Real-world data of siltuximab for Chinese patients with iMCD: combination with BCD regimen as a potential approach for severe cases

Abstract

Idiopathic multicentric Castleman disease (iMCD) is a rare disease characterized by polyclonal lymphoproliferation and systemic inflammation. Siltuximab, targeting interleukin-6 (IL-6), has been recommended as the first-line therapy for iMCD. However, substantial real-world data from China were still lacking, and treatment for patients with severe iMCD remained challenging. This single-center retrospective study investigated the real-world efficacy and safety of siltuximab-based therapy in 43 consecutive patients with iMCD in China from July 2022 to March 2024. The overall response rate (including symptomatic and biochemical response) was 59% at week 3 and increased to 91% at week 12, with complete and partial response rates of 54% and 37%, respectively. Patients who received siltuximab as a first-line treatment exhibited better treatment response (OR = 0·040, 95% CI, 0·004 − 0·390, p = 0·006). Inflammatory markers (such as interleukin-6 and high-sensitivity C-reactive protein [hsCRP]) and pathologic types showed no predictive role in the treatment responses. Eighteen patients, who were all classified as severe iMCD, received combined therapy of siltuximab and BCD regimen (bortezomib, cyclophosphamide and dexamethasone). Of them, the overall response rate was 50% at week 3, which increased to 100% at week 12. Our findings reinforced the existing evidence on the efficacy and safety of siltuximab and highlighted the potential benefits of combining siltuximab with BCD regimen in severe iMCD patients.

Introduction

Castleman disease (CD) was first described by Benjamin Castleman in 1954 as a rare lymphoproliferative disorder [1]. Human herpesvirus-8–negative/idiopathic multicentric Castleman disease (iMCD) accounts for one-third to slightly more than 50% of all CD cases, which involves systemic lymphadenopathy, constitutional inflammatory symptoms, polyclonal lymphoproliferation, and multiple organ system dysfunction. It is predominantly driven by a cytokine storm, with interleukin-6 (IL-6) being the key mediator [2, 3]. iMCD is classified into two main categories: iMCD with thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome (iMCD-TAFRO) and iMCD-not otherwise specified (iMCD-NOS). iMCD-TAFRO is unique for its severe clinical manifestations and rapid progression, whereas iMCD-NOS represents a broader category encompassing a diverse array of presentations and outcomes [3, 4]. Variations in clinical presentation and differences in disease severity between the two iMCD categories call for specific and stratified treatment strategies. Therefore, the concept of severe iMCD was proposed by the Castleman Disease Collaborating Network (CDCN) in 2018 [5]. Siltuximab monotherapy showed a high rate of response in patients with non-severe iMCD [6–8], whereas severe iMCD was treated with more aggressive intervention combining siltuximab with high-dose steroids [4, 9]. However, there remains a lack of consensus on the most effective treatment for patients with severe iMCD.

Siltuximab has emerged as a pivotal therapy because of its high affinity for IL-6, with clinical trials demonstrating significant efficacy in reducing the inflammatory state and improving survival rate [10–12]. However, clinical trials on iMCD are difficult to conduct as it is a rare disease [13]. A systematic review including the data from 1995 to 2021 revealed that 91.8% of patients with iMCD were Asians [14]. Considering the significant population size of China in Asia, our center previously presented comprehensive insights on the treatment and prognosis of Chinese patients with CD before IL-6-targeted therapy was introduced [15]. Furthermore, the approval and commercialization of siltuximab by the National Medical Products Administration in China have significantly advanced the clinical management of patients with iMCD. At this juncture, it is important to understand the treatment efficacy of siltuximab in real-world clinical practice. Here, we conducted the first retrospective study focusing on the effectiveness and safety of siltuximab in Chinese patients with iMCD, offering crucial real-world insights.

