Tagraxofusp, a first-in-class CD123-targeted anticancer agent: A pharmacovigilance study based on the FAERS database

Tagraxofusp, a first-in-class CD123-targeted anticancer agent: A pharmacovigilance study based on the FAERS database | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Tagraxofusp, a first-in-class CD123-targeted anticancer agent: A pharmacovigilance study based on the FAERS database Chunyong Xia, Ya Gan, Jie Liu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7678895/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Tagraxofusp is a targeted therapy for blastic plasmacytoid dendritic cell neoplasm (BPDCN) that works by targeting cluster of differentiation 123 (CD123). It was the first drug approved by the FDA for this disease, and also represents the world's first approved CD123-targeting agent. However, existing evidence regarding the safety of tagraxofusp is primarily derived from clinical trials, which limits the ability to provide timely updates on associated adverse events(AEs). Aim: By using the FAERS database, we aim to mine and systematically describe AEs related to tagraxofusp from January 2019 to March 2025. Methods: All statistics were extracted from FAERS by four disproportional methods, which were reporting odds ratio, proportional reporting ratio, information component and empirical Bayes geometric mean. These four methods were perfomed to detect risk signals in the FAERS database to identify potential associations between tagraxofusp and AEs. Results: A total of 492 adverse event reports with tagraxofuspas the “primary suspect” were collected. A total of 1099 preferred terms and 22 system organ categories were obtained. The highest incidence of populations related to AEs was 26.2% in the 18-65 age group. Notably, Capillary Leak Syndrome (n = 92, reporting odds ratio 3457.54, proportional reporting ratio 2646.31, information component 11.29, empirical Bayes geometric mean 2506.77) exhibited the highest incidence and signal intensity. In addition, uncommon, but apparently strong adverse event signals were observed, such as blastic plasmacytoid dendritic cell neoplasia (n = 4, reporting odds ratio 2866.17, proportional reporting ratio 2836,93, information component 11.39, empirical Bayes geometric mean 2677.16), leukaemia recurrent(n = 8, reporting odds ratio 248.42, proportional reporting ratio 243.37, information component 7.92, empirical Bayes geometric mean 242.14),neoplasm recurrence(n = 13, reporting odds ratio 208.29, proportional reporting ratio 201.42, information component 7.65, empirical Bayes geometric mean 200.57) and blood albumin decreased(n = 23, reporting odds ratio 160.86, proportional reporting ratio 151.48, information component 7.24, empirical Bayes geometric mean 151.01). Multiple Organ Dysfunction Syndrome(n = 6, reporting odds ratio 12.56, proportional reporting ratio 12.38, information component 3.63, empirical Bayes geometric mean 12.38) also showed strong adverse event signals, which was not included in the instructions. Conclusion: In the clinical application of tagraxofusp, AEs with high signal strength should be closely monitored. At the same time, healthcare professionals should remain vigilant for the emergence of adverse event signals not described in the prescribing information and take appropriate preventive measures to ensure patient safety. tagraxofusp adverse events disproportionality analysis FAERS database Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1.Introduction Tagraxofusp (tagraxofusp-erzs) is a novel targeted therapy agent approved for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). It is composed of a recombinant human interleukin-3 (IL-3) receptor-binding domain fused to a truncated diphtheria toxin payload, which selectively delivers cytotoxic activity to cells expressing Cluster of Differentiation 123 (CD123), a marker highly expressed on BPDCN cells [ 1 , 2 ] . Tagraxofusp was approved by the United States Food and Drug Administration (FDA) in December 2018, representing the first approved therapy specifically indicated for BPDCN. The mechanism of action of tagraxofusp involves high-affinity binding to CD123, which facilitates cellular internalization. Subsequently, it inhibits protein synthesis by ADP-ribosylating elongation factor 2, ultimately leading to apoptosis in malignant cells [ 3 , 4 ] . This targeted approach minimizes off-target effects while maximizing antitumor efficacy, making it a cornerstone in the management of BPDCN. Despite its clinical benefits, safety concerns related to tagraxofusp, particularly the risk of capillary leak syndrome (CLS) and other treatment-emergent adverse events (AEs), remain a significant consideration in clinical practice [ 5 ] . Post-marketing safety evaluation is essential for characterizing the real-world risk profile of novel biologics such as tagraxofusp. Real-world data (RWD) play an increasingly critical role in complementing clinical trial findings and identifying rare or delayed adverse events. The FDA Adverse Event Reporting System (FAERS) database serves as a key resource for pharmacovigilance, enabling the detection of potential safety signals through quantitative disproportionality analysis [ 6 – 8 ] . Although several studies have investigated tagraxofusp-related toxicities, most have focused on specific AEs such as CLS, hepatotoxicity or hypoalbuminemia, often within limited patient subgroups [ 9 – 13 ] . Therefore, in this study, we employed a combination of four disproportionality methods to systematically evaluate tagraxofusp-associated AEs based on FAERS data. This multi-method approach enhances signal detection robustness, reduces false positives and negatives, and improves overall sensitivity. We anticipate that our findings will contribute to refining drug safety labeling and supporting the rational use of tagraxofusp in clinical settings. 2.Methods 2.1 Research design and data sources The adverse event reports used in this study were obtained from the FAERS database, which has been publicly available since 2004 and does not require ethical approval or patient informed consent. The analyzed reports cover the period from the first quarter of 2004 to the first quarter of 2025. 2.2 data extraction and procession AEs in the FAERS database were coded by Medical Dictionary for Regulatory Activities 26.0 (MedDRA). All AEs of tagraxofusp reports taken from the coded for the adverse events files in the FAERS database were identified to describe the frequency and intensity based on MedDRA at system organ class(SOC) and preferred term (PT) levels in our study. FAERS permits the reporting of arbitrary drug names approved by the FDA, and the target drugs in our study were defined as generic name (tagraxofusp) and brand name (elzonris) in the drug information (DURG) dictionary. In order to improve accuracy, we limited our analysis reports to those in which the role_cod of drug was “PS” (primary suspected) in the DRUG files. A disproportionality analysis using a four-fold table approach was applied to identify potential signals of adverse drug events associated with tagraxofusp. This widely adopted method compares observed versus expected frequencies of events in exposed versus unexposed populations ( Supplementary Table 1 ). Signal strength was evaluated using multiple measures: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM) ( Supplementary Table 2 ). A signal was considered valid only if all four algorithms met the positive criteria. Signals not previously documented in FDA drug labels were classified as new adverse event signals. The overall data extraction and analysis workflow is summarized in Fig. 1 . 3.Results 3.1 Baseline characteristics From the first quarter of 2004 to the first quarter of 2025, a total of 492 tagraxofusp-associated AE reports were recorded in the FAERS database. After removing duplicates and incomplete reports, a total of 1099 PTs were involved. Tagraxofusp-associated AEs involved 22 SOCs, as illustrated in Fig. 2 . Among these, the five SOCs with the highest frequency were general disorders and administration site conditions(n = 231), investigations(n = 181), vascular disorders(n = 125), blood and lymphatic system disorders(n = 59), and metabolism and nutrition disorders(n = 55). The number of reported AEs associated with tagraxofusp was shown in Supplementary Fig. 1 . The trend of occurence rate of AE happening was generally increase by years, which rised to the highest point (n = 116) in 2023. In addition, the total of 492 events were analysed within different aspects of gender, age, outcomes, report countries and reporters through this study (Table 1 ) . In this large-scale statistics, the proportion of male that suffered AEs was 58.7% comparing with 25.4% females and 15.9% unknown genders. The highest proportion of age group with reported AEs was 26.2% in the 18–65 group. United States(n = 278, 56.5%), Germany(n = 91, 18.5%), Italy(n = 58, 11.8%), United Kingdom(n = 10, 2%) and Austria(n = 8, 1.6%) were the top 5 countries that repoted largest number of tagraxofusp-associated AEs. Majority of reports recorded in FAERS database were collected from physician(n = 219, 44.5%) while the second most of reporters were health professional(n = 174, 35.4%). The most frequently reported outcomes were disability (33.5%), followed by death(29.9%), hospitalization (12.4%), and life-threatening (2%). Table 1 Clinical characteristics of reports with tagraxofusp from the FAERS database Characteristics Case number Case proportion (%) number of events 492 — Gender Female 125 25.4 Male 289 58.7 missing 78 15.9 Age <18 21 4.3 18–65 129 26.2 65–85 251 51 missing 91 18.5 Outcomes Life-Threatening 10 2 Hospitalization 61 12.4 Disability 165 33.5 Death 147 29.9 Other 109 22.2 Top 5 reported countries United States 278 56.5 Germany 91 18.5 Italy 58 11.8 United Kingdom 10 2 Austria 8 1.6 Reportertype Consumer 51 10.4 Health Professional 174 35.4 Pharmacist 37 7.5 Physician 219 44.5 Other 11 2.2 3.2 Top 30 PTs based on report frequency Based on the frequency of AE reports, Fig. 3 shows the top 30 PTs. Capillary Leak Syndrome (n = 92, 8.37%) was the most frequently reported PT, followed by pyrexia (n = 40, 3.64%), death (n = 34, 3.09%), disease progression(n = 32, 2.91%), and thrombocytopenia (n = 25, 2.27%). 