Cost‐Effectiveness of Epcoritamab Plus Lenalidomide and Rituximab Versus Lenalidomide and Rituximab for Relapsed/Refractory Follicular Lymphoma: A US Payer Perspective

ABSTRACT

The Phase 3 EPCORE FL‐1 trial demonstrated that adding epcoritamab to lenalidomide plus rituximab (R ²) significantly improved response rates and prolonged progression‐free survival in patients with relapsed or refractory (r/r) follicular lymphoma (FL). However, the cost‐effectiveness of this combination has not been evaluated. The objective of this study was to assess the cost‐effectiveness of epcoritamab plus R ² compared with R ² alone for patients with r/r FL from a US payer perspective. A three‐state Markov model was constructed with a 30‐year time horizon to compare costs and health outcomes of epcoritamab plus R ² versus R ². The primary outcome was the incremental cost‐effectiveness ratio (ICER), expressed as cost per quality‐adjusted life‐year (QALY) gained. Parameter uncertainty was evaluated through one‐way sensitivity analysis, probabilistic sensitivity analysis, and scenario analyses. In the base‐case analysis, epcoritamab plus R ² yielded an additional 3.94 QALYs at an incremental cost of $267,721.01 resulting in an ICER of $67,974.64 per QALY gained compared with R ² alone. In the one‐way sensitivity analysis, the ICER ranged from $53,819.80 to $82,129.49 per QALY across all parameters tested. In the probabilistic sensitivity analysis, epcoritamab plus R ² had a 100% probability of being cost‐effective at a willingness‐to‐pay (WTP) threshold of $150,000 per QALY. From a US payer perspective, epcoritamab plus R ² is estimated to be a cost‐effective treatment option compared with R ² for patients with relapsed or refractory follicular lymphoma at a willingness‐to‐pay threshold of $150,000 per QALY.

1. Introduction

Follicular lymphoma (FL) is one of the most common indolent subtypes of non‐Hodgkin lymphoma (NHL), accounting for approximately 20% of NHL cases in the United States [1, 2]. Its incidence increases with age, and the age‐related incidence rate in the United States is approximately 2.4 per 100,000 persons [1, 3]. Although FL is typically characterized by an indolent clinical course and initial responsiveness to first‐line treatment, the disease remains largely incurable and is marked by a pattern of repeated remissions and relapses [2].

Although first‐line immunochemotherapy achieves favorable outcomes in many patients, relapse remains common and many patients ultimately require multiple lines of therapy [4, 5]. In the relapsed/refractory (R/R) setting, available treatment options include anti‐CD20 based chemoimmunotherapy, targeted agents, bispecific antibodies, and chimeric antigen receptor T‐cell (CAR‐T) therapy [6, 7]. However, no consensus has been reached regarding the optimal treatment sequence, and durable disease control remains difficult to achieve for many patients. Novel treatment strategies capable of inducing deeper and more sustained responses are therefore urgently needed [6, 7].

Epcoritamab is a subcutaneously administered CD20 × CD3 bispecific antibody that redirects T cells to target CD20‐expressing malignant B cells. In the Phase 3 EPCORE FL‐1 trial, epcoritamab in combination with lenalidomide plus rituximab (R ²) demonstrated superior efficacy compared with R ² alone in patients with r/r FL, with a significantly higher overall response rate (95% vs. 79%) and prolonged progression‐free survival (hazard ratio, 0.21). The estimated 16‐month progression‐free survival rate was 85.5% with epcoritamab plus R ² versus 40.2% with R ² [8]. Based on these results, epcoritamab in combination with R ² received approval from the US Food and Drug Administration (FDA) in November 2025 for the treatment of adult patients with r/r FL [9]. Although epcoritamab plus R ² has demonstrated substantial clinical benefit, adding a bispecific antibody to R ² is expected to increase treatment costs considerably. In addition, the economic burden of relapsed or refractory follicular lymphoma increases as patients progress through successive lines of therapy, whereas economic evidence for newly introduced bispecific antibody‐based regimens remains limited [10]. Therefore, the objective of this study was to evaluate the cost effectiveness of epcoritamab plus R ² versus R ² alone in patients with relapsed or refractory follicular lymphoma from a US payer perspective.

