Долгосрочная последующая работа с клеточной терапией BCMA CAR-T у пациентов с множественным миелом рецидива/отключения.

WHAT IS ALREADY KNOWN ON THIS TOPIC

B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell therapy has shown promise in treating relapsed or refractory multiple myeloma (R/RMM), but data on its long-term efficacy and safety in larger patient cohorts remain insufficient.

WHAT THIS STUDY ADDS

Prior autologous stem cell transplantation (ASCT) and extramedullary disease are adverse prognostic factors for patients with R/RMM receiving BCMA CAR-T therapy. Patients with a history of ASCT show limited peak CAR-T cell expansion.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

For patients at higher risk of early relapse after ASCT, lymphocyte collection prior to ASCT is recommended to achieve more durable responses with subsequent autologous BCMA CAR-T therapy.

Introduction

Multiple myeloma (MM) is a malignant plasma cell tumor that primarily occurs in elderly individuals and is characterized by bone destruction and extramedullary involvement. 1 , 3 Advances in treatment, including the use of immunomodulators, proteasome inhibitors, and CD38-targeting monoclonal antibodies, along with various drug combinations, have markedly improved the prognosis. 4 , 7 For eligible patients, autologous stem cell transplantation (ASCT) following high-dose chemotherapy remains the standard consolidation therapy, effectively reducing relapse rates. 8 , 10 Nevertheless, despite these advancements, most patients eventually experience relapsed or refractory disease, where treatment options become increasingly limited. In recent years, chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) has emerged as a promising therapeutic approach. 11 In patients with relapsed or refractory multiple myeloma (R/RMM), BCMA CAR-T cell therapy has shown remarkable efficacy, with overall response rates (ORR) ranging from 81% to 97.9% and complete remission (CR) rates between 33% and 82.5%, 12 , 18 confirming its significant potential in the treatment of R/RMM. With the growing application of BCMA CAR-T therapy, there is growing interest in understanding its long-term efficacy and safety in larger patient cohorts.

Relapse or disease progression was observed in approximately 20–52% of patients during a median follow-up period of 8–27.7 months. 13 17 19 20 In previous studies, a deeper response was closely associated with improved progression-free survival (PFS) and overall survival (OS). 21 A better understanding of the factors associated with CR rates and a durable response is crucial for improving treatment outcomes. Published data suggest that adequate CAR-T cell expansion is a fundamental prerequisite for achieving CAR-T cell efficacy. 12 13 15 Sufficient CAR-T cell expansion not only exerts direct antitumor effects but also enhances endogenous T cell and natural killer cell activity, thereby contributing to tumor destruction. 22 Insights from prior studies indicate that the characteristics of apheresis T cells may play an integral role, with the presence of specific T-cell subtypes, such as a high proportion of early memory cells, being associated with greater peak expansion. 23 24 However, these studies were limited by small sample sizes and did not provide further analysis of infused CAR-T cells. A comprehensive evaluation of product quality, along with a well-defined strategy for optimizing treatment regimens, remains essential to advancing therapeutic efficacy.

This study comprehensively evaluated the long-term efficacy and safety of BCMA CAR-T therapy in a large cohort of patients with R/RMM. It further investigated the influence of extramedullary disease and prior ASCT on the outcomes of subsequent BCMA CAR-T therapy. Besides, the post-infusion dynamics and immunophenotypic characteristics of the administered CAR-T cells were analyzed to elucidate potential mechanisms underlying the poor prognosis observed in specific subgroups.

Materials and methods

CAR-T cell production

BCMA CAR-T cells were generated from autologous T cells obtained through leukapheresis. A lentiviral vector was employed to introduce a second-generation BCMA-targeted CAR, incorporating 4-1BB as a costimulatory domain and CD3ζ as the signaling domain ( online supplemental figure S1 ). 25

Patients

Two clinical trials were included in this study (ChiCTR1800017404 and NCT05430945 ), which were conducted across different time periods. Both trials employed the same BCMA CAR-T cell product and followed identical treatment protocols. Patients underwent lymphodepletion chemotherapy consisting of cyclophosphamide (500 mg/m 2 administered on days −3 to −2) and fludarabine (30 mg/m 2 administered on days −4 to −2), followed by the infusion of autologous BCMA CAR-T cells on day 0. All patients provided written informed consent, and all procedures adhered to the principles of the Declaration of Helsinki and its subsequent amendments.