3.3 Signal detection of tagraxofusp-related AEs Figure 4 illustrates the Venn diagram for the four algorithms used (ROR, PRR, MGPS, BCPNN), highlighting 39 PTs that meet the criteria for a positive signal according to all four algorithms. Based on ROR signal intensity, Fig. 5 shows the top 30 positive PTs with the strongest signal strength. Among these PTs, the top 5 PTs were capillary leak syndrome (ROR = 3457.54), blastic plasmacytoid dendritic cell neoplasia (ROR = 2866.17), leukaemia recurrent(ROR = 248.42), neoplasm recurrence(ROR = 208.29) and blood albumin decreased(ROR = 160.86). Table 2 displays the signal intensity of tagraxofusp at the SOC level. Significant SOCs that met the criteria for the four indices were investigations, vascular disorders, blood and lymphatic system disorders, metabolism and nutrition disorders, neoplasms benign, malignant and unspecified (incl cysts and polyps), renal and urinary disorders, cardiac disorders, hepatobiliary disorders, surgical and medical procedures, and eye disorders. Table 3 lists the top 30 positive PTs with the highest number of reports. The results showed that capillary leak syndrome(92 cases) was the most frequently reported positive PT, followed by pyrexia (40 cases), disease progression (32 cases), thrombocytopenia (25 cases), blood albumin decreased (23 cases). Table 2 Signal strength of reports of tagraxofusp at the System Organ Class (SOC) level in FAERS database SOC case numbers ROR (95% CI) PRR (X 2 ) EBGM (EBGM05) IC(IC025) General Disorders and Administration Site Conditions 231 2.84 (2.33–3.48) a 1.76 (112.28) 1.76 (1.54) a 0.81 (0.54) Investigations 181 9.01 (7.38–10.98) a 5.31 (688.57) a 5.31 (4.59) a 2.41 (2.10) a Vascular Disorders 125 16.97 (13.72–20.98) a 11.87 (1267.76) a 11.87 (9.96) a 3.57 (3.20) a Blood and Lymphatic System Disorders 59 4.94 (3.74–6.51) a 4.34 (153.85) a 4.34 (3.37) a 2.12 (1.58) a Metabolism and Nutrition Disorders 55 5.05 (3.80–6.72) a 4.48 (150.04) a 4.48 (3.44) a 2.16 (1.61) a Respiratory, Thoracic and Mediastinal Disorders 51 1.97 (1.47–2.65) a 1.85 (20.42) 1.85 (1.40) a 0.89 (0.31) Infections and Infestations 50 2.30 (1.71–3.10) a 2.14 (30.96) a 2.14 (1.62) a 1.10 (0.51) Gastrointestinal Disorders 43 0.67 (0.49–0.92) 0.71 (5.80) 0.71 (0.52) -0.50 (-1.13) Nervous System Disorders 40 1.00 (0.72–1.38) 1.00 (0.00) 1.00 (0.73) -0.004 (-0.66) Neoplasms Benign, Malignant and Unspecified (Incl Cysts and Polyps) 39 10.77 (7.74-15.00) a 9.80 (302.48) a 9.80 (7.16) a 3.29 (2.63) a Injury, Poisoning and Procedural Complications 38 0.83 (0.59–1.16) 0.85 (1.01) 0.85 (0.62) -0.24 (-0.91) Renal and Urinary Disorders 32 3.89 (2.71–5.59) a 3.65 (60.42) a 3.65 (2.58) a 1.87 (1.14) a Cardiac Disorders 30 3.77 (2.60–5.47) a 3.56 (53.72) a 3.56 (2.49) a 1.83 (1.08) a Hepatobiliary Disorders 24 8.18 (5.41–12.36) a 7.74 (135.23) a 7.74 (5.19) a 2.95 (2.11) a Musculoskeletal and Connective Tissue Disorders 22 0.82 (0.53–1.26) 0.83 (0.66) 0.83 (0.55) -0.27 (-1.15) Psychiatric Disorders 22 1.23 (0.80–1.89) 1.21 (0.67) 1.21 (0.80) 0.28 (-0.60) Skin and Subcutaneous Tissue Disorders 21 2.06 (1.33–3.20) a 2.01 (9.89) a 2.01 (1.31) a 1.00 (0.11) Surgical and Medical Procedures 19 3.29 (2.08–5.22) a 3.18 (26.70) a 3.18 (2.03) a 1.67 (0.73) a Eye Disorders 9 4.53 (2.34–8.77) a 4.45 (20.84) a 4.45 (2.31) a 2.15 (0.80) a Immune System Disorders 6 1.19 (0.53–2.67) 1.19 (0.04) 1.19 (0.53) 0.25 (-1.38) Product Issues 1 3.50 (0.49–24.88) 3.49 (0.16) 3.49 (0.49) 1.80 (-1.60) Reproductive System and Breast Disorders 1 9.46 (1.33–67.36) a 9.44 (1.47) 9.44 (1.33) 3.24 (-0.16) a Indicates statistically significant signals in tagraxofusp. ROR, reporting odds ratio; CI, confidence interval; PRR, proportional reporting ratio; χ2, chi-squared; IC, information component; EBGM, empirical Bayesian geometric mean; EBGM05, the lower limit of 95% CI of EBGM. Table 3 The top 30 positive PTs with the highest reported number PT case numbers ROR (95% CI) PRR (X 2 ) EBGM (EBGM05) IC(IC025) Capillary Leak Syndrome 92 3457.54 (2723.85-4388.86) 2646.31 (227965.67) 2506.77 (2043.47) 11.29 (10.86) Pyrexia 40 6.64 (4.79–9.21) 6.07 (167.02) 6.07 (4.45) 2.60 (1.95) Disease Progression 32 15.67 (10.92–22.50) 14.48 (390.18) 14.47 (10.23) 3.86 (3.13) Thrombocytopenia 25 12.68 (8.46–19.02) 11.94 (240.96) 11.94 (8.06) 3.58 (2.75) Blood Albumin Decreased 23 160.86 (105.50-245.28) 151.48 (3280.17) 151.00 (100.34) 7.24 (6.38) Transaminases Increased 20 49.81 (31.76–78.13) 47.32 (861.21) 47.28 (30.50) 5.56 (4.64) Tumour Lysis Syndrome 19 125.79 (79.29-199.56) 119.74 (2115.61) 119.44 (76.19) 6.90 (5.96) Acute Kidney Injury 18 6.64 (4.14–10.66) 6.38 (76.93) 6.38 (4.02) 2.67 (1.71) Liver Function Test Increased 18 49.77 (31.01–79.89) 47.53 (774.10) 47.49 (29.92) 5.57 (4.60) Weight Increased 18 4.48 (2.79–7.19) 4.32 (43.18) 4.32 (2.72) 2.11 (1.14) Hypoalbuminaemia 15 110.61 (65.98-185.42) 106.42 (1460.00) 106.18 (64.01) 6.73 (5.67) Hypotension 15 4.05 (2.42–6.79) 3.94 (30.29) 3.94 (2.37) 1.98 (0.92) Hepatic Enzyme Increased 14 11.51 (6.75–19.62) 11.13 (119.50) 11.13 (6.59) 3.48 (2.38) Sepsis 14 6.79 (3.98–11.58) 6.58 (61.17) 6.58 (3.90) 2.72 (1.63) Neoplasm Recurrence 13 208.29 (119.70-362.46) 201.42 (2386.20) 200.57 (116.46) 7.65 (6.52) Hepatotoxicity 11 27.58 (15.14–50.23) 26.83 (248.45) 26.82 (14.85) 4.75 (3.52) Platelet Count Decreased 9 4.53 (2.34–8.76) 4.44 (20.81) 4.44 (2.31) 2.15 (0.80) Skin Lesion 9 18.07 (9.33–34.99) 17.67 (125.51) 17.67 (9.19) 4.14 (2.79) Alanine Aminotransferase Increased 8 6.89 (3.42–13.87) 6.77 (33.85) 6.76 (3.38) 2.76 (1.33) Aspartate Aminotransferase Increased 8 7.95 (3.95–16.02) 7.81 (41.04) 7.81 (3.91) 2.97 (1.54) Atrial Fibrillation 8 4.37 (2.17–8.81) 4.31 (17.21) 4.31 (2.15) 2.11 (0.68) Hypoxia 8 12.40 (6.16–24.98) 12.17 (71.31) 12.16 (6.08) 3.60 (2.18) Leukaemia Recurrent 8 248.42 (123.13-501.21) 243.37 (1687.74) 242.14 (121.09) 7.92 (6.49) Hypertransaminasaemia 7 64.89 (30.71-137.09) 63.75 (371.47) 63.66 (30.35) 5.99 (4.47) Febrile Neutropenia 6 4.93 (2.20-11.05) 4.87 (14.85) 4.87 (2.19) 2.28 (0.65) Multiple Organ Dysfunction Syndrome 6 12.56 (5.61–28.13) 12.38 (51.96) 12.38 (5.56) 3.63 (2.00) Oedema 5 4.97 (2.06–12.02) 4.92 (11.98) 4.92 (2.05) 2.30 (0.52) Blastic Plasmacytoid Dendritic Cell Neoplasia 4 2866.17 (1040.03-7898.71) 2836.93 (8192.00) 2677.16 (1004.77) 11.39 (9.42) Blood Lactate Dehydrogenase Increased 4 12.66 (4.73–33.92) 12.55 (31.76) 12.54 (4.71) 3.65 (1.69) Disseminated Intravascular Coagulation 4 14.65(5.47–39.24) 14.51(37.73) 14.51(5.44) 3.86(1.89) 3.4 Onset time The time interval between tagraxofusp administration and the onset of tagraxofusp-related AEs was analyzed (Fig. 6 ). This study found that the median time to onset of tagraxofusp-induced adverse events was 4 days, highlighting the necessity for continuous early monitoring and proactive risk management. 4.Discussion To the best of our knowledge, this is the first post-marketing study to conduct a systematic and comprehensive pharmacovigilance analysis of tagraxofusp using real-world data. In this study, we conducted pharmacovigilance analysis using real data to evaluate the safety of tagraxofusp based on the FAERS database. These findings provide critical real-world evidence to guide clinical decision-making and enhance medication safety monitoring for tagraxofusp. Notably, during the study period, males accounted for the majority of reported reactions submitted to the FDA, representing 58.7% of the cases. Interestingly, most AE reports (44.5%) were submitted by physicians rather than consumers, suggesting that healthcare professionals are the primary source of reports or that patients might underreport. Furthermore, the majority of the reports originated from the United States (56.5%), suggesting the presence of potential regional or cultural variations in reporting practices that merit further investigation. The age distribution indicates that tagraxofusp-related AEs can affect patients across various age groups, but is predominantly concentrated in the 18–65 age group, which has the highest proportion of cases. This suggests that heightened vigilance is also necessary for the adult population. In this study, capillary leak syndrome (CLS) exhibited the highest incidence and signal intensity among tagraxofusp-related adverse events. It is a well-recognized and potentially serious complication of this CD123-directed therapy, making an understanding of its mechanism crucial for prevention and management.Tagraxofusp-induced capillary leak syndrome is characterized by a rapid onset of vascular leakage, leading to hypotension, hypoalbuminemia, and peripheral edema, which can progress to severe organ hypoperfusion and shock; it is often triggered by the initial cycles of therapy or underlying endothelial vulnerability [ 14 , 15 ] . Tagraxofusp is a fusion protein composed of recombinant human interleukin-3 (IL-3) linked to a truncated form of diphtheria toxin (DT). The proposed mechanism underlying tagraxofusp-associated CLS involves vascular endothelial uptake of the diphtheria toxin component, leading to apoptosis of endothelial cells and increased vascular permeability [ 5 ] . In another study, CLS was reported in 55% (7% Grade 3) of patients treated with tagraxofusp for BPDCN during clinical trials, with a median time to onset of 5 days [ 2 ] . This high incidence and rapid onset underscore the significant clinical risk associated with tagraxofusp therapy. Therefore, clinicians must maintain a high index of suspicion, particularly during the initial treatment cycles. Proactive monitoring for early signs (e.g., sudden weight gain, hypotension, or hypoalbuminemia) is imperative to enable the early application of measures to reverse the fluid retention and oncotic effects of CLS. In our study, several uncommon yet pharmacologically significant adverse event signals were also detected, including blastic plasmacytoid dendritic cell neoplasia (n = 4, reporting odds ratio 2866.17, proportional reporting ratio 2836,93, information component 11.39, empirical Bayes geometric mean 2677.16), leukaemia recurrent(n = 8, reporting odds ratio 248.42, proportional reporting ratio 243.37, information component 7.92, empirical Bayes geometric mean 242.14), neoplasm recurrence(n = 13, reporting odds ratio 208.29, proportional reporting ratio 201.42, information component 7.65, empirical Bayes geometric mean 200.57) and blood albumin decreased(n = 23, reporting odds ratio 160.86, proportional reporting ratio 151.48, information