspirin (≤ 100 mg per day) is also recommended unless contraindicated due to major bleeding or gastric intolerance [9]. These approaches are consistent with the current European LeukemiaNet (ELN) 2021 recommendations for the management of polycythemia vera [13].

Interferon alfa belongs to type I of the three interferon groups. Type I interferons include standard interferon alfa-2b (Intron A), pegylated interferon alfa-2a (Pegasys), pegylated interferon alfa-2b (PegIntron), and ropeginterferon alfa-2b (Besremi). Pegylated interferon is associated with molecular response rates of 20–60% in JAK2-mutated patients. The presence of concurrent non-driver mutations is linked to smaller reductions in JAK2 V617F allele burden during pegylated interferon treatment [14–17].

Therefore, the aim of this study is to evaluate the efficacy and safety of Ropeginterferon alfa-2b in patients with polycythemia vera, based on available evidence from clinical trials.

Methodology

Search strategy

A systematic literature search was conducted to identify studies evaluating the efficacy and safety of Ropeginterferon alfa-2b in patients with polycythemia vera (PV). The search was performed on May 8, 2025, using the following electronic databases: PubMed, Cochrane Library, Web of Science, Google Scholar, and Scopus. The search terms included: (“Ropeginterferon alfa-2b” OR “AOP2014” OR “Ropeginterferon alfa-2b-njft”) AND (“polycythemia vera” OR “Primary Polycythemia” OR “Polycythemia Ruba Vera” OR “Osler Vaquez Disease” OR “Erythremia”). This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [18]. The protocol of this meta-analysis was registered on PROSPERO and is accessible at https://www.crd.york.ac.uk/PROSPERO/view/CRD420251051466.

Eligibility criteria

Search results were exported into EndNote X8. Screening was carried out in two phases, first by title and abstract, followed by full-text screening using Excel and the Rayyan platform. Each stage was completed independently by at least two authors, with disagreements resolved through discussion. Duplicate records and non-English articles were excluded. Only randomized and non randomized controlled trials that met the following criteria were included:

• Investigated Ropeginterferon alfa-2b for treating polycythemia vera.

• Reported clinical outcomes such as hematologic response, molecular response, or safety data.

• Were designed as randomized and non randomized controlled trials (RCTs).

Studies were excluded if they were case reports, review articles, editorials, or did not provide sufficient data for analysis. Any unresolved disagreements were addressed through consultation with a third reviewer.

Quality assessment

The risk of bias in the included studies was assessed using the RoB 2.0 tool for randomized controlled trials and the ROBINS-I tool for non-randomized studies.

Statistical analysis

All statistical analyses were performed using R software. A random-effects model was applied to account for possible heterogeneity among studies. The I² statistic was used to assess variability, with values exceeding 50% indicating substantial heterogeneity. Pooled results were expressed as risk ratios (RRs) or mean differences (MDs), each with 95% confidence intervals (CIs).

Results

Study selection

Our search strategy yielded extensive compilation of 293 articles, sourced from PubMed, WOS, Cochrane, Scopus. After eliminating 158 duplicates, we conducted title and abstract screenings on 135 articles, excluding an additional 104 articles to remain 31 articles, 18 of them were not retrieved. Subsequent full-text screening of 17 articles identified eight eligible studies [19–26]. Among these, six studies [21–26] met the criteria for inclusion in the single-arm meta-analysis. The remaining two studies [19, 20]. were not eligible for quantitative synthesis but were discussed narratively in the main text due to the importance of their findings (Fig. 1).

Fig. 1.