CAR-T cell immunophenotypes and cellular kinetics

Immunophenotype analysis of the CAR-T cell products was conducted using the CytoFLEX flow cytometer (Beckman, California, USA) following the completion of the CAR-T cell manufacturing process. The analysis employed the BCMA CAR Detection Reagent Anti-(G4S) n (B02H1) mAb FITC (GS-ARFT100, Hycells) in combination with the following antibodies: CD3-APC (555335, BD), CD45RA-BV421 (562885, BD), CD62L-BV650 (563808, BD), CD8-PE-CF594 (562311, BD), and CD4-APC-CY7 (557871, BD).

The dynamic changes in the cellular kinetics of CAR-T cells post-infusion were routinely monitored using the following antibody combinations: Anti-(G4S)n (B02H1) mAb FITC (GS-ARFT100, Hycells), CD45-APC (368512, BioLegend ), CD3-PECY7 (980010, BioLegend ), CD4-PC5.5 (317428, BioLegend ) and CD8-PE (300907, BioLegend ). All data analyses were performed using FlowJo software (V.10, TreeStar, USA). Due to the low sensitivity of flow cytometry in tracking low quantities of CAR-T cells, quantitative PCR was used as a complementary method to monitor CAR transgene levels at 6 and 12 months post-CAR-T cell infusion.

Evaluation of long-term outcomes

Toxicity was classified based on the Common Terminology Criteria for Adverse Events V.5.0. Cytokine release syndrome (CRS) was evaluated using the modified criteria proposed by Lee et al . 26 Disease responses were evaluated based on the criteria established by the International Myeloma Working Group. 27 Responses to BCMA CAR-T cell therapy were categorized as CR, very good partial response (VGPR), or partial response (PR). Non-responses included progressive disease (PD), stable disease (SD), and minimal response (MR). The ORR was calculated as the sum of CR, VGPR, and PR. PFS was defined as the time from CAR-T cell infusion to the first occurrence of disease progression or death from any cause. OS was defined as the time from infusion until the patient’s death. For patients who attained CR, the cumulative incidence of relapse (CIR) was calculated from the initiation of CR to the point of relapse. Minimal residual disease (MRD) was evaluated using flow cytometry with a sensitivity threshold of 10 − ⁴.

Statistical analysis

Descriptive statistics encompassed medians with ranges for continuous variables and counts with corresponding percentages for categorical variables. Categorical variables were compared using the χ 2 test or Fisher’s exact test, as appropriate, while continuous variables were analyzed using the Mann-Whitney U test. The Kaplan-Meier method was used to estimate PFS and OS. Multivariable Cox regression analyses were conducted to identify risk factors associated with PFS and OS. Besides, multivariable logistic regression analyses were employed to examine factors influencing CR rates. A multivariable competing risk analysis was performed to assess the CIR among patients who achieved CR. All p values were two-sided, with statistical significance set at p<0.05. Statistical analyses were conducted using SPSS V.26.0 (SPSS, Chicago, Illinois, USA) and R V.4.2.0 (R Core Team, Vienna, Austria).

Results

Baseline characteristics of patients between July 30, 2018, and September 27, 2023, a total of 141 patients with R/RMM who underwent BCMA CAR-T therapy were enrolled in the study ( figure 1 ). As of the data cut-off date (June 5, 2024), the median follow-up duration was 20.2 months (range: 0.3–70.1 months). The baseline characteristics of the patients are summarized in table 1 . The median age at the time of CAR-T cell infusion was 60 years (range: 16–79) years. Among the enrolled patients, 107 (75.9%) exhibited bone marrow (BM) plasma cell infiltration at baseline, with 27 patients (19.1%) presenting a high tumor burden (≥50% BM plasma cells). Moreover, 65 patients (46.1%) had extramedullary lesions, 122 (86.5%) were classified as having Durie-Salmon stage 3 disease, and 60 (42.6%) were categorized as International Staging System stage 3. High-risk cytogenetic abnormalities in the relapsed/refractory state were observed in 90 patients (63.8%). Regarding prior treatments, 114 patients (80.9%) had received two to four prior lines of therapy, 111 (78.7%) had been treated with a combination of proteasome inhibitors and immunomodulatory agents, 48 (34.0%) had received daratumumab, and 56 (39.7%) had undergone ASCT before CAR-T cell infusion.