component 7.23, empirical Bayes geometric mean 151.01). Among these signals, blastic plasmacytoid dendritic cell neoplasm, leukemia recurrence, and neoplasm recurrence are likely associated with the underlying primary disease and its natural progression or relapse, rather than being directly attributable to the drug itself. In contrast, decreased serum albumin is a recognized and documented adverse drug reaction of tagraxofusp, consistent with its known toxicity profile and described in the prescribing information [ 16 ] . Given these findings, clinicians should carefully differentiate between disease-related progression and genuine treatment-emergent AEs. Close monitoring for signs of disease recurrence and regular assessment of serum albumin levels, especially during early treatment cycles, are recommended. Prompt supportive measures, such as albumin supplementation, should be initiated when indicated to mitigate potential complications. In addition to the signals already documented in the prescribing information, our study also identified novel safety signals associated with tagraxofusp. Among these, Multiple Organ Dysfunction Syndrome(MODS) (n = 6, reporting odds ratio 12.56, proportional reporting ratio 12.38, information component 3.63, empirical Bayes geometric mean 12.38) exhibited a significant disproportionality signal, suggesting a potential association with the drug that was previously unrecognized and not included in its official labeling. MODS is a severe, life-threatening condition characterized by the progressive dysfunction of two or more organ systems—such as respiratory, renal, hepatic, or cardiovascular failure—often resulting from a catastrophic physiological insult [ 17 – 20 ] . In the context of tagraxofusp therapy, MODS may occur as an extreme manifestation of CLS or systemic inflammatory response triggered by the drug’s mechanism of action. The fusion protein’s binding to CD123-expressing cells—including certain immune and endothelial cells—followed by diphtheria toxin–mediated cell damage, may lead to a cascade of cytokine release, endothelial apoptosis, and loss of vascular integrity. This can subsequently precipitate systemic hypoperfusion, tissue ischemia, and ultimately, multi-organ failure. However, the precise pathophysiological pathway linking tagraxofusp to MODS remains to be fully elucidated and warrants further investigation. Although this signal was detected with a relatively small number of cases, the strength of the pharmacometric scores warrants serious clinical attention. Physicians should be aware of the potential risk of MODS, especially in patients showing signs of severe CLS, rapid clinical deterioration, or pre-existing organ compromise. Early intensive support and organ-function monitoring are critical in mitigating outcomes associated with this rare but highly serious adverse event. Our study has several limitations that should be considered when interpreting the findings related to tagraxofusp. First, the potential influence of underlying conditions such as BPDCN or other hematologic malignancies on the reported adverse events was not fully accounted for. Additionally, confounding factors including concomitant medications, potential drug-drug interactions, and variations in tagraxofusp dosing regimens were not adjusted for in the analysis, which may introduce bias into the results. Second, as the FAERS database relies on spontaneous reporting, it is subject to potential inaccuracies in the identification and attribution of adverse events due to incomplete documentation, under-reporting, and heterogeneous reporting practices across institutions. These limitations may introduce variability in data quality and affect the reliability of the disproportionality analyses. Therefore, further prospective studies and clinical trials are necessary to confirm and further elucidate the safety signals associated with tagraxofusp. 5.Conclusion In summary, this study utilized four disproportionality analysis methods to mine and evaluate adverse drug reaction signals associated with tagraxofusp based on the FAERS database. Close attention should be paid to adverse events demonstrating strong signals in this analysis, including capillary leak syndrome and decreased albumin. Furthermore, potential severe complications such as MODS related to tagraxofusp warrant further investigation and validation in real-world settings. This study provides valuable insights for optimizing the clinical application of tagraxofusp, thereby supporting improved drug safety and treatment outcomes. Declarations Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Ethical approval The FAERS database contains anonymized patient information. The Hospital Ethics Committee has confirmed that no ethical approval was required. Funding Statement This work was sponsored by Natural Science Foundation of Chongqing, China (CSTB2022NSCQ-MSX1207) . Author Contribution Chunyong Xia: Writing-review & editing, Writing-original draft, Validation, Conceptualization. Jie Liu: Writing-review & editing, Writing-original draft, Validation, Conceptualization. Ya Gan: Validation, Writing-review & editing, Validation, Supervision, Data curation, Formal analysis, Software, Visualization. Acknowledgements Not applicable. Data Availability Data associated with our study has been deposited into a publicly available repository(https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html). References Syed YY (2019) Tagraxofusp: First Global Approval. Drugs 79(5):579–583 Pemmaraju N, Lane AA, Sweet KL, Stein AS, Vasu S, Blum W, Rizzieri DA, Wang ES, Duvic M, Sloan JM, Spence S, Shemesh S, Brooks CL, Balser J, Bergstein I, Lancet JE, Kantarjian HM, Konopleva M (2019) Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm. N Engl J Med 380(17):1628–1637 Hammond D, Pemmaraju N (2020) Tagraxofusp for Blastic Plasmacytoid Dendritic Cell Neoplasm. Hematol Oncol Clin North Am 34(3):565–574 FitzGerald DJ (2014) Targeted diphtheria toxin to treat BPDCN. 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Supplementary Files SupplementaryMaterial.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7678895","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":524290977,"identity":"3a10b713-5dea-433e-9b75-18bbdca5400d","order_by":0,"name":"Chunyong Xia","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAv0lEQVRIiWNgGAWjYBAC+/PNBww+VNjI2bc3EKvnxrGEwhln0owNeA4Qq+VAjsFn3rbDiQYSCUTqYGw4Y7gRaEuCueTjjTcYamyiCWphZm4rBvklz3J2WrEFw7G03AZCWtgYDm8zBNpSzHA7x0yCseEwYS08DAnmv0F+abh5hkgtEgwpBsYgLRtu8BCpxUDiWALIYcaSPUC/JBDjFwN+aFTysx/eeONDjQ1hLag2JpCiHKKFVB2jYBSMglEwMgAAZZNGgkdcKBsAAAAASUVORK5CYII=","orcid":"","institution":"Chongqing university jiangjin hospital","correspondingAuthor":true,"prefix":"","firstName":"Chunyong","middleName":"","lastName":"Xia","suffix":""},{"id":524290978,"identity":"59e24b87-0910-46d6-81a9-26a75580a54d","order_by":1,"name":"Ya Gan","email":"","orcid":"","institution":"Sichuan University, Sichuan University West China Hospital Guang'an Hospital, Guang'an People's Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ya","middleName":"","lastName":"Gan","suffix":""},{"id":524290979,"identity":"03a8a5dd-096b-47be-85ce-428d9c756104","order_by":2,"name":"Jie Liu","email":"","orcid":"","institution":"Chongqing university jiangjin hospital","correspondingAuthor":false,"prefix":"","firstName":"Jie","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2025-09-22 14:38:50","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7678895/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7678895/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":92843496,"identity":"55033b60-af5b-4771-88f0-7369386562ae","added_by":"auto","created_at":"2025-10-06 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1","display":"","copyAsset":false,"role":"figure","size":74192,"visible":true,"origin":"","legend":"\u003cp\u003eThe flow diagram of selecting tagraxofusp-related AEs from FAERS database\u003c/p\u003e","description":"","filename":"image1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7678895/v1/0a5382b2d6d23185d4c94428.jpeg"},{"id":92845786,"identity":"8b91b56f-724b-4566-a93d-c07e115a9322","added_by":"auto","created_at":"2025-10-06 09:34:39","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":78459,"visible":true,"origin":"","legend":"\u003cp\u003eThe cases of AEs of tagraxofusp at the SOC level in FAERS database\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-7678895/v1/c35fb0613dee63beb8f40e82.png"},{"id":92843498,"identity":"099abe44-33f1-4b9b-8491-ccf050b245a8","added_by":"auto","created_at":"2025-10-06 09:18:38","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":96978,"visible":true,"origin":"","legend":"\u003cp\u003eThe top 30 PTs with the highest reported number of tagraxofusp\u003c/p\u003e","description":"","filename":"image3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7678895/v1/cf524f40247578bf6a365b55.jpeg"},{"id":92843500,"identity":"d72e7c50-d5e8-4b94-bc4b-ee5ed8ce0871","added_by":"auto","created_at":"2025-10-06 09:18:38","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":114990,"visible":true,"origin":"","legend":"\u003cp\u003eVenn diagrams of PTs under four algorithms: ROR, PRR, MGPS, and BCPNN. ROR, Reporting Odds Ratio; PRR, Proportional Reporting Ratio; BCPNN, Bayesian Confidence Propagation Neural Network; MGPS, Multiitem Gamma Poisson Shrinker.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-7678895/v1/7558fb93bd146ee66b8bc98a.png"},{"id":92843504,"identity":"bbd9a9c6-c183-4cf6-9ccc-bbd25b3c3e0c","added_by":"auto","created_at":"2025-10-06 09:18:38","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":28974,"visible":true,"origin":"","legend":"\u003cp\u003eForest map of positive PTs with the top 30 signal strengths under the ROR algorithm\u003c/p\u003e","description":"","filename":"image5.png","url":"https://assets-eu.researchsquare.com/files/rs-7678895/v1/2f70d8f3ab87987b70b195c7.png"},{"id":92843511,"identity":"cc4e96a6-ac3a-424c-94e8-2e3e4af71746","added_by":"auto","created_at":"2025-10-06 09:18:39","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":12721,"visible":true,"origin":"","legend":"\u003cp\u003eCumulative incidence of tagraxofusp-related AEs\u003c/p\u003e","description":"","filename":"image6.png","url":"https://assets-eu.researchsquare.com/files/rs-7678895/v1/390786ae4c6743524bc79bb2.png"},{"id":101207101,"identity":"f053d0d0-dfe7-4fcb-8792-b451e2d90498","added_by":"auto","created_at":"2026-01-27 09:57:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1366000,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7678895/v1/d4d1c59f-d73b-400a-92b5-6e39188cef37.pdf"},{"id":92843497,"identity":"99156407-ca47-4755-98ca-30d4f63bd465","added_by":"auto","created_at":"2025-10-06 09:18:38","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":49219,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryMaterial.docx","url":"https://assets-eu.researchsquare.com/files/rs-7678895/v1/08c8450cc6d72c6cdab04f43.