Molecular response

Quality, summary, and baseline characteristics of included studies

The quality assessment of the included studies, as determined by the Cochrane risk of bias assessment. For randomized trials (rob2) Both trials Gisslinger et al. 2020 [20]and Barbui 2023 [19] had some concerns of bias in randomization and reporting but raised some concerns due to their open-label design, missing data, and potential measurement bias in subjective outcomes (Figs. 4 and 5). For non-randomized (ROBINS-I) The risk of bias assessment for the included studies revealed varying levels of bias across domains. Gisslinger et al. 2015 (25)and Sau et al. 2024 (23)were judged to have a low overall risk of bias, with moderate concerns in confounding and deviations from intended interventions. Edahiro et al. 2022 (22)and Qin et all 2024 (24) had a moderate overall risk due to serious bias in confounding and moderate bias in outcome measurement. In contrast, Yoon et al. 2024 (26) and Them et al. 2014 (21) exhibited serious risks across multiple domains, including confounding, selection bias, missing data, and outcome measurement, leading to an overall critical risk of bias. Figures 2 and 3 provides a comprehensive overview of the quality assessment domains. 761 patients were included in our study. 328 patients of them included in the single arm meta-analysis with Table 1 briefly summarizes the design, main results of the included studies, number of patients, the aim of the study, patents eligibility criteria and assessed outcomes, while Table 2 presents the baseline characteristics of the respective study populations by detecting the platelet count, white blood cell (WBC) counts, hematocrit value (%), JAK2V617F allelic burden % and positive status for JAK2 Val617Phe mutations (Figs. 4 and 5).

Fig. 4.

Risk of bias 2 (ROB 2) for randomized trials

Fig. 5.

Summary of risk of bias assessment across randomized controlled trials using the RoB 2 tool

Fig. 2.

ROBINS-I for non randomized trials

Fig. 3.

Summary of risk of bias assessment across non-randomized studies using the ROBINS-I tool

Table 1.