Methods

Study design and patients

This single-center, retrospective study was conducted at the Peking Union Medical College Hospital involving patients diagnosed with iMCD. Patients treated with siltuximab as part of their treatment regimens from July 2022 to March 2024 were consecutively included. The diagnostic criteria for iMCD were given as follows: (1) histopathologic lymph node features consistent with the iMCD spectrum, (2) enlarged lymph nodes in two or more lymph node stations, and (3) satisfying at least two of 11 criteria including one laboratory criterion as proposed by the CDCN and failing to satisfy any of the CDCN’s suggested exclusion criteria [3]. Patients with iMCD were further classified into iMCD-TAFRO and iMCD-NOS. The diagnostic criteria for iMCD-TAFRO were defined as the validated international definition in 2021 [16, 17]. It necessitates a combination of at least four clinical manifestations (including thrombocytopenia, anasarca, fever/hyperinflammatory state, and organomegaly), renal impairment, or specific bone marrow changes (e.g., reticulin fibrosis or megakaryocyte proliferation), alongside histopathologic evidence in lymph nodes indicative of iMCD and adherence to exclusion criteria. Patient severity was categorized according to the CDCN consensus [3]. Severe iMCD was defined as per a minimum of two of the following five criteria: (1) an Eastern Cooperative Oncology Group Performance Status ≥ 2, (2) stage IV renal impairment, (3) anasarca, (4) hemoglobin level ≤ 80 g/L, and (5) pulmonary complications/interstitial pneumonitis accompanied by dyspnea.

Treatment and outcomes

All patients received siltuximab at a dose of 11 mg/kg intravenously every 3 weeks or in a weekly schedule for patients with severe iMCD at the physician’s discretion. Based on the clinical condition of the patient, siltuximab was prescribed with or without steroid or as a combined treatment with BCD regimen (subcutaneous bortezomib 1.3 mg/m² weekly, oral cyclophosphamide 300 mg/m² weekly, oral dexamethasone 40 mg weekly, all administered on days 1, 8, 15, and 22 of a 4-week cycle). For patients in the siltuximab with or without steroid group, if siltuximab was proven to be consistently effective, the treatment interval for some patients was extended to 6 weeks after careful clinical evaluation. For patients receiving combination therapy, siltuximab and BCD were administered in parallel during the early stage of the disease (i.e., intravenous siltuximab on days 1, 8, 15, 22 in a weekly schedule, or on days 1, 22 in a 3-week schedule). After several cycles of siltuximab, a proportion of patients were transferred to BCD regimen without siltuximab at the physician’s discretion. Treatment continued until the disease progression or discontinuation because of severe adverse events or economic limitations of the respective patient. Follow-up data of patients were systematically collected from outpatient clinics, phone contacts, and records of patient visits from hospital database. Study endpoints include overall response rates (ORRs) at weeks 3, 6, 9, and 12 and adverse events during the treatment and follow-up periods.

Treatment response was evaluated as per the CDCN consensus guidelines [5]. According to the criteria, the overall response was defined as the symptomatic and biochemical response, with the exception of the lymph node response in imaging. An overall complete response (CR) was defined as the complete biochemical and symptomatic inflammation-related (fever, fatigue, anorexia, and weight loss) response. An overall partial response (PR) was defined as an improvement in all four symptomatic inflammation-related responses and > 50% improvement in all the biochemical parameters (high-sensitivity C-reactive protein, hemoglobin, albumin, estimated glomerular filtration rate). An overall progressive disease (PD) was defined as > 25% deterioration in laboratory tests and aggravation of any of the four inflammation-related symptoms. The overall stable disease (SD) was defined as the absence of PR, CR, or PD. “Responders” were defined as patients who achieved at least overall PR to siltuximab therapy during the follow-up period. Adverse events were assessed according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (version 5·0), until the end of follow-up period.

Statistical analyses

For continuous variables, descriptive statistics were presented as median with range. Categorical variables were compared using the chi-square test or Fisher’s exact test. Comparison of continuous variables was performed using Student’s t-test for normally distributed data. Univariate logistic regression was performed to analyze the potential factors for treatment response. Continuous variables were classified based on the consensus criteria or the median values from our patient group. Statistical significance was set at p < 0.05, and all p-values reported were two sided. Statistical analyses were performed using SPSS version 24·0 (IBM Inc., Chicago, IL, USA) software package.