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Tagraxofusp, a first-in-class CD123-targeted anticancer agent: A pharmacovigilance study based on the FAERS database","fulltext":[{"header":"1.Introduction","content":"\u003cp\u003eTagraxofusp (tagraxofusp-erzs) is a novel targeted therapy agent approved for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). It is composed of a recombinant human interleukin-3 (IL-3) receptor-binding domain fused to a truncated diphtheria toxin payload, which selectively delivers cytotoxic activity to cells expressing Cluster of Differentiation 123 (CD123), a marker highly expressed on BPDCN cells\u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Tagraxofusp was approved by the United States Food and Drug Administration (FDA) in December 2018, representing the first approved therapy specifically indicated for BPDCN.\u003c/p\u003e\u003cp\u003eThe mechanism of action of tagraxofusp involves high-affinity binding to CD123, which facilitates cellular internalization. Subsequently, it inhibits protein synthesis by ADP-ribosylating elongation factor 2, ultimately leading to apoptosis in malignant cells\u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. This targeted approach minimizes off-target effects while maximizing antitumor efficacy, making it a cornerstone in the management of BPDCN. Despite its clinical benefits, safety concerns related to tagraxofusp, particularly the risk of capillary leak syndrome (CLS) and other treatment-emergent adverse events (AEs), remain a significant consideration in clinical practice\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003ePost-marketing safety evaluation is essential for characterizing the real-world risk profile of novel biologics such as tagraxofusp. Real-world data (RWD) play an increasingly critical role in complementing clinical trial findings and identifying rare or delayed adverse events. The FDA Adverse Event Reporting System (FAERS) database serves as a key resource for pharmacovigilance, enabling the detection of potential safety signals through quantitative disproportionality analysis\u003csup\u003e[\u003cspan additionalcitationids=\"CR7\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Although several studies have investigated tagraxofusp-related toxicities, most have focused on specific AEs such as CLS, hepatotoxicity or hypoalbuminemia, often within limited patient subgroups\u003csup\u003e[\u003cspan additionalcitationids=\"CR10 CR11 CR12\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eTherefore, in this study, we employed a combination of four disproportionality methods to systematically evaluate tagraxofusp-associated AEs based on FAERS data. This multi-method approach enhances signal detection robustness, reduces false positives and negatives, and improves overall sensitivity. We anticipate that our findings will contribute to refining drug safety labeling and supporting the rational use of tagraxofusp in clinical settings.\u003c/p\u003e"},{"header":"2.Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Research design and data sources\u003c/h2\u003e\u003cp\u003eThe adverse event reports used in this study were obtained from the FAERS database, which has been publicly available since 2004 and does not require ethical approval or patient informed consent. The analyzed reports cover the period from the first quarter of 2004 to the first quarter of 2025.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 data extraction and procession\u003c/h2\u003e\u003cp\u003eAEs in the FAERS database were coded by Medical Dictionary for Regulatory Activities 26.0 (MedDRA). All AEs of tagraxofusp reports taken from the coded for the adverse events files in the FAERS database were identified to describe the frequency and intensity based on MedDRA at system organ class(SOC) and preferred term (PT) levels in our study. FAERS permits the reporting of arbitrary drug names approved by the FDA, and the target drugs in our study were defined as generic name (tagraxofusp) and brand name (elzonris) in the drug information (DURG) dictionary. In order to improve accuracy, we limited our analysis reports to those in which the role_cod of drug was \u0026ldquo;PS\u0026rdquo; (primary suspected) in the DRUG files.\u003c/p\u003e\u003cp\u003eA disproportionality analysis using a four-fold table approach was applied to identify potential signals of adverse drug events associated with tagraxofusp. This widely adopted method compares observed versus expected frequencies of events in exposed versus unexposed populations (\u003cb\u003eSupplementary Table\u0026nbsp;1\u003c/b\u003e). Signal strength was evaluated using multiple measures: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM) (\u003cb\u003eSupplementary Table\u0026nbsp;2\u003c/b\u003e). A signal was considered valid only if all four algorithms met the positive criteria. Signals not previously documented in FDA drug labels were classified as new adverse event signals. The overall data extraction and analysis workflow is summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"3.Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Baseline characteristics\u003c/h2\u003e\u003cp\u003eFrom the first quarter of 2004 to the first quarter of 2025, a total of 492 tagraxofusp-associated AE reports were recorded in the FAERS database. After removing duplicates and incomplete reports, a total of 1099 PTs were involved. Tagraxofusp-associated AEs involved 22 SOCs, as illustrated in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Among these, the five SOCs with the highest frequency were general disorders and administration site conditions(n\u0026thinsp;=\u0026thinsp;231), investigations(n\u0026thinsp;=\u0026thinsp;181), vascular disorders(n\u0026thinsp;=\u0026thinsp;125), blood and lymphatic system disorders(n\u0026thinsp;=\u0026thinsp;59), and metabolism and nutrition disorders(n\u0026thinsp;=\u0026thinsp;55).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe number of reported AEs associated with tagraxofusp was shown in \u003cb\u003eSupplementary Fig.\u0026nbsp;1\u003c/b\u003e. The trend of occurence rate of AE happening was generally increase by years, which rised to the highest point (n\u0026thinsp;=\u0026thinsp;116) in 2023. In addition, the total of 492 events were analysed within different aspects of gender, age, outcomes, report countries and reporters through this study (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. In this large-scale statistics, the proportion of male that suffered AEs was 58.7% comparing with 25.4% females and 15.9% unknown genders. The highest proportion of age group with reported AEs was 26.2% in the 18\u0026ndash;65 group. United States(n\u0026thinsp;=\u0026thinsp;278, 56.5%), Germany(n\u0026thinsp;=\u0026thinsp;91, 18.5%), Italy(n\u0026thinsp;=\u0026thinsp;58, 11.8%), United Kingdom(n\u0026thinsp;=\u0026thinsp;10, 2%) and Austria(n\u0026thinsp;=\u0026thinsp;8, 1.6%) were the top 5 countries that repoted largest number of tagraxofusp-associated AEs. Majority of reports recorded in FAERS database were collected from physician(n\u0026thinsp;=\u0026thinsp;219, 44.5%) while the second most of reporters were health professional(n\u0026thinsp;=\u0026thinsp;174, 35.4%). The most frequently reported outcomes were disability (33.5%), followed by death(29.9%), hospitalization (12.4%), and life-threatening (2%).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinical characteristics of reports with tagraxofusp from the FAERS database\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCase number\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eCase proportion (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003enumber of events\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e492\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e\u0026mdash;\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e289\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e58.7\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003emissing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u0026lt;18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.3\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e18\u0026ndash;65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e129\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e65\u0026ndash;85\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e251\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e51\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003emissing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOutcomes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLife-Threatening\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHospitalization\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisability\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e165\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e33.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDeath\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e147\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29.9\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e109\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTop 5 reported countries\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnited States\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e278\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e56.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGermany\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e91\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eItaly\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUnited Kingdom\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAustria\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReportertype\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eConsumer\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHealth Professional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e174\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e35.