Pharmacovigilance Analysis of Blinatumomab in Children Based on Clinical Practice Combined with FAERS Database

Pharmacovigilance Analysis of Blinatumomab in Children Based on Clinical Practice Combined with 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 Pharmacovigilance Analysis of Blinatumomab in Children Based on Clinical Practice Combined with FAERS Database Yingqiu Tu, Xin Lai, Nan Zhong This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7875023/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 7 You are reading this latest preprint version Abstract Background: This study aimed to analyze adverse drug events (ADEs) of blinatumomab monotherapy using the Food and Drug Administration Adverse Event Reporting System (FAERS) database, providing a valuable reference for clinical drug safety. Research design and methods: FAERS data for blinatumomab from their market approval in the United States until the fourth quarter of 2024 were retrieved. Signal detection was performed using the reporting odds ratio (ROR) and proportional reporting ratio (PRR) methods. ADEs were classified according to the System Organ Class (SOC) in the Medical Dictionary for Regulatory Activities (MedDRA) version 26.0. Results: A total of 987 ADE reports were retrieved for blinatumomab , respectively, involving 18 SOC categories. blinatumomab marboxil demonstrated a strong association with leukaemic infiltration extramedullary, bone marrow leukaemic cell infiltration , acute biphenotypic leukaemia, acute lymphocytic leukaemia refractory , central nervous system leukaemia, tumour associated fever, transformation to acute myeloid leukaemia, ib precursor type acute leukaemia, malignant ascites, and acute lymphocytic leukaemia recurrent. In our hospital, there were 11 instances of blinatumomab administration in children, with reported adverse effects including hematological adverse reactions, cytokine release syndrome ,neurotoxicity, gastrointestinal adverse reactions, elevated liver enzymes and musculoskeletal pain. Conclusions: When using blinatumomab clinically, attention should be paid not only to common ADEs but also to those not mentioned on the drug label. blinatumomab signal detection adverse drug events pharmacovigilance Analysis Figures Figure 1 1. Introduction With ongoing advancements in diagnostic techniques and therapeutic protocols for acute lymphoblastic leukemia (ALL), the long-term survival rate for pediatric patients with ALL has approached nearly 90% in numerous countries[ 1 – 3 ]. Nonetheless, 15–20% of these patients continue to experience relapse or refractory disease. Furthermore, second-line chemotherapy not only fails to enhance prognosis but may also elevate the risk of complications and mortality[ 4 ]. Additionally, the high incidence of chemotherapy-related adverse events in this population frequently impedes standard treatment regimens. As a result, targeted immunotherapy has emerged as a pivotal therapeutic strategy for managing refractory and relapsed ALL. Blinatumomab, marketed under the Chinese brand name Beilituo and the English brand name Blincyto, received approval from the U.S. Food and Drug Administration (FDA) in 2014 as the first bispecific antibody therapy globally, targeting CD3 and CD19 for the treatment of acute lymphoblastic leukemia (ALL). In 2017, its use was extended to include the treatment of relapsed or refractory B-cell ALL (B-ALL) in pediatric populations. The drug became available in China in 2020 and subsequently obtained approval from China's National Medical Products Administration (NMPA) in 2022 for the treatment of pediatric relapsed/refractory B-ALL. Current safety data predominantly derive from clinical trials, which are constrained by limitations such as small sample sizes and short observation periods, thereby impeding the detection of delayed and rare adverse drug events (ADEs). Consequently, continuous safety monitoring is imperative. Furthermore, the relatively brief history of clinical use in Asian pediatric populations highlights the urgent need for comprehensive safety assessments. This study integrates clinical practice with an analysis of adverse drug event (ADE) signals associated with the use of blinatumomab in pediatric populations by utilizing data mining techniques on the FDA Adverse Event Reporting System (FAERS) database. The objective is to augment the existing safety data of blinatumomab in children and to offer guidance for its safe clinical application. 