Results

Baseline characteristics

A cohort of 43 consecutive patients with iMCD treated with siltuximab was included and analyzed. The median age at the initiation of treatment with siltuximab was 42 years (range: 15–70 years), and 51.2% of the pateints were men (n = 22). On the basis of the clinical classification, 72.1% (n = 31) of the patients were categorized as iMCD-NOS and 27.9% (n = 12) of patients as iMCD-TAFRO. Severe iMCD was observed in 20 patients (46·5%), including 8 patients with iMCD-NOS and 12 with iMCD-TAFRO. Disease histology varied, with most patients showing plasmacytic histology (n = 28; 65.1%). Fatigue was the most common disease-related symptom observed (n = 38; 88.4%). The baseline laboratory data of all 43 patients were collected. Anemia was prevalent with a median hemoglobin level of 90 g/L (57–134 g/L). The systemic inflammatory state was indicated by the elevated levels of high-sensitivity C-reactive protein (hsCRP, 70 mg/L), fibrinogen (4.6 g/L), and IL-6 (21 pg/mL). Most of the patients received (n = 31; 72.1%) siltuximab as their initial therapy. In terms of the treatment regimens, 25 patients were treated with siltuximab (with or without steroids), whereas the remaining 18 patients received a combined treatment of siltuximab and the BCD regimen by drawing significant insights obtained from our previous observations [18, 19]. The baseline characteristics including clinical symptoms and laboratory results are summarized in Table 1.

Table 1.

Baseline characteristics of the siltuximab-treated patients with iMCD

Characteristic	All patients (n = 43)
Age at siltuximab initiation in years, median (range)	42 (15–70)
Male, n (%)	22 (51.2%)
Clinical classification, n (%)
iMCD-NOS	31 (72.1%)
iMCD-TAFRO	12 (27.9%)
Severe iMCD	20 (46.5%)
Disease histology, n (%)
Hyaline vascular	7 (16.3%)
Plasmacytic	28 (65.1%)
Mixed	8 (18.6%)
Disease-related symptom, n(%)
Fatigue	38 (88.4%)
Fever	29 (67.4%)
Weight loss	25 (58.1%)
Anorexia	22 (51.2%)
Organomegaly	22 (51.2%)
Pleural/pericardial effusion/ascites	19 (44.2%)
Sweats	8 (18.6%)
Dyspnea	11 (25.6%)
Skin involvement	10 (23.3%)
Laboratory data, median (range)
Hb, g/L	90 (57–134)
PLT,×109/L	255 (11–529)
Alb, g/L	32 (21–45)
ALP, g/L	111 (52–581)
ALT, g/L	15 (4-107)
sCr,µmol/L	71 (34–977)
IgG, g/L	20 (8–92)
IL-6, pg/ml	21 (3-3493)
hsCRP, mg/L	70 (5-240)
Fbg, g/L	4.6 (1.5–9.5)
Follow-up period, median(range), month	8.6 (1.0-19.5)
Siltuximab as first-line therapy, n (%)	31 (72.1%)
Siltuximab-containing regimen, n (%)
Siltuximab ± steroids	25 (58.1%)
Siltuximab + BCD	18 (41.9%)

Abbreviations: Alb, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; BCD, bortezomib, cyclophosphamide and dexamethasone; Fbg, fibrinogen; Hb, hemoglobin; hsCRP, hypersensitive C-reactive protein; Ig, immunoglobulin; IL-6, interleukin-6; iMCD, idiopathic multicentric Castleman disease; iMCD-NOS, iMCD-not otherwise; iMCD-TAFRO, iMCD-thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly; PLT, platelet; sCr, serum creatinine

Efficacy and safety of Siltuximab treatment

In our study, the efficacy of siltuximab for 12 weeks was evaluated, categorizing patient response into CR, PR, SD, and PD across biochemical, symptomatic, and overall assessments (Fig. 1). At week 3, the initial efficacy of siltuximab was 34%, 59% and 27% for biochemical CR, symptomatic CR, and overall CR, respectively. By week 6, improvement was observed particularly in symptomatic response, with CR increasing to 77%. At week 9, both biochemical and symptomatic CR rates rose to 47% and 84%, respectively, contributing to an overall CR rate of 45%. By week 12, the efficacy peaked with the highest CR rates: biochemical CR at 54% and symptomatic CR at 89%. The ORR was 91%, with an overall CR rate of 54% and an overall PR of 37%.

Fig. 1.

Efficacy evaluation within 12 weeks of siltuximab treatment. CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease

The potential predictive factors for siltuximab treatment responses were analyzed (Table 2). Patients were categorized into responders and nonresponders based on their treatment responses. Univariate logistic regression analysis highlighted that patients who received siltuximab as a first-line treatment showed better treatment response (OR = 0.040, 95% CI, 0.004–0.390, p = 0.006). Inflammatory markers (IL-6 and hsCRP) and the pathologic types of CD did not have a significant predictive role in the responses of siltuximab-based treatment.