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePharmacist\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePhysician\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e219\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e44.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.2\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e3.2 Top 30 PTs based on report frequency\u003c/h2\u003e\u003cp\u003eBased on the frequency of AE reports, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the top 30 PTs. Capillary Leak Syndrome (n\u0026thinsp;=\u0026thinsp;92, 8.37%) was the most frequently reported PT, followed by pyrexia (n\u0026thinsp;=\u0026thinsp;40, 3.64%), death (n\u0026thinsp;=\u0026thinsp;34, 3.09%), disease progression(n\u0026thinsp;=\u0026thinsp;32, 2.91%), and thrombocytopenia (n\u0026thinsp;=\u0026thinsp;25, 2.27%).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Signal detection of tagraxofusp-related AEs\u003c/h2\u003e\u003cp\u003eFigure \u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e illustrates the Venn diagram for the four algorithms used (ROR, PRR, MGPS, BCPNN), highlighting 39 PTs that meet the criteria for a positive signal according to all four algorithms. Based on ROR signal intensity, Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e shows the top 30 positive PTs with the strongest signal strength. Among these PTs, the top 5 PTs were capillary leak syndrome (ROR\u0026thinsp;=\u0026thinsp;3457.54), blastic plasmacytoid dendritic cell neoplasia (ROR\u0026thinsp;=\u0026thinsp;2866.17), leukaemia recurrent(ROR\u0026thinsp;=\u0026thinsp;248.42), neoplasm recurrence(ROR\u0026thinsp;=\u0026thinsp;208.29) and blood albumin decreased(ROR\u0026thinsp;=\u0026thinsp;160.86). Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e displays the signal intensity of tagraxofusp at the SOC level. Significant SOCs that met the criteria for the four indices were investigations, vascular disorders, blood and lymphatic system disorders, metabolism and nutrition disorders, neoplasms benign, malignant and unspecified (incl cysts and polyps), renal and urinary disorders, cardiac disorders, hepatobiliary disorders, surgical and medical procedures, and eye disorders. Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e lists the top 30 positive PTs with the highest number of reports. The results showed that capillary leak syndrome(92 cases) was the most frequently reported positive PT, followed by pyrexia (40 cases), disease progression (32 cases), thrombocytopenia (25 cases), blood albumin decreased (23 cases).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSignal strength of reports of tagraxofusp at the System Organ Class (SOC) level in FAERS database\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSOC\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ecase numbers\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eROR (95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePRR (X\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eEBGM\u003c/p\u003e\u003cp\u003e(EBGM05)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIC(IC025)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGeneral Disorders and Administration Site Conditions\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e231\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.84 (2.33\u0026ndash;3.48)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.76 (112.28)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.76 (1.54)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.81 (0.54)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInvestigations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e181\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9.01 (7.38\u0026ndash;10.98)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5.31 (688.57)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e5.31 (4.59)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.41 (2.10)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVascular Disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e16.97 (13.72\u0026ndash;20.98)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11.87 (1267.76)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e11.87 (9.96)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.57 (3.20)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood and Lymphatic System Disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.94 (3.74\u0026ndash;6.51)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.34 (153.85)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.34 (3.37)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.12 (1.58)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMetabolism and Nutrition Disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.05 (3.80\u0026ndash;6.72)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.48 (150.04)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.48 (3.44)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.16 (1.61)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRespiratory, Thoracic and Mediastinal Disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.97 (1.47\u0026ndash;2.65)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.85 (20.42)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.85 (1.40)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.89 (0.31)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInfections and Infestations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.30 (1.71\u0026ndash;3.10)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.14 (30.96)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.14 (1.62)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.10 (0.51)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGastrointestinal Disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.67 (0.49\u0026ndash;0.92)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.71 (5.80)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.71 (0.52)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.50 (-1.13)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNervous System Disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.00 (0.72\u0026ndash;1.38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.00 (0.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.00 (0.73)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.004 (-0.66)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeoplasms Benign, Malignant and Unspecified (Incl Cysts and Polyps)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10.77 (7.74-15.00)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9.80 (302.48)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e9.80 (7.16)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.29 (2.63)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInjury, Poisoning and Procedural Complications\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.83 (0.59\u0026ndash;1.16)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.85 (1.01)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.85 (0.62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.24 (-0.91)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRenal and Urinary Disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.89 (2.71\u0026ndash;5.59)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.65 (60.42)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.65 (2.58)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.87 (1.14)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCardiac Disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.77 (2.60\u0026ndash;5.47)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.56 (53.72)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.56 (2.49)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.83 (1.08)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHepatobiliary Disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8.18 (5.41\u0026ndash;12.36)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7.74 (135.23)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e7.74 (5.19)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.95 (2.11)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMusculoskeletal and Connective Tissue Disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.82 (0.53\u0026ndash;1.26)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.83 (0.66)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.83 (0.55)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e-0.27 (-1.15)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePsychiatric Disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.23 (0.80\u0026ndash;1.89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.21 (0.67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.21 (0.80)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.28 (-0.60)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSkin and Subcutaneous Tissue Disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.06 (1.33\u0026ndash;3.20)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.01 (9.89)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.01 (1.31)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.00 (0.11)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSurgical and Medical Procedures\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.29 (2.08\u0026ndash;5.22)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.18 (26.70)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.18 (2.03)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.67 (0.73)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEye Disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.53 (2.34\u0026ndash;8.77)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.45 (20.84)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4.45 (2.31)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.15 (0.80)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eImmune System Disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.19 (0.53\u0026ndash;2.67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.19 (0.04)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.19 (0.53)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.25 (-1.38)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProduct Issues\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.50 (0.49\u0026ndash;24.88)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.49 (0.16)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3.49 (0.49)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.80 (-1.60)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReproductive System and Breast Disorders\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9.46 (1.33\u0026ndash;67.36)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9.44 (1.47)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e9.44 (1.33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3.24 (-0.16)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003e\u003csup\u003ea\u003c/sup\u003eIndicates statistically significant signals in tagraxofusp.