2. Materials and Methods 2.1 Data Source 1)FAERS Database The data for this study were obtained from the FAERS database. Data were extracted from the FAERS database from the first quarter of 2004 until the fourth quarter of 2024. The data were imported into a MYSQL database. After removing erroneous reports and duplicate records from the "DEMO" table in the Deleted folder based on case IDs, the data were filtered using the generic names "Blinatumomab". Generic names such as "Blinatumomab" were matched with the "drugname" field in MYSQL using fuzzy matching. Information identified as "PS (primary suspect)" was located in the database, and reports where the drug was not the primary suspected agent were excluded. 2)Clinical Practice Data The medical records of pediatric patients discharged between July 2024 and July 2025, who had been administered belinoue monoclonal antibody and met the established selection criteria, were retrieved from the hospital information system. A retrospective analysis was conducted to assess the incidence of adverse reactions. Inclusion criteria are as follows: (1)Age between 28 days and 18 years, with no gender restrictions; (2)Refractory response to initial chemotherapy, characterized by an inability to continue due to severe complications during the standard induction remission protocol or consolidation therapy, or a suboptimal response to chemotherapy, indicated by minimal residual disease (MRD) levels of ≥ 0.01% as determined by flow cytometry, PCR, or next-generation sequencing after two standard induction cycles; progression to the maintenance phase or bridge transplantation; relapsed B-cell acute lymphoblastic leukemia (B-ALL), defined by ≥ 5% bone marrow involvement post-complete remission or extramedullary relapse; or recurrence of MRD, indicated by MRD levels of ≥ 0.01% reoccurring after achieving < 0.01% on standard treatment. Exclusion criteria included: pediatric patients presenting with extramedullary recurrence confined solely to the central nervous system; individuals who did not undergo bone marrow evaluation both prior to and following blinatumomab therapy; patients who failed to complete the prescribed course of treatment due to various reasons; patients who did not undergo assessments for cytokines, liver function, and other relevant tests during the course of blinatumomab treatment. 2.2 Data Processing FAERS Database In this study, the System Organ Class (SOC) classification from the Medical Dictionary for Regulatory Activities (MedDRA) (version 26.0) ADE term set was used for categorical analysis. Since a single preferred term (PT) can map to multiple SOCs, to avoid duplicate counting, this study only analyzed the main SOCs related to the PTs. Clinical Practice Data Statistical analysis of all data was performed using SPSS 21.0 software. Count data is expressed as the number of occurrence cases (incidence%). 2.3 Data Mining Method This study utilized the reporting odds ratio (ROR) and proportional reporting ratio (PRR) methods to identify the association between drugs and target ADRs [ 8 ]. The Reporting Odds Ratio (ROR) and the Proportional Reporting Ratio (PRR) are frequently employed signal detection methodologies in pharmacovigilance, utilized to identify potential associations between drugs and adverse events based on spontaneous reporting data. These methods are primarily intended to generate hypotheses rather than to establish causal relationships[ 9 – 10 ]. By employing stratified analysis, potential confounding variables, such as age and sex, are controlled to enhance the precision of signal detection. The results of signal detection necessitate further investigation, such as epidemiological studies or clinical trials, to confirm their clinical significance[ 11 – 12 ]. The calculation formulas were as follows: ROR= (Formula 1); (CI) = eln (ROR) ± 1.96 (Formula 2); Where ROR > 1, a ≥ 3, and the lower limit of the 95% CI of ROR > 1, indicating a statistically significant association between the ADE and the target drug. A higher ROR indicates a stronger association between the ADE and the drug [ 13 ]. PRR = a(c + d)/c(a + b) (Formula 3); =[(ad-bc)^2](a + b + c + d)/[(a + b)(c + d)(a + c)(b + d)] (Formula 4); Where PRR ≥ 2, ≥ 4, and a ≥ 3. When the calculated results between the target drug and the adverse reaction exceed a given threshold, an imbalance occurs, generating a signal. The strength of the signal is directly proportional to the statistical association between blinatumomab and the target ADR [ 14 ]. In this study, ADRs were extracted when at least one of the two indicators met the criteria. All statistical analyses were performed using Microsoft Excel 2019. The Proportional Imbalance Method is presented in Table 1 . Table 1 Proportional Imbalance Method Table Drug Category Target ADE Reports Other ADE