Table 2.

Prognostic analysis using the univariate logistic regression

Risk factors	Univariate analysis
	OR (95% CIs)	p value
Age at siltuximab treatment	0.977 (0.915–1.043)	0.480
Sex, male	0.133 (0.015–1.224)	0.075
Hyaline-vascular variate	1.200 (0.121–11.865)	0.876
Severe iMCD	2.500 (0.428–14.607)	0.309
iMCD-TAFRO	2.640 (0.283–24.616)	0.394
Anemia (Hb < 100 g/L)	0.477 (0.093–2.461)	0.377
Hypoalbuminemia (Alb < 35 g/L)	0.424 (0.082–2.195)	0.306
Elevated immunoglobulin G (> 17 g/L)	5.368 (0.586–49.223)	0.137
Elevated hsCRP (> 70 mg/L)	0.794 (0.154–4.082)	0.738
Elevated IL-6 (> 21pg/ml)	1.333 (0.260–6.828)	0.730
Comination therapy	0.186(0.020–1.708)	0.137
Siltuximab as first-line treatment	0.040 (0.004–0.390)	0.006

Abbreviations: Alb, albumin; CIs, confidence intervals; Hb, hemoglobin; hsCRP, hypersensitive C-reactive protein; IL-6, interleukin-6; iMCD-TAFRO, iMCD-thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly; MCD, idiopathic multicentric Castleman disease; OR, odd ratio

Note: Hb, Alb, and IgG were classified according to the Castleman disease in China (2021) consensus criteria. IL-6 and hsCRP were classified based on the median values of this patient group

As far as the adverse events are concerned, three patients had skin-related adverse reactions (grade 1 or 2), characterized by pruritus, desquamation, and rashes, accompanied by pigmentation alterations primarily on the facial, limb, palmar, and plantar regions. In addition, one patient presented with swelling in the interphalangeal joints of the hands and knee. All dermatologic and articular symptoms were self-limiting and were resolved without specific treatment. Furthermore, one patient with iMCD-TAFRO who was treated with siltuximab and BCD combination encountered severe pneumonia (grade 3), which required treatment with antibiotics and antifungal agents along with oxygen supplement. After these interventions, the patient fully recovered from the infection and resumed his siltuximab and BCD treatment with continuous clinical improvement and sustained biochemical CR.

Combination therapy of Siltuximab with BCD regimens for severe iMCD

In our cohort, treatment regimens were categorized into two groups: siltuximab combined with BCD regimens (siltuxiamb + BCD) and siltuximab with or without steroids (siltuximab ± steroids). All patients receiving siltuximab + BCD (n = 18) were diagnosed with severe iMCD, highlighting the prominence of the cytokine storm in severe iMCD. Although the proportion of severe iMCD patients varied significantly between these two groups, the ORRs from week 3 to week 12 showed no significant differences between the two treatment approaches (siltuximab + BCD vs. siltuximab ± steroids) (Table 3). Specifically, for patients receiving siltuximab + BCD, the ORR was 50% at week 3, gradually improving to 100% at week 12.

Table 3.

Comparison of baseline characteristics and treatment responses between patients treated with siltuximab + BCD and siltuximab ± steroids

Characteristic	Siltuximab + BCD (n = 18)	Siltuximab ± steroids (n = 25)	p value
iMCD-TAFRO, n (%)	12 (66.7%)	0 (0%)	<0.001
Severe iMCD, n (%)	18 (100%)	2 (8%)	<0.001
Overall response rate, n/N (%)
3-week	9/18 (50%)	15/23 (65.2%)	0.326
6-week	12/16 (75%)	17/22 (77.3%)	0.871
9-week	15/16 (93.8%)	17/22 (77.3%)	0.355
12-week	14/14 (100%)	18/21 (85.7%)	0.259
Duration of siltuximab treatment, median (range), month	2 (1–11)	8(1–19)	<0.001

Abbreviations: BCD, bortezomib, cyclophosphamide and dexamethasone; iMCD, idiopathic multicentric Castleman disease; iMCD-NOS, iMCD-not otherwise; iMCD-TAFRO, iMCD-thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly; n, number of patients; N, total number

A significantly shorter siltuximab treatment duration was observed in the combination treatment group compared to the siltuximab ± steroids group (P < 0.01). By the end of follow-up of this study, the median siltuximab treatment duration was 8 months (range: 1–19 months) in the siltuximab ± steroids group, compared to 2 months (range: 1–11 months) in the siltuximab + BCD group. This difference can largely be attributed to the fact that 77.8% (14/18) of patients in the combination treatment group transitioned to BCD monotherapy after a short course of combined therapy, with the median duration of siltuximab treatment being 2 months (range: 1–6 months). Importantly, 12 of these 14 patients maintained their response for at least 3 months after discontinuing siltuximab.