\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003eROR, reporting odds ratio; CI, confidence interval;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003ePRR, proportional reporting ratio;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003eχ2, chi-squared;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003eIC, information component;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003eEBGM, empirical Bayesian geometric mean;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"6\"\u003eEBGM05, the lower limit of 95% CI of EBGM.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe top 30 positive PTs with the highest reported number\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePT\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ecase numbers\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eROR (95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePRR (X\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eEBGM\u003c/p\u003e\u003cp\u003e(EBGM05)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eIC(IC025)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCapillary Leak Syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3457.54 (2723.85-4388.86)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2646.31 (227965.67)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2506.77 (2043.47)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e11.29 (10.86)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePyrexia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.64 (4.79\u0026ndash;9.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6.07 (167.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e6.07 (4.45)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e2.60 (1.95)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisease Progression\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15.67 (10.92\u0026ndash;22.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e14.48 (390.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e14.47 (10.23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3.86 (3.13)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eThrombocytopenia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12.68 (8.46\u0026ndash;19.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e11.94 (240.96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e11.94 (8.06)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3.58 (2.75)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood Albumin Decreased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e23\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e160.86 (105.50-245.28)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e151.48 (3280.17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e151.00 (100.34)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e7.24 (6.38)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTransaminases Increased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e49.81 (31.76\u0026ndash;78.13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e47.32 (861.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e47.28 (30.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e5.56 (4.64)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTumour Lysis Syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e125.79 (79.29-199.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e119.74 (2115.61)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e119.44 (76.19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e6.90 (5.96)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAcute Kidney Injury\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.64 (4.14\u0026ndash;10.66)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6.38 (76.93)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e6.38 (4.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e2.67 (1.71)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLiver Function Test Increased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e49.77 (31.01\u0026ndash;79.89)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e47.53 (774.10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e47.49 (29.92)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e5.57 (4.60)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWeight Increased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.48 (2.79\u0026ndash;7.19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.32 (43.18)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4.32 (2.72)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e2.11 (1.14)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypoalbuminaemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e110.61 (65.98-185.42)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e106.42 (1460.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e106.18 (64.01)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e6.73 (5.67)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypotension\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.05 (2.42\u0026ndash;6.79)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.94 (30.29)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e3.94 (2.37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e1.98 (0.92)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHepatic Enzyme Increased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11.51 (6.75\u0026ndash;19.62)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e11.13 (119.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e11.13 (6.59)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3.48 (2.38)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSepsis\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.79 (3.98\u0026ndash;11.58)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6.58 (61.17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e6.58 (3.90)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e2.72 (1.63)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNeoplasm Recurrence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e208.29 (119.70-362.46)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e201.42 (2386.20)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e200.57 (116.46)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e7.65 (6.52)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHepatotoxicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e27.58 (15.14\u0026ndash;50.23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e26.83 (248.45)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e26.82 (14.85)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e4.75 (3.52)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePlatelet Count Decreased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.53 (2.34\u0026ndash;8.76)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.44 (20.81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4.44 (2.31)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e2.15 (0.80)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSkin Lesion\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18.07 (9.33\u0026ndash;34.99)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e17.67 (125.51)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e17.67 (9.19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e4.14 (2.79)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlanine Aminotransferase Increased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.89 (3.42\u0026ndash;13.87)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6.77 (33.85)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e6.76 (3.38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e2.76 (1.33)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAspartate Aminotransferase Increased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7.95 (3.95\u0026ndash;16.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e7.81 (41.04)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e7.81 (3.91)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e2.97 (1.54)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAtrial Fibrillation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.37 (2.17\u0026ndash;8.81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.31 (17.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4.31 (2.15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e2.11 (0.68)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypoxia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12.40 (6.16\u0026ndash;24.98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e12.17 (71.31)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e12.16 (6.08)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3.60 (2.18)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLeukaemia Recurrent\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e248.42 (123.13-501.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e243.37 (1687.74)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e242.14 (121.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e7.92 (6.49)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertransaminasaemia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e64.89 (30.71-137.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e63.75 (371.47)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e63.66 (30.35)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e5.99 (4.47)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFebrile Neutropenia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.93 (2.20-11.