The summary table for included studies

Study ID	Number of patients	NCT	Age range/years	the study Setting	The intervention dose dose
Barbui et al., 2023	127	NCT03003325	~ 50	21 hematology centers in Italy	Ropeginterferon alfa-2b, fixed dose of 100 mg every 2 weeks
Edahiro et al., 2022	29	NCT04182100	26–72	8 sites in Japan	Ropeginterferon alfa-2b, starting at 100 µg every 2 weeks, titrated to a maximum of 500 µg
Gisslinger et al., 2015	51	NCT01193699	35–82	Multicenter, phase 1/2 dose-escalation study in Austria	Ropeginterferon alfa-2b subcutaneous every 2 weeks (50–540 µg tested)
Gisslinger et al., 2020	306	EudraCT 2012–005259-18 (PROUD-PV) and 2014-001357-17 (CONTINUATION-PV)	21–85	48 clinical centers across Europe	Ropeginterferon alfa-2b: Subcutaneous every 2 weeks, starting at 100 µg Hydroxyurea: Oral, starting at 500 mg/day
Qin et al., 2024	49	NCT05485948	29–70	Conducted in China	Ropeginterferon alfa-2b subcutaneous administration: Week 0: 250 µg Week 2: 350 µg Week 4: 500 µg Maintenance dose: 500 µg if tolerated (adjusted as needed)
Suo et al., 2024	49	Not mentioned	53	Conducted at 15 major hospitals in China	Ropeginterferon alfa-2b subcutaneous administration: Week 0: 250 µg Week 2: 350 µg Week 4 and beyond: Target dose of 500 µg Adjusted based on tolerability for up to 52 weeks
Them et al., 2014	51	NCT01193699	35–82	Phase I/II clinical study (PEGINVERA) conducted in Austria	Peg-proline-IFNa-2b (AOP2014/P1101) Median dose: 244 µg (range: 56–540 µg)
Yoon et al., 2025	99	KCT0006138	25–81	Conducted at 16 sites in South Korea	Ropeginterferon alfa-2b subcutaneously every 2 weeks: 250 µg (Week 1) 350 µg (Week 3) 500 µg (Week 5) Continued until Week 48
The aim of the study		Patents eligibility criteria		Assessed outcomes
To compare ropeginterferon alfa-2b versus phlebotomy alone in maintaining hematocrit < 45% in low-risk polycythemia vera patients		- Low-risk polycythemia vera (age < 60, no thrombosis history) - JAK2 mutation-positive - No history of interferon-alpha use		-Primary Outcome: Maintenance of hematocrit ≤ 45% at 12 months -Secondary Outcomes: Leukocyte/platelet count changes, symptom burden, JAK2V617F allele burden changes, safety outcomes
To evaluate the efficacy and safety of ropeginterferon alfa-2b in Japanese patients with polycythemia vera		- Age ≥ 20 years - PV diagnosis per WHO 2008/2016 criteria - JAK2 V617F mutation-positive - No prior interferon use		-Primary Outcome: Durable complete hematologic response (CHR) without phlebotomy at 9 and 12 months -Secondary Outcomes: Hematocrit, WBC, platelet count changes, spleen size, molecular response, phlebotomy requirements, safety
To evaluate the safety, efficacy, and maximum tolerated dose (MTD) of ropeginterferon alfa-2b in polycythemia vera (PV) patients		- Confirmed PV diagnosis (WHO 2008 or PVSG criteria) JAK2 V617F mutation-positive - Previously untreated or hydroxyurea (HU)-exposed patients		-Primary Outcome: Maximum tolerated dose (MTD) determination -Secondary Outcomes: Hematologic and molecular response, JAK2 allele burden reduction, safety
To compare the efficacy and safety of ropeginterferon alfa-2b versus hydroxyurea in PV patients		- Diagnosed with PV per WHO 2008 criteria JAK2V617F mutation-positive - No prior cytoreductive treatment or < 3 years on hydroxyurea		-Primary Outcome: Complete hematologic response with normal spleen size at 12 months -Secondary Outcomes: JAK2 allele burden reduction, disease-related symptoms, quality of life, long-term safety
To evaluate the exposure–efficacy and exposure–safety relationship of ropeginterferon alfa-2b in polycythemia vera (PV) patients		- Diagnosed with PV per WHO 2016 criteria - No prior interferon-based therapy - Good liver and kidney function		-Primary Outcome: Complete hematologic response (CHR) at 24 weeks -Secondary Outcomes: JAK2V617F allele burden reduction Safety (treatment-related adverse events)
To evaluate the efficacy and safety of a higher starting dose and faster intra-patient dose escalation of ropeginterferon alfa-2b in patients with PV		- Diagnosed with PV - Intolerant to hydroxyurea (HU) JAK2V617F mutation-positive - No prior interferon-based therapy		-Primary Outcome: Complete hematologic response (CHR) at 24 weeks -Secondary Outcomes: CHR rates at 12, 36, and 52 weeks, changes in JAK2V617F allele burden, time to CHR, and safety outcomes
To evaluate the molecular responses and chromosomal aberrations in PV patients treated with peg-proline-IFNa-2b		- Diagnosed with PV - JAK2-V617F mutation-positive - No prior interferon treatment		-Primary Outcome: Hematologic and molecular response -Secondary Outcomes: JAK2 allele burden reduction, complete cytogenetic remissions
To assess the association between complete hematologic response (CHR) and molecular response (MR) in patients with polycythemia vera treated with ropeginterferon alfa-2b		- Diagnosed with polycythemia vera according to 2016 WHO criteria - JAK2 V617F mutation-positive - Hematocrit > 45% at screening - Required cytoreductive therapy (regardless of risk and previous treatment) - Aged ≥ 19 years - Exclusion criteria included contraindications to interferon therapy and pregnancy/lactation		-Primary Outcome: Hematologic response and molecular response at 48 weeks -Secondary Outcomes: Association between CHR and MR Safety and tolerability Time to CHR and MR JAK2 V617F allele burden reduction

Table 2.