2. Methods and Materials

2.1. Decision Model

A Markov cost‐effectiveness model was developed to evaluate the costs and health outcomes of treatment for patients with relapsed or refractory follicular lymphoma who had received at least one prior line of therapy. The model comprised three mutually exclusive health states: progression‐free survival (PFS), progressed disease (PD), and death (Figure 1). All patients entered the model in the PFS state. Upon transitioning to the PD state, patients were assigned to post‐progression treatment, consisting of subsequent‐line therapy followed by ongoing routine healthcare resource use. To implement this time‐varying post‐progression cost structure within the cohort Markov model, a tunnel‐state approach was adopted to assign costs according to time since entry into the PD state. In this approach, patients entering PD were allocated to predefined post‐progression care pathways and then tracked by the number of cycles spent in each pathway, allowing line‐specific treatment costs to be applied for their durations and healthcare resource use costs thereafter. Only direct medical costs were considered. A cycle length of 28 days was used to reflect the treatment schedule in EPCORE FL‐1, and a 30‐year time horizon was adopted to capture long‐term costs and health outcomes. Half‐cycle correction was applied. Costs and health outcomes were discounted at an annual rate of 3%. Model outcomes included total costs, life‐years (LYs), quality‐adjusted life‐years (QALYs), and incremental cost‐effectiveness ratio (ICER). A willingness‐to‐pay (WTP) threshold of $150,000 per QALY gained was used to assess cost‐effectiveness. All analyses were conducted in R (https://www.r‐project.org).

FIGURE 1.

Three‐state Markov model structure. A three‐state markov model was developed, consisting of progression‐free survival (PFS), progressed disease (PD), and death. All patients entered the model in the PFS state and could transition from PFS to PD or death, and from PD to death. The dashed arrow from PFS to death represents background mortality.

2.2. Model Probabilities

Transition probabilities from PFS to PD and from each health state to death were derived from the overall survival (OS) and progression‐free survival (PFS) curves reported in EPCORE FL‐1 trial. Data points from the published Kaplan–Meier curves were extracted using WebPlotDigitizer (version 4.8). The reconstructed survival data were then fitted to standard parametric survival distributions to extrapolate outcomes beyond the observed follow‐up period. The optimal distribution was selected based on the Akaike information criterion (AIC), Bayesian information criterion (BIC), and visual inspection of the fitted curves (Supporting Information S1: Tables S1–S4, Figure S1). An exponential distribution was selected for OS in both treatment arms. For PFS, an exponential distribution was selected for the epcoritamab plus R ² arm, whereas a log‐logistic distribution was selected for the R ² arm. Visual inspection suggested that the fitted survival curves were consistent with the trial‐based Kaplan–Meier curves (Supporting Information S1: Figure S2). The scale and shape parameters of each fitted distribution were estimated and used to calculate cycle‐specific transition probabilities (Table 1). The probability of direct transition from PFS to death was assumed to be equal to background mortality in the US general population, based on US life table [27].

TABLE 1.

Parameters for cost‐effectiveness analysis model.

Parameter	Base value	Range	Distribution
PFS for epcoritamab plus R 2	Exponential: λ = 0.0114
PFS for R 2	Log‐logistic: α = 13.48 β = 1.917
OS for epcoritamab plus R 2	Exponential: λ = 0.0029
OS for R 2	Exponential: λ = 0.0071
Utilities
PFS [11]	0.8373	0.8073–0.8657	Beta
PD [11]	0.765	0.7197–0.8117	Beta
Disutilities
Neutropenia [12]	0.47	0.45432–0.48568	Beta
Anemia [12]	0.29	0.27236–0.30764	Beta
Thrombocytopenia [13]	0.108	0.097–0.119	Beta
Infection [14]	0.218	0.1744–0.2616	Beta
CRS [15]	0.05	0.03–0.06	Beta
Cost ($)
Epcoritamab 48 mg [16]	16,809.96	13,447.97–20,171.95	Gamma
Epcoritamab 4 mg [16]	1400.83	1120.66–1680.99	Gamma
Lenalidomide per cycle [17]	18,723.00	14,978.40–22,467.60	Gamma
Rituximab 10 mg [18]	93.95	75.16–112.74	Gamma
Monthly third‐line treatment cost [19]	25,596.63	20,477.30–30,715.96	Gamma
Monthly fourth‐line or later therapy cost [19]	31,795.79	25,436.63–38,154.95	Gamma
Monthly healthcare resource cost of PD [20]	495.27	396.22–594.32	Gamma
Terminal cost [21]	66,889.17	53,511.33–80,267.00	Gamma
Cost of neutropenia [22]	15,048.85	12,039.08–18,058.62	Gamma
Cost of anemia [22]	7977.88	6382.30–9573.46	Gamma
Cost of thrombocytopenia [22]	12,598.47	10,078.78–15,118.16	Gamma
Cost of infection [22]	7781.26	6225.00–9337.51	Gamma
Cost of CRS [11]	7579.34	6063.47–9095.21	Gamma
Unit cost of follow‐up [23, 24]	71.49	57.19–85.79	Gamma
Unit cost of CT [23, 25]	671.65	537.32–805.98	Gamma
Chemotherapy IV infusion, first h [23]	119.36	95.49–143.23	Gamma
Chemotherapy IV infusion additional h [23]	25.55	20.44–30.66	Gamma
Body surface area [26]	1.835	1.468–2.202	Log‐normal