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.87 (14.85)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4.87 (2.19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e2.28 (0.65)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMultiple Organ Dysfunction Syndrome\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12.56 (5.61\u0026ndash;28.13)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e12.38 (51.96)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e12.38 (5.56)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3.63 (2.00)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOedema\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.97 (2.06\u0026ndash;12.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.92 (11.98)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4.92 (2.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e2.30 (0.52)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlastic Plasmacytoid Dendritic Cell Neoplasia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2866.17 (1040.03-7898.71)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e2836.93 (8192.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e2677.16 (1004.77)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e11.39 (9.42)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlood Lactate Dehydrogenase Increased\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12.66 (4.73\u0026ndash;33.92)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e12.55 (31.76)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e12.54 (4.71)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3.65 (1.69)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisseminated Intravascular Coagulation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14.65(5.47\u0026ndash;39.24)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e14.51(37.73)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e14.51(5.44)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e3.86(1.89)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.4 Onset time\u003c/h2\u003e\u003cp\u003eThe time interval between tagraxofusp administration and the onset of tagraxofusp-related AEs was analyzed (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e). This study found that the median time to onset of tagraxofusp-induced adverse events was 4 days, highlighting the necessity for continuous early monitoring and proactive risk management.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"4.Discussion","content":"\u003cp\u003eTo the best of our knowledge, this is the first post-marketing study to conduct a systematic and comprehensive pharmacovigilance analysis of tagraxofusp using real-world data. In this study, we conducted pharmacovigilance analysis using real data to evaluate the safety of tagraxofusp based on the FAERS database. These findings provide critical real-world evidence to guide clinical decision-making and enhance medication safety monitoring for tagraxofusp.\u003c/p\u003e\u003cp\u003eNotably, during the study period, males accounted for the majority of reported reactions submitted to the FDA, representing 58.7% of the cases. Interestingly, most AE reports (44.5%) were submitted by physicians rather than consumers, suggesting that healthcare professionals are the primary source of reports or that patients might underreport. Furthermore, the majority of the reports originated from the United States (56.5%), suggesting the presence of potential regional or cultural variations in reporting practices that merit further investigation. The age distribution indicates that tagraxofusp-related AEs can affect patients across various age groups, but is predominantly concentrated in the 18\u0026ndash;65 age group, which has the highest proportion of cases. This suggests that heightened vigilance is also necessary for the adult population.\u003c/p\u003e\u003cp\u003eIn this study, capillary leak syndrome (CLS) exhibited the highest incidence and signal intensity among tagraxofusp-related adverse events. It is a well-recognized and potentially serious complication of this CD123-directed therapy, making an understanding of its mechanism crucial for prevention and management.Tagraxofusp-induced capillary leak syndrome is characterized by a rapid onset of vascular leakage, leading to hypotension, hypoalbuminemia, and peripheral edema, which can progress to severe organ hypoperfusion and shock; it is often triggered by the initial cycles of therapy or underlying endothelial vulnerability\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. Tagraxofusp is a fusion protein composed of recombinant human interleukin-3 (IL-3) linked to a truncated form of diphtheria toxin (DT). The proposed mechanism underlying tagraxofusp-associated CLS involves vascular endothelial uptake of the diphtheria toxin component, leading to apoptosis of endothelial cells and increased vascular permeability\u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e. In another study, CLS was reported in 55% (7% Grade 3) of patients treated with tagraxofusp for BPDCN during clinical trials, with a median time to onset of 5 days\u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. This high incidence and rapid onset underscore the significant clinical risk associated with tagraxofusp therapy. Therefore, clinicians must maintain a high index of suspicion, particularly during the initial treatment cycles. Proactive monitoring for early signs (e.g., sudden weight gain, hypotension, or hypoalbuminemia) is imperative to enable the early application of measures to reverse the fluid retention and oncotic effects of CLS.\u003c/p\u003e\u003cp\u003eIn our study, several uncommon yet pharmacologically significant adverse event signals were also detected, including blastic plasmacytoid dendritic cell neoplasia (n\u0026thinsp;=\u0026thinsp;4, reporting odds ratio 2866.17, proportional reporting ratio 2836,93, information component 11.39, empirical Bayes geometric mean 2677.16), leukaemia recurrent(n\u0026thinsp;=\u0026thinsp;8, reporting odds ratio 248.42, proportional reporting ratio 243.37, information component 7.92, empirical Bayes geometric mean 242.14), neoplasm recurrence(n\u0026thinsp;=\u0026thinsp;13, reporting odds ratio 208.29, proportional reporting ratio 201.42, information component 7.65, empirical Bayes geometric mean 200.57) and blood albumin decreased(n\u0026thinsp;=\u0026thinsp;23, reporting odds ratio 160.86, proportional reporting ratio 151.48, information component 7.23, empirical Bayes geometric mean 151.01). Among these signals, blastic plasmacytoid dendritic cell neoplasm, leukemia recurrence, and neoplasm recurrence are likely associated with the underlying primary disease and its natural progression or relapse, rather than being directly attributable to the drug itself. In contrast, decreased serum albumin is a recognized and documented adverse drug reaction of tagraxofusp, consistent with its known toxicity profile and described in the prescribing information\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Given these findings, clinicians should carefully differentiate between disease-related progression and genuine treatment-emergent AEs. Close monitoring for signs of disease recurrence and regular assessment of serum albumin levels, especially during early treatment cycles, are recommended. Prompt supportive measures, such as albumin supplementation, should be initiated when indicated to mitigate potential complications.\u003c/p\u003e\u003cp\u003eIn addition to the signals already documented in the prescribing information, our study also identified novel safety signals associated with tagraxofusp. Among these, Multiple Organ Dysfunction Syndrome(MODS) (n\u0026thinsp;=\u0026thinsp;6, reporting odds ratio 12.56, proportional reporting ratio 12.38, information component 3.63, empirical Bayes geometric mean 12.38) exhibited a significant disproportionality signal, suggesting a potential association with the drug that was previously unrecognized and not included in its official labeling. MODS is a severe, life-threatening condition characterized by the progressive dysfunction of two or more organ systems\u0026mdash;such as respiratory, renal, hepatic, or cardiovascular failure\u0026mdash;often resulting from a catastrophic physiological insult\u003csup\u003e[\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e. In the context of tagraxofusp therapy, MODS may occur as an extreme manifestation of CLS or systemic inflammatory response triggered by the drug\u0026rsquo;s mechanism of action. The fusion protein\u0026rsquo;s binding to CD123-expressing cells\u0026mdash;including certain immune and endothelial cells\u0026mdash;followed by diphtheria toxin\u0026ndash;mediated cell damage, may lead to a cascade of cytokine release, endothelial apoptosis, and loss of vascular integrity. This can subsequently precipitate systemic hypoperfusion, tissue ischemia, and ultimately, multi-organ failure. However, the precise pathophysiological pathway linking tagraxofusp to MODS remains to be fully elucidated and warrants further investigation. Although this signal was detected with a relatively small number of cases, the strength of the pharmacometric scores warrants serious clinical attention. Physicians should be aware of the potential risk of MODS, especially in patients showing signs of severe CLS, rapid clinical deterioration, or pre-existing organ compromise. Early intensive support and organ-function monitoring are critical in mitigating outcomes associated with this rare but highly serious adverse event.\u003c/p\u003e\u003cp\u003eOur study has several limitations that should be considered when interpreting the findings related to tagraxofusp. First, the potential influence of underlying conditions such as BPDCN or other hematologic malignancies on the reported adverse events was not fully accounted for. Additionally, confounding factors including concomitant medications, potential drug-drug interactions, and variations in tagraxofusp dosing regimens were not adjusted for in the analysis, which may introduce bias into the results. Second, as the FAERS database relies on spontaneous reporting, it is subject to potential inaccuracies in the identification and attribution of adverse events due to incomplete documentation, under-reporting, and heterogeneous reporting practices across institutions. These limitations may introduce variability in data quality and affect the reliability of the disproportionality analyses. Therefore, further prospective studies and clinical trials are necessary to confirm and further elucidate the safety signals associated with tagraxofusp.