The baseline characteristics for the included studies

Study ID	Arms	Age, years mean ± SD	Male n (%)	Platelet count (×10⁹/L, mean ± SD	White Blood Cell (WBC) counts (× 10⁹ cells/L), mean ± SD	Haematocrit Value (%), mean ± SD	JAK2V617F Allelic Burden % mean ± SD	Positive status for JAK2 Val617Phe mutations n (%)	Splenomegaly n (%)
Barbui et al., 2023	Standard Group	49.8 ± 10.3	39 (61.9%)	391.5 ± 305.5	10.5 ± 4.7	44.03% ± 2.7	NA	NA	18 (28.6%)
	Experimental Group	50 ± 7.4	47 (73.4%)	392.3 ± 329.3	10.9 ± 3.9	43.87% ± 1.97	NA	NA	21 (33.3%)
Edahiro et al., 2022	Ropeginterferon	50.7 ± 35.9	13 (44.8%)	753.27 ± 603.75	17.04 ± 13.8	33.52%± 18.32	72.2%± 22.8	27 (93.1%)	NA
Gisslinger 2015	Ropeginterferon alfa-2b	57.7 ± 35.9	31 (61%)	531 ± 662.2	15.6 ± 19.98	37.5% ± 4.6	47.7%± 74.8	56 (100%)	31 (61%)
Gisslinger et al., 2020	PROUD-PV - Ropeginterferon alfa-2b group	51.67 ± 30.7	47 (49%)	640 ± 257.2 and 619 ± 186.3	10.67 ± 4.04	44.03% ± 2.62 and 43.9% ±1.9	41.9% ± 24	126 (99%)	12 (9%)
	PROUD-PV- Hydroxyurea group	58.3 ± 14.1	36 (47%)	482.3 ± 252.7	10.97 ± 4.9	48.4% ± 5.4	42.8% ± 24	125 (98%)	15 (12%)
	CONTINUATION-PV- Ropeginterferon alfa-2b group	57.3 ± 10.4	47 (49%)	513 ± 264.2	11.2 ± 4.96	48.03% ± 5.7	42.8% ± 23	94 (99%)	7 (7%)
	CONTINUATION-PV- Best available treatment	57.8 ± 12.2	36 (47%)	486.17 ± 264.1	11.7 ± 4.8	49·7% ± 5.2	42.9% ± 23​	74 (97%)	8 (11%)
Qin et al., 2024	Ropeginterferon alfa-2b	51.7 ± 31.3	31 (64.6%)​	NA	NA	NA	54.6% ± 70	49 (100%)​	NA
Suo et al., 2024	Ropeginterferon alfa-2b	53.0 ± 10.9​	31 (63.3%)	478.5 ± 238.8	11.4 ± 9.4	46.0% ± 5.3	58.5% ± 25.3​	49 (100%)	36 (73.5%)
Them et al., 2014	Ropeginterferon alfa-2b	57.7 ± 35.9	31 (61%)	NA	NA	NA	46.7% ± 75.5	51 (100%)​	NA
Yoon et al., 2025	Ropeginterferon alfa-2b	54.7 ± 42.1	51 (53.7%)	826.3 ± 1211.22	NA	52.3% ± 12.8	55.8% ± 72.8	NA	NA

Efficacy outcomes

Complete haematological response (HCT)

HCT after 12 months

After using Ropeginterferon alfa-2b for 12 months, we found the pooled propotion of participants complete hematological response is 0.63 (95% CI [0.51 to 0.73]). The were significant heterogeneity that was detected (P = 0.0135, I2 = 6.2%), which was not resolved, Fig. 6.

Fig. 6.

Complete haematological response (HCT)

HCT after 3 months

Furthermore, the pooled propotion of people with complete hematological response after 3 months 0.32 (9% CI [0.09 to 0.67]). The were significant heterogeneity that was detected (P = 0.0001, I2 = 91. %), which was not resolved, Fig. 6.

HCT aftetr 6 months

With regards to 6 months use of using Ropeginterferon alfa-2b, we found pooled propotion for complete hematological response 0.4 (95% CI [0.28 to 0.54]). The were significant heterogeneity that was detected (P = 0.0044, I2 = 77.1%), which was not resolved, Fig. 6.