Discussion

Patients with iMCD suffered from a broad range of life-threatening symptoms associated with cytokine storms, with IL-6 playing a crucial role in their development. Siltuximab was proven to be effective in about one-third of iMCD patients with durable response in a randomized controlled trial [8]. We have summarized the largest iMCD cohort in the world in 2023 before the era of IL-6 targeted therapy in China, indicating the importance of exploration of siltuximab for iMCD treatment in China [15]. This study, as the first real-world study for iMCD treatment in China, described the current use of siltuximab and evaluated the potential effectiveness of combination therapy involving siltuximab and BCD regimen.

Globally, notable efficacy of siltuximab was observed across various findings in patients with iMCD. The real-world studies from the United States, Korea, and Poland have shown ORRs ranging from 64 to 76% in 11–21 patients [19–21]. Contrarily, in an Italian study, a lower ORR of 33.3% was reported in siltuximab-treated patients with relapsed/refractory (r/r) iMCD [22]. Compared with these findings, our study showed an increased ORR of 91% by week 12, with overall CR and PR rates of 54% and 37%, respectively. One patient in our cohort had progressed to irreversible end-stage renal disease, requiring dialysis before siltuximab treatment, and could not achieve biochemical response as per the CDCN criteria. However, other key biochemical parameters of the patient returned to normal. This patient was regarded as a nonresponder in our study but responded well to siltuximab monotherapy. Apart from the high response rates, we also found a gradual increase in response rates with siltuximab-based therapy within 12 weeks of treatment. Thus, the findings of this current study support the continuous utilization of siltuximab unless a PD is observed in the early stage.

When the potential risk factors for siltuximab treatment were analyzed, our study did not find a significant association between IL-6 or hsCRP levels and treatment outcomes. Similar observations were found in a phase II clinical trial conducted by Casper et al., showing no significant association between baseline levels of IL-6 or CRP and siltuximab treatment response [23]. Contrastingly, Morra et al. observed a positive association between higher CRP and IL-6 levels and treatment response, after excluding patients with SD [24]. Our study conditions were more similar to those of the investigation of Casper et al., leading to parallel conclusions. Moreover, nearly 50% of our patients received a combined regimen of BCD and siltuximab, which might have influenced our results. We also assessed the relationship between pathologic type and efficacy of siltuximab. A previous randomized controlled trial indicated that the hyaline vascular subtype did not show durable tumor and symptomatic responses in the siltuximab treatment group [8]. However, our real-world data demonstrated that siltuximab treatment showed good effectiveness in patients with hyaline vascular as well as with other pathologic types, suggesting the effectiveness of siltuximab is independent of pathologic types. Treatment-naïve iMCD patients responded well to siltuximab, which was an important finding that was concerning from our study.

According to the CDCN guidelines, patients with severe iMCD were recommended to receive high-dose steroids in combination with siltuximab, with indefinite continuation for those who respond quickly [5]. However, the response rate was limited and once patients became nonresponsive to siltuximab plus high-dose steroids, no consensus on subsequent aggressive interventions was available. Our previous study showed that the BCD regimen was effective in newly diagnosed patients with iMCD, with a 70% ORR at week 24 [18]. Furthermore, the BCD regimen did not show a significant difference in 3-year overall survival between patients with non-severe and severe iMCD. This suggests that the combination therapy could be considered for patients with severe iMCD. Zhang et al. enrolled 24 patients with r/r iMCD; of whom, 15 patients achieved overall treatment responses by 6 months after the treatment with the BCD regimen [25]. Based on these findings, we introduced the combined regimen of siltuximab with BCD for patients with severe iMCD.