A total of 20 patients (14.2%) underwent bridging therapy between apheresis and lymphodepletion, following a comprehensive assessment of tumor burden and physical condition. The most frequently used agents were dexamethasone, pomalidomide, and cyclophosphamide ( online supplemental table S1 ). Among these patients, the clinical outcomes were as follows: PD (N=1, 5%), SD (N=5, 25%), MR (N=9, 45%), and PR (N=5, 25%).

Long-term efficacy

Seven patients experienced early mortality within the first month following the infusion of BCMA CAR-T cells. In the overall cohort, the ORR was 90.1% (127/141), with a CR rate of 48.2% (68/141). Among the 134 evaluable patients, the ORR was 94.8% (127/134), with 50.7% (68/134) achieving CR. Moreover, 16.4% (22/134) achieved VGPR, and 27.6% (37/134) reached PR ( figure 2F ). The median PFS was 15.2 months (95% CI, 7.6 to 22.8) ( figure 2A ). The 4-year PFS and OS rates were 37.4% (95% CI, 29.1% to 48.1%) and 63.2% (95% CI, 54.8% to 72.8%), respectively ( figure 2A, B ). Notably, 13 of the 60 patients with ongoing responses had responses lasting over 4 years, with the longest remission duration being 5.6 years. A total of 81 patients experienced PD and/or death. Of these, 32 PD patients had ongoing survival after receiving subsequent treatments. There were 49 deaths, primarily due to disease progression (N=38). Three patients died from intracerebral hemorrhage caused by tumor lysis and severe CRS, which led to coagulopathy and thrombocytopenia. Two of these patients had pre-existing grade 3 or higher thrombocytopenia prior to lymphodepletion. Seven patients died due to infections, including two from COVID-19. Moreover, one patient succumbed to liver failure resulting from hepatitis B reactivation.

Among the 68 patients who achieved CR, 66 (97.1%) attained MRD negativity at the 10 −4 threshold. The survival outcomes for CR patients were notably improved, with a median PFS of 42.37 months (range: 18.5 months to not reached), compared with 6.03 months (range: 3.2–13.27 months) in non-CR patients (p<0.001) ( figure 2C ). This significant benefit was also observed in OS (p=0.013), where the median OS was not reached ( figure 2D ). Among the CR patients, 33 (48.5%) experienced disease progression, with a 4-year CIR of 54.5% (95% CI, 40.0% to 69.1%) ( figure 2E ).

Safety

CRS occurred in 128 patients (90.8%), with 46 patients (32.6%) experiencing grade 3 CRS and 5 patients (3.5%) experiencing grade 4. Immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 11 patients (7.8%), all of whom had grade 1 or 2. The use of steroids, tocilizumab, or both for the management of CRS and ICANS was observed in 57 patients (40.4%) and 52 patients (36.9%), respectively ( table 2 ).

Regarding the prolonged cytopenias observed 1 month after infusion, grade ≥3 anemia persisted in 53 patients (39.6%), while 58 patients (43.3%) experienced grade ≥3 neutropenia, and 70 patients (52.2%) had grade ≥3 thrombocytopenia. Moreover, 66 patients (49.3%) continued to receive granulocyte colony-stimulating factor, 31 patients (23.1%) required packed red blood cell transfusions, and 36 patients (26.9%) received pooled platelet transfusions more than 1 month after BCMA CAR-T cell infusion ( table 2 ).

Secondary primary malignancies were reported in one case. The patient was diagnosed with acute myeloid leukemia 5.7 months after BCMA CAR-T cell infusion and subsequently received chemotherapy. The patient remains alive at the time of reporting.

Predictive factors associated with CR, CIR, PFS and OS

Multivariable logistic regression analyses revealed that prior ASCT was associated with a lower CR rate (relative risk (RR), 0.320 (95% CI, 0.132 to 0.778); p=0.012) ( figure 3A ). To further explore the risk factors for relapse among CR patients, multivariable competing risk models indicated that patients with extramedullary disease (RR, 2.191 (95% CI, 1.027 to 4.678); p=0.043) and those with prior ASCT (RR, 2.903 (95% CI, 1.120 to 7.524); p=0.028) had a higher CIR ( figure 3A ).