HCT after 9 months

We evaluated whether Ropeginterferon alfa-2b could impact HCT after 9 months. Subsequently, we found the pooled propotion of people with complete hematological response is 051 (95% CI [0.34 to 0.68]). The were significant heterogeneity that was detected (P = 0.0047, I = 81.3%), which was not resolved, Fig. 6.

We found over all pooled propotion of people with complete hematological response after receiving Ropeginterferon alfa-2b (RR:0.48, 95% CI [0.37 to 0.59]). The significant heterogeneity was detected in all subgroups (P = 0.0001, 2 = 83.6%). Unfortunately, after applying leave one out test for all studies, the heterogeneity is still unresolved, Fig. 6.

JAK2 V617F allele burden (%)

Upon analyzing the relative change in JAK2 V617F allele burden, our analysis yielded statistically significant finding in the absolute change in JAK2 V617F allele burden (MD 26.57, 95% CI [13.49 to 39.65]). The were Heterogeneity between groups (P = 0.0001 I2 = 88.9%). Unfortunately, after applying leave one out test for all studies, the heterogeneity is still unresolved, Fig. 7.

Fig. 7.

JAK2 V617F allele burden (%)

Hematocrit

We evaluated whether Ropeginterferon alfa-2b could impact Hematocrit. Subsequently, we found non significant statistical reduction in Hematocrit (D: 13.86, 95% CI [− 2.60 to 30.33). Significant heterogeneity was present between studies (P = 0.001, I2 = 98.5%). Unfortunately, after applying leave one out test for all studies, the heterogeneity is still unresolved, Fig. 8.

Fig. 8.

Hematocrit

Molecular response

The combined findings of 4 studies revealed the pooled propotion of people with molecular response after receiving the treatmnt is 0.25 (95% CI [0.04 to 0.70]). However, heterogeneity was noted among these studies (P = 0.001, I2 = 93.5%). By leave one out test for all studies, the heterogeneity is still unresolved, supplementary materials Fig. 1.

Safety outcomes

Liver enzymezs

Aspartate aminotransferase (AST) & Alanine aminotransferas (ALT)

We evaluated whether Ropeginterferon Alfa-2b could impact liver functions. Subsequently, we found a pooled proportion of patients with elevated Aspartate aminotranserase AST 0.28 (95% CI [0.13 to 0.51]). Similarly, the pooled proportion of patients with eleated Alanine aminotransferas (LT) was 0.32 (95% CI [0.17 to 0.52]). However, significant heterogeneity was detected in the both groups (P 0.0001, I2 = 91.3%) and (P 0.0001, I2 = 89.9%) respectively, which couldn’t be resolved, despite leave one out test for all studies, supplementary materials Figs. 2 and 3.

Gamma-glutamyl transferase

With regards to Gamma-glutamyl transferase, the pooled proportion of patients with elevated GGT upon using Ropeginterferon Alfa-2b was 0.20 (95% CI: [0.10–0.36]). However, significant heterogeneity was detected (= 0.0001, I2 = 85.3%), which couldn’t be resolved, supplementary materials Fig. 4.

Influenza-like illness

In assessing whether Ropeginterferon Alfa-2b could lead to influenza like ilness in participants, our analysis reported the pooled propotion of participants who aquired influenza like ilness was 0.11 (95% CI: [0.04–0.27]). Despite applying leave one out test for all studies, the heterogeneity is still unresolved(P = 0.0027, I2 = 83.1%), supplementary materials Fig. 5.

Anemia

We evaluated whether Ropeginterferon Alfa-2b would result in anemia. Subsequently, we identified the pooled propotions of participant with anemia is 0.09 (95% CI: [0.03–0.23]). We tried leave one out test for all studies to resolve the heterogeneity, but unfortunately was not resolvd (P = 0.0049, I2 = 81.2%), supplementary materials Fig. 6.