Abbreviations: CRS, cytokine release syndrome; CT, computed tomography; IV, intravenous; OS, overall survival; PD, progressed disease; PFS, progression‐free survival; R ², rituximab plus lenalidomide.

2.3. Cost and Utility Estimate

Direct medical costs included drug acquisition, administration, routine follow‐up, adverse event (AE) management, progressed disease, and end‐of‐life care. All costs were expressed in 2025 US dollars (USD). Costs obtained from earlier sources were inflated to 2025 USD using the medical care component of the US Consumer Price Index (CPI) [28]. Key inputs are presented in Table 1.

Drug treatment was assumed to be administrated only during the PFS state and was limited to cycles 1 through 12. Dosing schedules were based on the EPCORE FL‐1 trial protocol: epcoritamab was administered subcutaneously following a step‐up dosing schedule during cycle 1 (0.16 mg on day 1, 0.8 mg on day 8, 3 mg on day 15, and 48 mg on day 22), followed by 48 mg weekly during cycles 2–3, and 48 mg every 4 weeks during cycles 4–12. In both arms, lenalidomide was administered orally at 20 mg once daily on days 1–21 of each cycle (cycles 1–12), and rituximab was administered intravenously at 375 mg/m² weekly during cycle 1 and once every 4 weeks during cycles 2–5. An external mean body surface area of 1.835 m² was used to estimate rituximab dose [26]. Drug acquisition costs were based on wholesale acquisition cost (WAC) pricing [16, 17, 18].

After completion of the treatment period (cycle 12), patients remaining in the PFS state accrued routine follow‐up costs only, with no further drug treatment costs. Follow‐up items and their frequency were based on published clinical guidelines [29], including, physical examination, laboratory testing, and computed tomography (CT) scans. All follow‐up items and frequency are presented in Supporting Information S1: Table S6.

Administration costs were applied only to rituximab, which was administered intravenously. These costs were estimated based on infusion duration using the 2025 Centers for Medicare & Medicaid Services (CMS) Physician Fee Schedule [23].

Post‐progression costs consisted of subsequent‐line treatment expenses and healthcare resource use costs. Since post‐progression treatment patterns and their corresponding proportions were not reported in the EPCORE FL‐1 trial, these parameters were derived from a US retrospective claims study of follicular lymphoma patients experiencing early treatment failure following first‐line chemoimmunotherapy [19]. This study reported the mean per‐patient‐per‐month (PPPM) costs by subsequent line of therapy (inclusive of inpatient, outpatient, pharmacy, and other medical costs), the mean therapy durations and the proportions of patients receiving subsequent‐line therapy.

Given that the trial population represented a second‐line or later‐line treatment setting, post‐progression treatment was assumed to begin with a third‐line treatment phase. Based on the claims analysis, 38.0% of patients were modeled to receive third‐line treatment (duration, 14.5 months), and 15.5% were further modeled to receive fourth‐line or later therapy, representing a combined category of all treatment lines beyond third‐line (duration, 11.5 months). Patients who did not receive subsequent treatment after disease progression, as well as those who remained in the PD state after completing subsequent‐line therapy, were assumed to incur only monthly healthcare resource utilization costs, including routine inpatient, emergency department, and outpatient oncology visits [20].