In the multivariable Cox regression analysis, extramedullary disease (HR, 2.161 (95% CI, 1.340 to 3.484); p=0.002) and prior ASCT (HR, 2.375 (95% CI, 1.359 to 4.152); p=0.002) were identified as independent risk factors for PFS ( figure 3B ). Only extramedullary disease (HR, 1.887 (95% CI, 1.003 to 3.552); p=0.049) was significantly associated with shortened OS ( figure 3B ). At disease progression, 33.3% (47 out of 141) of patients developed extramedullary lesions, including 42 patients who had pre-existing extramedullary disease at baseline.

The peak expansion of CAR-T cells correlated with the response

The infused CAR-T cell dose in the overall cohort was 2.36×10⁶/kg (range: 0.58–7.1×10⁶/kg), with a CD4/CD8 ratio of 3.06 (range: 0.09–56.05). The median time to peak CAR-T cell expansion occurred at 14 days post-infusion (range: 5–33 days), with the peak CAR-T cell proportion reaching 83.4% of T cells (range: 0.91–98.8%). CAR-T cells were detected in 34 of 61 (55.7%) patients who did not experience disease progression and had evaluable samples at 6 months, and in 17 of 53 (32.1%) patients at 12 months.

A higher CAR-T cell expansion peak was observed in responding patients (84.0%) compared with non-responding patients (14.7%) (p<0.001) ( online supplemental figure S2A ), as well as in CR patients (87.7%) compared with non-CR patients (75.2%) (p<0.001) ( online supplemental figure S2B ). Although the infused CAR-T cell dose in the CR group (2.73×10 6 /kg) tended to be higher than that in the non-CR group (2.18×10 6 /kg) (p=0.034) ( online supplemental figure S2C ), the infused dose showed no correlation with the in vivo expansion capacity of CAR-T cells following infusion ( online supplemental figure S2B ).

Given that CAR-T cell expansion is a critical initial step in achieving CAR-T efficacy, the cellular dynamics were analyzed in subgroups that exhibited poor efficacy following CAR-T therapy. No significant decrease in peak expansion was observed in patients with extramedullary disease (p=0.814). Meanwhile, a detailed analysis of the ASCT subgroup was conducted. The baseline characteristics of the ASCT and non-ASCT groups are summarized in online supplemental table S2 . Infused CAR-T cell doses were also comparable between the two groups (p=0.812) ( online supplemental figure S3A ). The median number of peak CAR-T cell expansion in the ASCT group was significantly lower than that in the non-ASCT group (74.8% vs 89.8%, p<0.001) ( online supplemental figure S3B ). However, the CD4/CD8 ratio of CAR-T cells showed no significant difference between the two groups during the peak expansion period (p=0.812) ( online supplemental figure S3C ).

Recent ASCT adversely affected the fitness of infused CAR-T cells, potentially impacting expansion dynamics

An investigation was conducted to assess whether the intrinsic characteristics of infused CAR-T cells contributed to the observed variations in CAR-T cell expansion dynamics. The immunophenotypes of available infused CAR-T cell products from 55 patients in the ASCT group and 83 patients in the non-ASCT group were analyzed using flow cytometry. The CD4/CD8 ratio of the infused CAR-T cells showed no significant difference between the two groups (p=0.236). Furthermore, within the CD4 and CD8 CAR-T cell subsets, no notable differences were observed in the distribution of naive CAR-T cells (CART N ), central memory CAR-T cells (CART CM ), effector memory CAR-T cells (CART EM ), or effector CAR-T cells (CART EFF ) ( figure 4A,B ).

To evaluate the impact of varying time intervals between ASCT and CAR-T cell therapy, a detailed analysis was conducted on infused CAR-T cells derived from T cells collected more than 1 year post-ASCT. No significant differences were found in the CD4/CD8 ratio (p=0.148) or in the distribution of CART N , CART CM , CART EM , and CART EFF cells between patients who received CAR-T therapy more than 1-year post-ASCT and those who did not undergo ASCT ( figure 4C,D ).