\u003c/p\u003e"},{"header":"5.Conclusion","content":"\u003cp\u003eIn summary, this study utilized four disproportionality analysis methods to mine and evaluate adverse drug reaction signals associated with tagraxofusp based on the FAERS database. Close attention should be paid to adverse events demonstrating strong signals in this analysis, including capillary leak syndrome and decreased albumin. Furthermore, potential severe complications such as MODS related to tagraxofusp warrant further investigation and validation in real-world settings. This study provides valuable insights for optimizing the clinical application of tagraxofusp, thereby supporting improved drug safety and treatment outcomes.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eDeclaration of interest\u003c/h2\u003e\u003cp\u003eThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.\u003c/p\u003e\u003ch2\u003eEthical approval\u003c/h2\u003e\u003cp\u003eThe FAERS database contains anonymized patient information. The Hospital Ethics Committee has confirmed that no ethical approval was required.\u003c/p\u003e\u003ch2\u003eFunding Statement\u003c/h2\u003e\u003cp\u003eThis work was sponsored by Natural Science Foundation of Chongqing, China (CSTB2022NSCQ-MSX1207) .\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eChunyong Xia: Writing-review \u0026amp; editing, Writing-original draft, Validation, Conceptualization. Jie Liu: Writing-review \u0026amp; editing, Writing-original draft, Validation, Conceptualization. Ya Gan: Validation, Writing-review \u0026amp; editing, Validation, Supervision, Data curation, Formal analysis, Software, Visualization.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData associated with our study has been deposited into a publicly available repository(https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSyed YY (2019) Tagraxofusp: First Global Approval. Drugs 79(5):579\u0026ndash;583\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePemmaraju N, Lane AA, Sweet KL, Stein AS, Vasu S, Blum W, Rizzieri DA, Wang ES, Duvic M, Sloan JM, Spence S, Shemesh S, Brooks CL, Balser J, Bergstein I, Lancet JE, Kantarjian HM, Konopleva M (2019) Tagraxofusp in Blastic Plasmacytoid Dendritic-Cell Neoplasm. N Engl J Med 380(17):1628\u0026ndash;1637\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHammond D, Pemmaraju N (2020) Tagraxofusp for Blastic Plasmacytoid Dendritic Cell Neoplasm. Hematol Oncol Clin North Am 34(3):565\u0026ndash;574\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eFitzGerald DJ (2014) Targeted diphtheria toxin to treat BPDCN. Blood 124(3):310\u0026ndash;312\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMouhayar EN, Hammond D, Lopez-Mattei J, Banchs J, Konopleva M, Pemmaraju N (2021) Reversible Myocardial Edema Secondary to Tagraxofusp-Induced Capillary Leak Syndrome. JACC CardioOncol 3(5):752\u0026ndash;755\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSzarfman A, Machado SG, O'Neill RT (2002) Use of screening algorithms and computer systems to efficiently signal higher-than-expected combinations of drugs and events in the US FDA's spontaneous reports database. Drug Saf 25(6):381\u0026ndash;392\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eEvans SJ, Waller PC, Davis S (2001) Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf 10(6):483\u0026ndash;486\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHauben M, Patadia V, Gerrits C, Walsh L, Reich L (2005) Data mining in pharmacovigilance: the need for a balanced perspective. Drug Saf 28(10):835\u0026ndash;842\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDiPippo AJ, Wilson NR, Pemmaraju N (2021) Targeting CD123 in BPDCN: an emerging field. Expert Rev Hematol 14(11):993\u0026ndash;1004\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCangini D, Silimbani P, Cafaro A, Giannini MB, Masini C, Ghelli Luserna Di Ror\u0026agrave; A, Simonetti G, Martinelli G, Cerchione C (2020) Tagraxofusp and anti-CD123 in blastic plasmacytoid dendritic cell neoplasm: a new hope. Minerva Med. ;111(5):467\u0026ndash;477\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLuskin MR, Lane AA (2024) Tagraxofusp for blastic plasmacytoid dendritic cell neoplasm. Haematologica 109(1):44\u0026ndash;52\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePemmaraju N, Sweet KL, Stein AS, Wang ES, Rizzieri DA, Vasu S, Rosenblat TL, Brooks CL, Habboubi N, Mughal TI, Kantarjian H, Konopleva M, Lane AA (2022) Long-Term Benefits of Tagraxofusp for Patients With Blastic Plasmacytoid Dendritic Cell Neoplasm. J Clin Oncol 40(26):3032\u0026ndash;3036\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSamhouri Y, Ursu S, Dutton N, Tanvi V, Fazal S (2021) Tagraxofusp followed by combined azacitidine and venetoclax in blastic plasmacytoid dendritic cell neoplasm: A case report and literature review. J Oncol Pharm Pract 27(4):990\u0026ndash;995\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAlfayez M, Konopleva M, Pemmaraju N (2020) Role of tagraxofusp in treating blastic plasmacytoid dendritic cell neoplasm (BPDCN). Expert Opin Biol Ther 20(2):115\u0026ndash;123\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJain A, Sweet K (2023) Blastic Plasmacytoid Dendritic Cell Neoplasm. J Natl Compr Canc Netw 21(5):515\u0026ndash;521\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSyed YY (2019) Tagraxofusp: First Global Approval. Drugs 79(5):579\u0026ndash;583\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGourd NM, Nikitas N (2020) Multiple Organ Dysfunction Syndrome. J Intensive Care Med 35(12):1564\u0026ndash;1575\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZiesmann MT, Marshall JC (2018) Multiple Organ Dysfunction: The Defining Syndrome of Sepsis. Surg Infect (Larchmt) 19(2):184\u0026ndash;190\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChen P, Billiar T (2020) Gut Microbiota and Multiple Organ Dysfunction Syndrome (MODS). Adv Exp Med Biol 1238:195\u0026ndash;202\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSimko LC, Culleiton AL (2020) Cardiogenic shock with resultant multiple organ dysfunction syndrome. Nursing 50(7):54\u0026ndash;60\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"tagraxofusp, adverse events, disproportionality analysis, FAERS database","lastPublishedDoi":"10.21203/rs.3.rs-7678895/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7678895/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eTagraxofusp is a targeted therapy for blastic plasmacytoid dendritic cell neoplasm (BPDCN) that works by targeting cluster of differentiation 123 (CD123). It was the first drug approved by the FDA for this disease, and also represents the world's first approved CD123-targeting agent. However, existing evidence regarding the safety of tagraxofusp is primarily derived from clinical trials, which limits the ability to provide timely updates on associated adverse events(AEs).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAim: \u003c/strong\u003eBy using the FAERS database, we aim to mine and systematically describe AEs related to tagraxofusp from January 2019 to March 2025.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eAll statistics were extracted from FAERS by four disproportional methods, which were reporting odds ratio, proportional reporting ratio, information component and empirical Bayes geometric mean. These four methods were perfomed to detect risk signals in the FAERS database to identify potential associations between tagraxofusp and AEs.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eA total of 492 adverse event reports with tagraxofuspas the “primary suspect” were collected. A total of 1099 preferred terms and 22 system organ categories were obtained. The highest incidence of populations related to AEs was 26.2% in the 18-65 age group. Notably, Capillary Leak Syndrome (n = 92, reporting odds ratio 3457.54, proportional reporting ratio 2646.31, information component 11.29, empirical Bayes geometric mean 2506.77) exhibited the highest incidence and signal intensity. In addition, uncommon, but apparently strong adverse event signals were observed, such as blastic plasmacytoid dendritic cell neoplasia (n = 4, reporting odds ratio 2866.17, proportional reporting ratio 2836,93, information component 11.39, empirical Bayes geometric mean 2677.16), leukaemia recurrent(n = 8, reporting odds ratio 248.42, proportional reporting ratio 243.37, information component 7.92, empirical Bayes geometric mean 242.14),neoplasm recurrence(n = 13, reporting odds ratio 208.29, proportional reporting ratio 201.42, information component 7.65, empirical Bayes geometric mean 200.57) and blood albumin decreased(n = 23, reporting odds ratio 160.86, proportional reporting ratio 151.48, information component 7.24, empirical Bayes geometric mean 151.01). Multiple Organ Dysfunction Syndrome(n = 6, reporting odds ratio 12.56, proportional reporting ratio 12.38, information component 3.63, empirical Bayes geometric mean 12.38) also showed strong adverse event signals, which was not included in the instructions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eIn the clinical application of tagraxofusp, AEs with high signal strength should be closely monitored. At the same time, healthcare professionals should remain vigilant for the emergence of adverse event signals not described in the prescribing information and take appropriate preventive measures to ensure patient safety.\u003c/p\u003e","manuscriptTitle":"Tagraxofusp, a first-in-class CD123-targeted anticancer agent: A pharmacovigilance study based on the FAERS database","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-06 09:18:34","doi":"10.21203/rs.3.rs-7678895/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"a5662182-a1d8-4ef3-9a02-36bfd4219e0b","owner":[],"postedDate":"October 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-27T07:58:11+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-06 09:18:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7678895","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7678895","identity":"rs-7678895","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}