Reports Total Target Drug a b a + b Other Drugs c d c + d Total a + c b + d a + b + c + d ADE: Adverse Drug Event; a: Number of individual reports of target ADEs for the target drug; b: Number of individual reports of other ADEs for the target drug; c: Number of individual reports of target ADEs for other drugs; d: Number of individual reports of other ADEs for other drugs 3. Results 3.1 Basic Information for Children The proportion of ADE reports for blinatumomab was higher among females compared to males. The United States was the leading country in reporting ADEs from FAERS. Further details are presented in Table 2.Since their inclusion in 2015, reports of ADEs related to blinatumomab have shown a steady increasing trend (Fig. 1). The number of Blinatumomab-related ADEs reported yearly after 2015. X‐axis shows the timeline when the drug was used, and Y-axis displays the number of reports per year. ADEs, adverse drug events. 3.2 ADE Signal Detection Results for the Blinatumomab From FAERS Database A total of 987 adverse drug event (ADE) reports were identified for blinatumomab use in children aged 0–18 years, encompassing 18 System Organ Class (SOC) categories(Figure1 ).The three most frequently reported SOCs for ADEs associated with blinatumomab were neoplasms benign, malignant and unspecified (incl cysts and polyps) (N = 228), general disorders and administration site conditions and mediastinal disorders(N = 188), and immune system disorders(N = 155). Additionally, 91 Preferred Terms (PTs) related to clinically and scientifically significant ADEs for doxycycline use in this pediatric population were documented (Table 3). The top ten adverse drug event (ADE) safety signals with significant and robust associations related to blinatumomab use in children are as follows: leukaemic infiltration extramedullary(ROR = 7846.11), bone marrow leukaemic cell infiltration (ROR = 1561.38), acute biphenotypic leukaemia (ROR = 1169.25), acute lymphocytic leukaemia refractory (ROR = 964.47), central nervous system leukaemia (ROR = 848.254), tumour associated fever(ROR = 779.497),transformation to acute myeloid leukaemia (ROR = 463.461), ib precursor type acute leukaemia(ROR = 411.595), malignant ascites (ROR = 389.746), and acute lymphocytic leukaemia recurrent(ROR = 345.835). Notably, leukaemic infiltration extramedullary exhibited the strongest signal intensity and the highest association (Table 3). Within the SOC category for General Disorders and Administration Site Conditions, there was a noted increase in the incidence of pyrexia and treatment non-response. Multiple clinical studies on blinatumomab in pediatric patients have identified fever as a prevalent adverse reaction [ 15 – 17 ]. Additionally, some literature documents instances of non-responsiveness to blinatumomab in pediatric patients, potentially due to drug resistance. Chitadze et al. [ 18 ] have shown that resistance to blinatumomab may be linked to the low immunogenicity of tumor cells and dysfunction of T lymphocytes. Within the SOC for general disorders and administration site conditions, cytokine release syndrome (CRS) and various graft-versus-host diseases (GVHDs) are prominent. CRS emerges as the most frequently reported condition (N = 93), with the package insert explicitly cautioning that CRS may be life-threatening or fatal. This necessitates that healthcare professionals prioritize this potentially lethal acute disease event (ADE). Notably, the package insert does not report any instances of GVHDs, and the potential association between their occurrence and blinatumomab requires further clinical investigation for validation. Within the SOC classification of benign, malignant, and unspecified neoplasms (encompassing cysts and polyps), all categories, with the exception of central nervous system leukemia, were absent from drug labeling documentation, yet all exhibited pronounced signals. Notably, the intensity of leukemic infiltration medullary signals was the most pronounced, serving as a significant contributing factor to leukemia recurrence. Among these categories, acute lymphoblastic leukemia recurrence (N = 96) was the most frequently observed. This phenomenon may be intrinsically linked to the pathology of the disease. Patients diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) have the potential to experience relapse or develop refractory disease following systemic chemotherapy. Moreover, recurrence can occur even after hematopoietic stem cell transplantation. Therefore, in clinical practice, it is imperative to conduct long-term follow-up studies on patients receiving blinatumomab to rigorously assess and validate its sustained efficacy over time. In other SOC analyses, several unreported signals were identified in the package insert, including moderate-to-severe malignant ascites and immune effector cell-associated neurotoxicity syndrome, as well as rare cases of venoocclusive disease, hypokalemia, hemorrhagic cystitis, tinnitus, and neutropenic colitis. These signals occur infrequently and require continued monitoring, with their causal relationship to blinatumomab still needing clinical validation. 