Notably, the proportion of CART N significantly decreased in infused CAR-T cells in patients who received ASCT in the past year compared with those who had not (p=0.006) in the CD4 subset ( figure 4E ). The CD8 subset exhibited a significant decrease in CART N (p=0.005) and a marked increase in CART EM (p=0.006) in patients who received ASCT within the previous year compared with those who had not ( figure 4F ). The CD4/CD8 ratio remained comparable between the two groups (p=0.920).

Compared with the group more than 1-year post-ASCT, no significant difference was observed in the CD4/CD8 ratio (p=0.349). However, in the group within 1-year post-ASCT, there was a significant decrease in CART N (p=0.004, 0.021) and a marked increase in CART EM (p=0.03, 0.01) for both the CD4 and CD8 subsets ( figure 4G,H ).

Salvage therapies after progression

Among patients with disease progression, seven received only palliative care, and data regarding salvage therapy were unavailable for six patients. Of the 57 patients eligible for salvage therapy, the median PFS2 was 4.1 months (95% CI, 2.3 to 5.9 months). Detailed information on salvage therapy is provided in online supplemental table S3 . A total of 18 patients (31.6%) were treated with doublet, triplet, and quadruplet combinations of approved agents, yielding an ORR of 44.4% (8/18). Additionally, 16 patients (28.1%) who received chemotherapy had an ORR of 43.8% (7/16). Besides, 19 patients (33.3%) underwent CAR-T cell therapy or bispecific antibody therapy, achieving an ORR of 63.2% (12/19). Notably, one patient achieved CR following salvage allogeneic hematopoietic stem cell transplantation, and another patient with relapsed solitary plasmacytoma achieved CR after radiotherapy. Given the limited number of patients, these results warrant cautious interpretation.

Discussion

This study presents updated efficacy and safety results from 141 patients with R/RMM who underwent BCMA CAR-T cell therapy at our center. The findings are consistent with previously published clinical trial data. 13 17 19 20 The median OS for these patients with advanced R/RMM has not yet been reached and is projected to exceed 60 months. Notably, among the 60 patients who demonstrated ongoing responses, 13 have maintained long-term responses for over 4 years. For these individuals, CAR-T cell therapy has proven to be profoundly impactful, enabling most to resume normal life and work without the need for long-term medication. This represents a transformative shift from traditional treatment paradigms.

Despite the promising efficacy of BCMA CAR-T cell therapy in R/RMM, a subset of patients fails to achieve CR or experiences relapse after an initial response. 13 17 19 20 The depth of response has been identified as a critical factor linked to durable remission, 21 with survival outcomes significantly improved in patients who achieve CR compared with those who do not. The exceptionally high rate of MRD negativity in BM, observed in 97.1% of CR patients, is promising. The clearance of BM plasma cells was rapid, typically occurring within 1 month, consistent with findings from prior studies. 13 However, the accuracy of MRD detection may be limited at a sensitivity threshold of 10 −4 nucleated cells. Despite the high rate of MRD negativity observed, this did not invariably lead to sustained remission for all patients, possibly due to the advanced, refractory nature of the disease, as well as the presence of extramedullary disease in a proportion of patients at baseline.

Extramedullary disease has been identified as an independent predictor of PFS, OS and relapse following CR in patients with R/RMM undergoing BCMA CAR-T cell therapy. Recently published prospective studies and real-world evidence have consistently supported these findings. 28 , 33 Notably, prior extramedullary disease remains the predominant site of relapse following CAR-T cell therapy, indicating that extramedullary disease may act as an immunological sanctuary, predisposing it to tumor recurrence. 34 This could be attributed to the high heterogeneity of extramedullary tumors, which may harbor clones inclined to evade CAR-T cell therapy. Furthermore, the unique microenvironment of extramedullary disease appears to impede CAR-T cell infiltration and sustained activity, thereby limiting therapeutic efficacy. 35 36 Despite being less effective in patients with extramedullary disease compared with those without, it still yields meaningful clinical responses. In the absence of more effective treatments or other therapeutic options, CAR-T cell therapy remains a viable treatment option. Strategies for optimization should be considered, such as administering chemotherapy or radiation before the CAR-T cell infusion, to reduce tumor burden and enhance the clinical responses of CAR-T cell therapy.