As described, all patients receiving the siltuximab + BCD therapy were severe iMCD, while those diagnosed as non-severe iMCD were treated with siltuximab ± steroids. In the early stage of the disease, patients in the combination therapy group received both treatments concurrently. The rationale behind the approach was to rapidly control the cytokine storm in severe cases and minimize the potential for organ dysfunction, thereby reducing the risk of poor prognosis [11]. Our results demonstrated that this combined therapy achieved an impressive ORR of 100% at week 12, presenting similiar positive outcomes for both severe and non-severe iMCD patients. In addition to its favorable efficacy, this combination treatment also reduced the duration of siltuximab use. While CDCN guidelines recommended long-term use of siltuximab [5], patients in our study transitioned to the BCD regimen after a median of 2 months (range: 1–6 months). Of those, 85.7% (12 out of 14) patients maintained their response for at least 3 months after discontinuing siltuximab. Given that siltuximab was expensive and required continuous intravenous administration, our strategy of short-term intensified treatment followed by long-term maintenance with BCD which could be conveniently used at home [25] offered a more sustainable approach for managing severe iMCD patients.

Adverse events observed in our cohort, predominantly dermatologic reactions, were consistent with those reported in the Polish and Italian studies [21, 22]. The self-limiting nature of these adverse events supported the tolerability of siltuximab. In addition, the blockade of IL-6 signaling could potentially increase the risk of infection by impairing the acute-phase response. Previous data showed that the patients treated with siltuximab had an exposure-adjusted incidence rate of serious infections of 20 per 1000 patient-years [12]. Our study observed one case of severe pneumonia. After timely supportive treatment, the patient recovered quickly and received the subsequent dose of siltuximab without any concern. In point of fact, it was difficult to establish the etiology of adverse events between the two drugs in patients treated with siltuximab and BCD combination.

There are several limitations to this study. First, because of its retrospective nature, potential biases and unmeasured confounding variables were unavoidable. Second, the criteria for determining the overall response varied among the studies. For example, the Korean cohort emphasized symptomatic responses, whereas Italian research included both radiologic and symptomatic assessments [20, 22]. Considering that the resolution of lymphadenopathy may be slow in anti-IL-6 therapy, which was evaluated as a median time of 5 months to the response of lymph node [8], our cohort focused on symptomatology and biochemical markers to better reflect the early therapeutic effects. Furthermore, the biochemical response could well reflect the essence of inflammatory disease. Third, because of the recent introduction of siltuximab in China, our cohort had a shorter median follow-up period of 8.6 months compared with other cohorts, which typically ranged from 9 to 16 months [20–22]. Although limited follow-up duration may compromise the quality of the statistical outcomes, it was reasonable to speculate that improved therapeutic outcomes may be observed with extended follow-up as some of our patients were in the early stage of treatment. Lastly, given the design of our combination therapy, it was difficult to directly compare the effectiveness of siltuximab, BCD alone, and siltuximab + BCD, as the majority of patients ultimately received long-term maintenance with BCD. However, considering the rapid onset of siltuximab and based on our real-world results [11], this combination therapy appeared to be a promising strategy, at least in the early stages of severe cases. Future research comparing these three treatment arms was essential to determine the most effective therapy for severe iMCD.

In summary, our findings reinforced the existing evidence regarding the efficacy and safety of siltuximab in treating iMCD in the Chinese population and underscored the remarkable effectiveness of combining siltuximab with the BCD regimen for patients with severe iMCD.

Author contributions

LZ and JL designed the study; LC, KN-S, HC-C, DQ-Z, CW, JF, and ZL recruited the patients; SY-L, YH-G, and YD collected the data; SY-L and YH-G performed the analysis; SY-L, YH-G, LZ, and JL interpreted the data and wrote the manuscript; and all authors had access to primary clinical trial data and gave final approval to submit for publication.

Funding statement

This work was supported by the National High-Level Hospital Clinical Research Funding (Grant 2022-PUMCH-A-021 to LZ), the Research and Translation Application of Beijing Clinical Diagnostic Technologies Funds from Beijing Municipal Commission of Science and Technology (Grant Z211100002921016 to LZ), CAMS Innovation Fund for Medical Sciences (Grant No. 2021-1-I2M-019, to JL), and the Dongcheng District Outstanding Talent Nuturing Program (Grant 2022-dchrcpyzz-69 to LZ).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics statement

This study was conducted in accordance with the principles outlined in the Declaration of Helsinki, with prior approval granted by the ethics committee of the local hospital (PUMCH; Beijing, China).

Patient consent statement

The requirement for informed consent was waived due to the retrospective nature of the study.

Competing interests

The authors declare no competing interests.