3.3 ADE Results for the Blinatumomab From Clinical Practice Data In this study, a total of 11 clinical cases were documented. During the administration of belintuo monoclonal antibody, four pediatric patients experienced adverse reactions classified as grade 3 or higher according to the CTCAE 5.0 evaluation criteria [ 19 ]. Notably, one case involved a grade 4 adverse reaction, characterized by a severe convulsion occurring on the fourth day of belintuo monoclonal antibody infusion, which resolved spontaneously following the discontinuation of the treatment. On the fourth day of treatment, another patient discontinued blinatumomab due to the onset of neurological toxicity, characterized by sudden loss of consciousness and unresponsiveness. The patient was transitioned to levetiracetam therapy. Following a two-week course of levetiracetam, blinatumomab treatment was resumed with the concurrent administration of levetiracetam to mitigate the risk of neurological toxicity, including seizures. This therapeutic adjustment successfully prevented further neurological adverse effects.In this clinical study, the incidence of various adverse reactions was observed as follows: hematological adverse reactions occurred in 27.27% of participants, cytokine release syndrome in 63.64%, neurotoxicity in 36.36%, gastrointestinal adverse reactions in 9.09%, elevated liver enzymes in 45.45%, and musculoskeletal pain in 18.18%. 4. Discussion Upon excluding product-related issues, the 17 System Organ Classification (SOC) categories identified within the FAERS database—excluding neoplasms (benign, malignant, and unspecified types, including cysts and polyps), renal and urinary disorders, and ear and labyrinth disorders—were consistently referenced in drug labeling and clinical trials. Furthermore, the database revealed specific warnings regarding cytokine release syndrome (CRS) and neurotoxicity in drug instructions, alongside prevalent Adverse Drug Events (ADEs) such as fever, infections, and neutropenia. These findings underscore the reliability of the FAERS database. This study integrates clinical practice with an analysis of the FAERS database, demonstrating that adverse drug event (ADE) signals such as cytokine release syndrome, neurotoxicity, and fever align with the information provided in the Beilinouo monoclonal antibody package insert. However, the FAERS database also identified risk signals with increased intensity, such as leukocyte extramedullary infiltration and acute myeloid leukemia transformation, which are not mentioned in the Beilinouo package insert. These findings contribute additional insights to the post-marketing safety data of the drug. Furthermore, the FAERS database revealed additional system organ classes (SOCs) not explicitly listed in the package insert, including benign, malignant, and poorly defined tumors (such as cystic and polypoid lesions), renal/urological disorders, and ocular diseases. It is imperative for clinical practitioners to monitor pediatric patients for these potential adverse events during treatment. This study offers evidence-based support for the safety profile of Beilinouo, promoting safe and rational use of the medication in pediatric patients. Declarations 1.Clinical trial number Clinical trial number: not applicable 2.Ethics approval and consent to participate This study involved the analysis of existing, de-identified data from the FAERS database. The requirement for informed consent was waived by the The First Affiliated Hospital of Nanchang University Ethics Committee as the study posed minimal risk to the participants and the data were anonymized. 3.Consent for publication We hereby submit the manuscript entitled "Pharmacovigilance Analysis of Blinatumomab in Children Based on Clinical Practice Combined with FAERS Database" for exclusive consideration for publication in BMC Pediatrics. All authors have reviewed the manuscript, and we confirm that none of the material related to this submission has been previously published or is currently under consideration for publication elsewhere, including online platforms. 