Costs associated with adverse events (AEs) were also incorporated into the model. AEs of grade ≥ 3 with an incidence of ≥ 5% in either treatment arm of the EPCORE FL‐1 trial were included. In addition, cytokine release syndrome (CRS) was included regardless of grade given its clinical relevance to epcoritamab‐based therapy. AE‐related costs were applied as one‐time costs during the treatment period. Unit costs for AE management were derived from published literature [11, 22]. AE incidence rates are presented in Supporting Information S1: Table S5.

End‐life care costs were applied as a one‐time cost upon death. Because the transition from PFS directly to death was assumed to reflect background mortality rather than disease‐related mortality, end‐life costs were applied only to patients who died following disease progression. The cost of end‐life care was obtained from published literature [21].

Because utility data were not reported in the EPCORE FL‐1 trial, health‐state utility values were derived from published studies [11]. The same utility values were assumed for both treatment arms. Disutilities associated with AEs were applied as one‐time decrements in the model cycle in which the event occurred. AE disutility values were obtained from published literature [12, 13, 14, 15]. All utility and disutility values are summarized in Table 1.

2.4. Sensitivity Analyses

Parameter uncertainty was evaluated through one‐way sensitivity analysis (OWSA), probabilistic sensitivity analysis (PSA), and scenario analyses. In the OWSA, each parameter was varied individually using reported standard errors (SEs) or 95% confidence intervals (CIs) where available; otherwise, a range of ± 20% of the base‐case value was assumed. In the PSA, all parameters were varied simultaneously over 1000 Monte Carlo simulations, with probability distributions assigned according to parameter type. Where standard errors were not reported, a standard error of 10% of the base‐case value was assumed to parameterize the distributions.

To explore the impact of potential differences in PFS utility values between treatment arms, a two‐way sensitivity analysis was conducted.

Scenario analyses were conducted to assess the robustness of the base‐case results under alternative structural assumptions. Three scenarios were examined: (1) assuming an NCCN‐informed post‐progression treatment strategy in which chimeric antigen receptor T‐cell(CAR‐T) therapy was used after disease progression [30], to represent a plausible contemporary later‐line treatment option with a high upfront cost structure; (2) adopting Weibull distributions for survival extrapolation, as their AIC and BIC values were similar to those of the base‐case model while providing greater flexibility in long‐term hazard modeling. The corresponding extrapolated OS and PFS curves are presented in Supporting Information S1: Figures S3 and S4, respectively; and (3) varying the analytic time horizon to 10 and 20 years to assess the sensitivity of cost‐effectiveness results to the choice of time horizon in a chronic, relapsing disease setting. All parameter inputs, base‐case values, ranges, and distributions used in sensitivity analyses are presented in Table 1.

3. Results

3.1. Base Case Results

In the base‐case analysis, the model projected a life expectancy of 13.16 LYs for patients receiving epcoritamab plus R ² and 8.40 LYs for those receiving R ². Accounting for quality of life, the epcoritamab plus R ² arm yielded 10.47 QALYs, compared with 6.53 QALYs for the R ² arm. The total cost was $739,293.10 for epcoritamab plus R ² and $471,572.09 for R ². Epcoritamab plus R ² was associated with an incremental gain of 3.94 QALY at an incremental cost of $267,721.01, resulting in an ICER of $67,974.64 per QALY gained compared with R ² (Table 2).

TABLE 2.

Base‐case cost‐effectiveness analysis results.

Result	Epcoritamab plus R 2	R 2	Incremental
LYs	13.16	8.40	4.76
QALYs	10.47	6.53	3.94
Total cost ($)	739,293.10	471,572.09	267,721.01
ICER($/QALY)			67,974.64

Abbreviations: ICER, incremental cost‐effectiveness ratio; LYs, life‐years; QALYs, quality‐adjusted life‐years; R ², lenalidomide and rituximab.

3.2. Sensitivity Analysis

The results of the OWSA are presented in Figure 2. The ICER was most sensitive to the acquisition cost of epcoritamab, ranging from $53,819.80 per QALY when the cost was reduced to 80% of the base‐case value to $82,129.49 per QALY when increased to 120%. All other parameters had a relatively limited impact on the ICER, which remained below $70,274.70 per QALY across all variations tested.