Discussion

This meta-analysis comprehensively investigated and summarized the efficacy and safety of ropeginterferon alfa-2b in PV patients. We analyzed data from eight studies from diverse populations conducted over the last ten years. Being a new site-selective agent with an appealing pharmacokinetic profile [27–29],ropeginterferon alfa-2b has been reported to be clinically effective and safe in treating PV, irrespective of race or ethnic background [20, 22, 25, 30].

Our meta-analysis demonstrated a significant improvement in CHR rates with ropeginterferon alfa-2b over time, with pooled estimates increasing from 32% after 3 months to 63% after 12 months. However, hematocrit levels, a specific parameter of CHR, revealed a non-significant reduction, which may be attributed to insufficient sample size, as only two studies measured this outcome separately. The observed steady improvement in CHR is consistent with an earlier clinical trial that reported that the response to pegylated interferon alfa deepens with longer treatment duration. A prior study found that ropeginterferon alfa-2b achieved a lasting CHR in PV patients, as CHRs were first detected at week 12, and over half of the patients (51.7%) had a CHR by week 52 [22]. Therefore, a substantial treatment duration is necessary for disease response, especially on a molecular and hematological level.

A recent meta-analysis by Bewersdorf et al. evaluated the efficacy of pegylated interferon (pegIFN) in patients with PV and essential thrombocythemia, reporting a CHR rate of 50.7% in patients with PV [15]. These results are comparable to our pooled CHR rate of 63% at 12 months for ropeginterferon alfa-2b. Notably, their analysis included various pegIFN formulations, whereas our study focused exclusively on Ropeginterferon alfa-2b, a monopegylated, long-acting agent with improved pharmacokinetics. Furthermore, the annualized treatment discontinuation rate for pegIFN in PV patients was 5.7%. The comparison underscores ropeginterferon’s potential as a more tolerable and targeted alternative, especially for long-term disease control. While both therapies show promise, further head-to-head trials are warranted to delineate their relative efficacy and safety profiles in different PV subgroups.

JAK2 V617F allele burden refers to the proportion of cells carrying the JAK2 V617F mutation, which indicates disease alterations in PV [31]. Our pooled analysis found a statistically significant reduction in the JAK2 V617F allele burden after treatment with ropeginterferon alfa-2b (MD: 26.57, 95% CI [13.49 to 39.65]). The literature corroborated this trend toward reduction of JAK2 V617F allele burden in PV patients using ropeginterferon alfa-2b. In a previous trial, nearly all patients (91.3%) showed a decrease in JAK2V617F allelic burden during 52 weeks of treatment. Additionally, CHR was more common in patients with a lower JAK2V617F allelic burden [23]. This supports that a reduction in the JAK2V617F allelic burden is linked to the possible disease-modifying impact of ropeginterferon alfa-2b. Higher JAK2V617 levels were associated with a higher risk of thrombotic problems [32] and may potentially play a role in the neoplastic progression to myelofibrosis and acute myeloid leukemia [7, 33, 34]. Still, more research is needed to determine how ropeginterferon alfa-2b’s effective decrease of the JAK2V617F allelic burden affects disease-modifying outcomes like longer progression-free or overall patient survival.

The pooled proportion of patients achieving a molecular response after receiving ropeginterferon alfa-2b was 25% (95% CI: 4–70%), highlighting the drug’s potential to induce molecular remission by reducing the JAK2 V617F mutant allele burden. Moreover, previous investigations with IFNα, involving the ropeginterferon alfa-2b, have documented a correlation between hematologic response and molecular response [25, 26, 35]. In particular, the JAK2 V617F allele burden was lower in the group that attained CHR during treatment than in the group that did not. Notably, a favorable molecular response was linked to the achievement of early CHR at 12 weeks of ropeginterferon alfa-2b treatment, indicating that this patient subgroup may be particularly sensitive to interferon treatment; nevertheless, more research is required [26]. The substantial heterogeneity (I² = 93.5%) in this outcome may be attributed to variations in the definition and timing of molecular response assessment across studies.