ASCT is currently the predominant standard of care for eligible patients; however, progression and relapse remain inevitable. 37 38 Several small-scale studies indicated that prior ASCT adversely affected the outcomes of subsequent BCMA CAR T-cell therapy, including PFS and ORR. 30 39 Notably, our observations revealed a significant reduction in the peak expansion levels of CAR-T cells in vivo among patients who had previously undergone ASCT. Peak CAR-T cell expansion has been identified as a critical determinant of response. 12 13 15 The insufficient expansion of CAR-T cells may be multifactorial. For autologous CAR-T cells, the functional capacity of the patient’s endogenous T cells potentially plays an integral role. 23 24 Variations in the composition of T-cell subpopulations among patients with MM were notable and may be influenced by factors such as exposure to various treatment medications. 40 Notably, MM is typically diagnosed in elderly patients, 2 a population in which the number and functional diversity of naïve T cells are significantly diminished due to age-related thymic involution. 41 , 43 After high-dose chemotherapy followed by ASCT, lymphocyte, the recovery of lymphocytes primarily depends on the peripheral expansion of memory cells, as the diversity of the T-cell repertoire available for lymphocyte expansion is limited. 44 45 Despite the fact that patients in the ASCT group were younger than those in the non-ASCT group in our study, a reduced proportion of naive cells was observed in the infused CAR-T cells of patients who had undergone ASCT within the past year. Previous studies have indicated that a higher proportion of early memory and naïve cells in infused BCMA CAR-T cells is associated with superior in vivo expansion of CAR-T cells. 23 24 However, due to the limited selection of makers, no significant differences were detected between the overall ASCT and non-ASCT groups, nor between patients more than 1-year post-ASCT and the non-ASCT group. Further research is needed to explore differences in CAR-T cell senescence and exhaustion among these patients. Given the significant impact of lymphocyte quality on the efficacy of CAR-T therapy, the timing of lymphocyte collection becomes crucial for enhancing clinical outcomes. Previous studies have demonstrated that patients with extramedullary disease, high-risk cytogenetic abnormalities, or those who did not achieve ≥VGPR before ASCT experienced significantly shorter PFS following ASCT. 46 , 48 For these high-risk patients, lymphocyte collection should be considered before proceeding with ASCT.

Patients who experience disease progression following BCMA CAR-T therapy present significant management challenges, as there is currently no established standard of care for this patient population. This study found that salvage therapy with CAR T-cell therapy or bispecific antibody therapy following CAR-T therapy is feasible and may lead to relatively higher ORR compared with other conventional treatment options. Notably, GPRC5D CAR-T cell therapy showed the highest ORR (66.7%) and CR rate (33.3%) within our limited data set. GPRC5D, which is predominantly expressed on the surface of myeloma cells independently of BCMA, emerges as a promising alternative therapeutic target. 49 Further studies with larger cohorts are needed to evaluate the efficacy of GPRC5D CAR-T cell therapy in treating patients with R/RMM with progressive disease after BCMA CAR-T cell therapy.

Overall, the long-term outcomes of this study highlight the safety and efficacy of BCMA CAR-T cell therapy in patients with R/RMM. Prior ASCT and extramedullary disease are recognized as adverse prognostic factors. The correlation between these adverse prognostic factors and the immunophenotype of the infused CAR-T cells, as well as post-infusion cell dynamics, has been identified, offering critical insights to further advance autologous CAR-T cell therapy. The ultimate goal is to refine treatment strategies to achieve the most durable and sustained responses in patients undergoing these therapies.

supplementary material

Acknowledgements

We express our gratitude to the entire team at Shanghai YaKe Biotechnology for their technical support and to the nurses at the Bone Marrow Transplantation Center, First Affiliated Hospital, Zhejiang University School of Medicine.

We also thank the editorial team of Home for Researchers ( www.home-for-researchers.com ) for their professional language editing services.

Footnotes

Funding: This work was supported by National Natural Science Foundation of China (82270234, 82130003 and 82425002), the Key Project of Science and Technology Department of Zhejiang Province (2021C03010 and 2023C03060), and the Key Research and Development Program of Zhejiang Province (2024SSYS0023, 2024SSYS0024, and 2024SSYS0025).

Provenance and peer review: Not commissioned; externally peer reviewed.

Patient consent for publication: Not applicable.

Ethics approval: The study received approval from the Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine (IIT20240442A).

Data availability statement

Data are available upon reasonable request.

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Associated Data

Supplementary Materials

Data Availability Statement

Data are available upon reasonable request.