FIGURE 2.

Tornado diagram of one‐way sensitivity analysis. The tornado diagram shows the parameters with the greatest influence on the incremental cost‐effectiveness ratio (ICER) for epcoritamab plus lenalidomide and rituximab(R ²) versus R ².

The results of the PSA are illustrated using the cost‐effectiveness acceptability curve (CEAC) (Figure 3). The CEAC demonstrated that the probability of epcoritamab plus R ² being cost‐effective increased with higher WTP thresholds. At a WTP threshold of $150,000 per QALY, epcoritamab plus R ² had a 100.0% probability of being cost‐effective. Overall, the PSA results were consistent with the base‐case findings, indicating that the model results were robust to parameter uncertainty.

FIGURE 3.

Cost‐effectiveness acceptability curve. The cost‐effectiveness acceptability curve shows the probability that epcoritamab plus R ² is cost‐effective compared with R ² across a range of willingness‐to‐pay (WTP) thresholds.

In the two‐way sensitivity analysis, at a willingness‐to‐pay threshold of $150,000 per QALY, epcoritamab plus R ² remained the cost‐effective strategy across all tested range (Supporting Information S1: Figure S5).

The results of the scenario analyses are summarized in Supporting Information S1: Table S7. When the OS curves were refitted using a Weibull distribution while keeping the PFS distributions unchanged from the base case, the ICER decreased to $56,218.26 per QALY. Conversely, fitting a Weibull distribution to the PFS curves for both arms increased the ICER to $75,594.95 per QALY. Assuming the use of CAR‐T therapy for post‐progression care decreased the ICER to $49,311.14 per QALY. Shortening the time horizon to 10 and 20 years yielded ICERs of $176,729.50 and $89,810.47 per QALY, respectively. Across all scenarios evaluated, the ICER remained below the threshold of $150,000 per QALY, except for the 10‐year time horizon scenario.

4. Discussion

The EPCORE FL‐1 trial demonstrated encouraging clinical outcomes for epcoritamab plus R ² in patients with relapsed or refractory follicular lymphoma. Our model projected that epcoritamab plus R ² yielded greater LYs and QALYs relative to R ², albeit at a higher total cost. The base‐case ICER was $67,974.64 per QALY, well below the WTP threshold of $150,000 per QALY, suggesting that epcoritamab plus R ² represents a cost‐effective treatment option.

To our knowledge, no published cost‐effectiveness analysis has specifically evaluated epcoritamab plus R ² in patients with relapsed or refractory follicular lymphoma. However, evidence from other novel therapies provides useful context. In relapsed or refractory diffuse large B cell lymphoma, epcoritamab was reported to be cost‐effective versus axicabtagene ciloleucel [31]. In relapsed or refractory follicular lymphoma, mosunetuzumab, another CD20×CD3 bispecific antibody, was cost‐effective compared with several approved regimens, although its lower costs and lower QALYs versus rituximab plus lenalidomide indicate that conclusions depend on the comparator selected [11]. CAR‐T therapy, such as axicabtagene ciloleucel, differs from bispecific antibodies by involving high one‐time costs and more complex administration, but may achieve favorable economic value when durable remission and reduced subsequent therapy are assumed. Accordingly, a US analysis found axicabtagene ciloleucel to be cost‐effective versus mosunetuzumab, mainly because of assumptions regarding long‐term remission, one‐time treatment costs, and fewer subsequent lines of therapy [32]. These findings suggest that the value of epcoritamab plus R ² should be interpreted within a broader treatment landscape in which CAR‐T therapies and bispecific antibodies differ in cost structure, delivery requirements, durability of benefit, and downstream treatment implications.