Composite outcomes have emerged as a clinically meaningful approach to assess treatment efficacy in PV. The LOW-PV trial introduced a composite endpoint that included sustained hematocrit control (< 45%), absence of disease progression (e.g., thrombosis, splenomegaly, leukocytosis, thrombocytosis), and reduction in symptom burden over 12 and 24 months [19]. This multidimensional measure reflects the complexity of PV management and aligns with real-world therapeutic goals. In the LOW-PV trial, ropeginterferon alfa-2b achieved the composite endpoint in 81% of patients at 12 months versus 51% with phlebotomy alone, with sustained response at 24 months (83% vs. 59%). These findings support the integration of composite outcomes in future PV trials to better capture disease control and patient benefit [19]. Our meta-analysis reinforces this approach, as ropeginterferon alfa-2b demonstrated improvements across hematologic, molecular, and symptomatic domains.

The majority of adverse events (AEs) were mild to moderate, and ropeginterferon alfa-2b was generally well tolerated without new safety concerns found in this meta-analysis. The pooled proportion of patients who developed anemia was 9%, while 11% experienced influenza-like symptoms. These findings are consistent with the known safety profile of interferon-based therapies, which commonly include flu-like symptoms due to immune activation and, less frequently, hematologic side effects such as anemia, suggesting good tolerance regarding red blood cell suppression, especially when compared to other cytoreductive agents [22, 23, 26]. Elevated LFTs, specifically ALT and AST, were significant, with pooled estimates of 0.410 and 0.384, respectively. These results align with earlier investigations, which reported that common AEs were ALT and AST elevations, stating that ropeginterferon alfa-2b has a manageable safety profile with no dose-limiting toxicity at doses up to 500 µg. The dose of 500 µg can be achieved within 4 weeks of the first treatment [23].

Thyroid toxicity is a well-documented adverse effect of interferon therapy, including ropeginterferon alfa-2b. In our included studies, Edahiro et al. (2022) reported one case of hyperthyroidism leading to treatment discontinuation in a Japanese cohort [22]. Similarly, Barbui et al. (2023) observed thyroid-related adverse events among patients receiving Ropeginterferon alfa-2b in the LOW-PV trial, although the incidence was low and manageable [19]. Despite these reports, the overall frequency and severity of thyroid dysfunction were inconsistently documented across studies, and standardized criteria for thyroid monitoring were not uniformly applied. Consequently, we were unable to perform a pooled meta-analysis for thyroid toxicity due to insufficient and heterogeneous data. Nonetheless, thyroid dysfunction remains a clinically relevant concern, particularly in long-term interferon therapy, and should be closely monitored in future trials.

This safety profile of high dosages of ropeginterferon alfa-2b allows individual dosing regimens according to a personalized long-term approach per tolerability and efficacy. For many years, hydroxyurea (HU) was the mainstay of cytoreductive therapy for PV [36]; however, there are concerns over the safety profile of this traditional treatment. Despite its effectiveness in controlling hematocrit levels and lowering the chance of thrombotic events [37], Long-term HU treatment typically results in resistance or intolerance, raising the chance of disease transformation, and lowering the patient’s overall survival [38–40].

Ropeginterferon alfa-2b works differently from HU. The efficacy of ropeginterferon alfa-2b is usually attributed to the selective inhibition of the driver mutation JAK2V617F carrying malignant hemopoietic stem or progenitor cells [41]. On the other hand, this disease-modifying effect is unusual with HU as it induces DNA damage and has an anti-PV activity by causing a non-specific cytotoxic effect [42]. Hence, from such a risk-benefit profile, ropeginterferon alfa-2b can be considered a potential first-line treatment for PV, providing notable enhancements in disease modulation and hematological response. The comparable efficacy to hydroxyurea, coupled with a favorable safety profile, positions ropeginterferon alfa-2b as a valuable alternative for long-term management of PV. Moreover, safety in pregnancy, and concerns about the development of leukemogenic with HU, position ropeginterferon alfa-2b as an alternative for younger and lower-risk patients with PV [2, 43].