One‐way sensitivity analysis identified drug acquisition cost as the most influential parameter affecting the ICER. To further explore the main cost drivers, total costs were decomposed into major categories (Supporting Information S1: Table S8). A previous study estimated the lifetime treatment cost of follicular lymphoma in the United States at approximately $515,884.00 and identified drug therapy as the largest cost component [33]. Consistent with that finding, treatment‐phase drug costs represented the largest share of total costs in both treatment arms, reaching $518,554.54 in the epcoritamab plus R ² arm and $217,574.06 in the R ² arm, whereas cumulative progressed disease costs were $174,981.65 and $199,458.33, respectively. Given the long disease course of follicular lymphoma and the need for multiple lines of therapy [34], disease progression is likely to increase subsequent healthcare resource use. Published evidence likewise suggests that costs are markedly higher among patients with disease progression than among those without progression [35]. In our analysis, although costs accrued in the progressed disease state remained substantial, drug acquisition costs during the treatment phase accounted for the largest share of total costs in both arms, and differences in drug acquisition costs between strategies contributed most directly to the incremental cost. This also explains why drug acquisition cost remained the most influential parameter in the one‐way sensitivity analysis. Notably, costs of PD state were lower in the epcoritamab plus R ² arm than in the R ² arm, reflecting the ability of more effective disease control to delay progression and thereby reduce the economic burden associated with the progressed disease.

Durable disease control remains a primary therapeutic goal in relapsed or refractory follicular lymphoma. The progression‐free survival benefit associated with epcoritamab plus R ² provides an important clinical basis for interpreting its economic value, as extended time spent in the progression‐free state directly translated into incremental QALY gains. This relationship was further corroborated by the scenario analyses. When the time horizon was shortened to 10 years, the ICER increased to $176,729.50 per QALY, exceeding the WTP threshold of $150,000 per QALY. This finding suggests that the cost‐effectiveness of epcoritamab plus R ² depends largely on the accumulation of long‐term health benefits. Under a shorter analytic horizon, substantial upfront treatment costs are incurred early, whereas the downstream health benefits have not fully accrued, resulting in a less favorable ICER. By contrast, over a longer time horizon, the clinical benefit of sustained disease control is more fully captured as incremental LYs and QALYs, allowing a greater proportion of the upfront treatment costs to be offset by accumulated health gains. Taken together, these findings indicate that the economic value of epcoritamab plus R ² is jointly determined by high acquisition cost and long‐term health gains from prolonged disease control.

Several limitations of the present analysis deserve consideration. First, cost and utility inputs were derived from external data sources, which may not fully reflect actual resource use and costs in all real‐world settings. In addition, although post‐progression costs were incorporated, the base‐case analysis did not model a specific post‐progression treatment regimen. Instead, progressed disease costs were estimated using published US data on mean monthly costs after failure of first‐line chemoimmunotherapy. Because post‐progression treatment pathways may vary across patients, these estimates may not fully capture the heterogeneity of treatment received after progression. However, this uncertainty was explored in sensitivity and scenario analyses, and the overall conclusions remained unchanged across most assumptions tested. Second, the trial did not provide mature long‐term survival data. Therefore, long‐term survival was extrapolated beyond the observed follow‐up period using parametric survival models. Although scenario analyses using alternative survival distributions supported the base‐case findings, uncertainty in long‐term survival estimates remains. These projections should be interpreted with caution and reassessed when longer‐term follow‐up data become available.

Third, not all adverse events in the PFS state were included in the model, which may have led to underestimation of total treatment costs and treatment‐related disutility. However, the excluded adverse events were generally infrequent and mostly low grade. In addition, the sensitivity analyses showed that the ICER was not sensitive to AE‐related parameters. Therefore, the exclusion of these adverse events is unlikely to change the conclusions of the study. Finally, utility values were not derived from the EPCORE FL‐1 trial, and identical health‐state utilities were applied to both arms because treatment‐specific data were unavailable. Although this may not fully capture quality‐of‐life differences between regimens, a two‐way sensitivity analysis varying PFS utilities showed that epcoritamab plus R ² remained cost‐effective, suggesting limited impact on the overall conclusion.

In conclusion, adding epcoritamab to standard R ² for patients with relapsed or refractory follicular lymphoma increased healthcare costs but also generated meaningful gains in LYs and QALYs. At a WTP threshold of $150,000/QALY, epcoritamab plus R ² is likely to be a cost‐effective treatment option.

Funding

Talent Project established by Chinese Pharmaceutical Association Hospital Pharmacy department (NO. CPA‐Z05‐ZC‐2025‐003); Hunan Provincial Natural Science Foundation of China (grant number: 2026JJ50239); Health Research Project of Hunan Provincial Health Commission (Grant No. 20254693). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supporting Information S1

Data Availability Statement

The data used in this study were derived from published literature and publicly available sources. All data generated or analyzed during this study are included in this article and its supplementary information files.