The substantial heterogeneity observed in our meta-analysis can be attributed to several factors. Firstly, variations in study designs, including differences in patient populations, treatment durations, and dosing regimens, contribute to heterogeneity. Secondly, differences in baseline characteristics, such as JAK2 allele burden and splenomegaly, can affect treatment outcomes. Lastly, variations in monitoring and reporting standards across studies can lead to discrepancies in reported side effects and efficacy.

Strengths and Limitations

This meta-analysis introduces a thorough overview of ropeginterferon alfa-2b as an effective and safe treatment for PV. It includes high- to medium-quality papers from diverse populations of different ethnicities, highlighting the potential for generalizing our findings across several demographics. Our analysis included both randomized and non-randomized trials, with risk of bias assessments conducted using the Cochrane ROB2 and ROBINS-I tools, ensuring transparency and reliability in evaluating study quality. However, there are still some drawbacks to be considered. We observed considerable heterogeneity in our analysis that can be attributed to differences in patient groups, treatment regimens, and study designs. Additionally, several limitations affected our safety and subgroup analyses. First, thyroid toxicity—a known adverse effect of interferon therapy—was not included in our pooled safety analysis due to insufficient and inconsistent reporting across the included studies. Second, although dosing regimens varied significantly, particularly with rapid escalation protocols in Asian cohorts, we were unable to perform subgroup meta-analyses based on dosing due to a lack of stratified data. Third, thrombotic and bleeding events were not consistently reported with adequate detail, preventing pooled analysis of these clinically significant outcomes. Despite our thorough search approach, we were able to access only 17 full-text papers in the full-text screening phase, which might have led to relevant data loss. Also, the risk of publication bias exists because only eight papers were considered for analysis, whereas more than ten studies are needed to evaluate publication bias. Due to the limited number of available studies on ropeginterferon alfa-2b, we included trials with varying quality, including those with a high risk of bias, such as Them et al. and Yoon et al. Although this may introduce potential bias, excluding these studies would have significantly reduced the data pool. We therefore emphasize the need for more high-quality randomized trials to strengthen future meta-analyses. Finally, the short follow-up period in some studies may affect our results negatively, indicating the need for more longitudinal studies.

Conclusion

This meta-analysis introduces a thorough overview of ropeginterferon alfa-2b as an effective and safe treatment for PV. Ropeginterferon alfa-2b achieves a notable increase in CHR rates and a decrease in JAK2 allele burden, coupled with a manageable safety profile with no dose-limiting toxicity at doses up to 500 µg. From such a risk-benefit profile, ropeginterferon alfa-2b can be considered a potential first-line treatment for PV. Further well-designed trials are needed to confirm our findings, focusing on long-term outcomes and standardized treatment approaches.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

- **Conceptualization: ** EAN (Eman Ayman Nada)- **Methodology: ** EAN, MAE (Mohamed Abdelhalim Elfagieh), FA (Fares Abdelsalam), FI (Fatima A. Idres), HH (Hasan Mohammad Masoum Hamoud)- **Formal analysis and investigation: ** AS (Abdelrahman Shata), IQ (Israa Ahmed Qutob), BH (Belal Mohamed Hamed)- **Writing – original draft preparation: ** EAN, AE (Asmaa Ahmed Elrashedy), FI, AO (Ali M. Othman), RA (Radwa Mohamed Awadalla)- **Writing – review and editing: ** EANAll authors read and approved the final manuscript.

Funding

The Science, Technology, & Innovation Funding Authority (STDF), in cooperation with the Egyptian Knowledge Bank (EKB), provides open-access funding.

Data availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.