4.Availability of data and material The data that support the findings of this study are openly available in at OpenVigil 2.1 (http://openvigil.sourceforge.net/). 5.Competing interests The authors declare no conflicts of interest or financial interest in any product or service mentioned in the article. 6.Funding Not applicable 7.Authors' contributions Yingqiu Tu, Xin Lai, and Nan Zhong contributed to the conception and design, as well as the analysis and interpretation of the data. Yingqiu Tu participated in drafting the manuscript and critically revising it for intellectual content, and they provided final approval of the version to be published. All authors concur with being accountable for all aspects of the work. 8.Acknowledgements First and foremost, I would like to extend my sincere gratitude to all individuals who have contributed to the completion of this paper. I am particularly indebted to my colleagues for their invaluable assistance and companionship throughout the preparation process. Furthermore, I am profoundly grateful to my family for their unwavering love and steadfast support. Lastly, I wish to express my deep appreciation to those who have dedicated considerable time to reviewing this thesis and providing insightful feedback, which will undoubtedly benefit my future academic endeavors. 9.Authors' information (optional) First author: Yingqiu Tu,First Affiliated Hospital of Nanchang University， [email protected] Other author: Xin Lai: First Affiliated Hospital of Nanchang University， [email protected] Nan Zhong:First Affiliated Hospital of Nanchang University， [email protected] Corresponding authors: Yingqiu Tu*,First Affiliated Hospital of Nanchang University， [email protected] References Shahriari M, Shakibazad N, Haghpanah S, Ghasemi K. Extramedullary manifestations in acute lymphoblastic leukemia in children: a systematic review and guideline-based approach of treatment. Am J Blood Res，2020,10:360-374. Tasian SK, Hunger SP. Genomic characterization of paediatric acute lymphoblastic leukaemia: an opportunity for precision medicine therapeutics. 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Locatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, Parasole R, Linderkamp C, Flotho C, Petit A, Micalizzi C, Mergen N, Mohammad A, Kormany WN, Eckert C, Möricke A, Sartor M, Hrusak O, Peters C, Saha V, Vinti L, von Stackelberg A. Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021,325(9):843-854. Locatelli F, Zugmaier G, Mergen N, Bader P, Jeha S, Schlegel PG, Bourquin JP, Handgretinger R, Brethon B, Rössig C, Kormany WN, Viswagnachar P, Chen-Santel C. Blinatumomab in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia: RIALTO expanded access study final analysis. Blood Adv. 2022,6(3):1004-1014. Chitadze G, Laqua A, Lettau M, Baldus CD, Brüggemann M. Bispecific antibodies in acute lymphoblastic leukemia therapy. Expert Rev Hematol. 2020,13(11):1211-1233. U.S. Department of Health and Human Services,National Institutes of Health,National Cancer Institute.Common Terminology Criteria for Adverse Events (CTCAE）Version 5.0[EB/OL][2022.08.25](2017.11.27) Tables Tables 2 to 4 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table2.xlsx Table3.xlsx table4.xlsx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 22 Nov, 2025 Reviewers agreed at journal 15 Nov, 2025 Reviewers invited by journal 14 Nov, 2025 Editor invited by journal 21 Oct, 2025 Editor assigned by journal 21 Oct, 2025 Submission checks completed at journal 21 Oct, 2025 First submitted to journal 16 Oct, 2025 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. 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09:50:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":558814,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7875023/v1/b60c79cd-21e0-4a2a-9ad3-b4c24eadbc4c.pdf"},{"id":96747579,"identity":"23b984d9-dc31-46e0-bdbd-8adb8bf9c01b","added_by":"auto","created_at":"2025-11-25 16:13:12","extension":"xlsx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":11506,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7875023/v1/6cff8aea61da70d005dc1d7a.xlsx"},{"id":96747575,"identity":"c6f1b49a-6fff-4d07-a2ab-e78166378ed1","added_by":"auto","created_at":"2025-11-25 16:13:11","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":23951,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7875023/v1/fd1f102431615407940b0f25.xlsx"},{"id":96747582,"identity":"a3e52ac0-28e8-4107-addd-c0eb8b624590","added_by":"auto","created_at":"2025-11-25 16:13:12","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":142934,"visible":true,"origin":"","legend":"","description":"","filename":"table4.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-7875023/v1/2e2d1a5154a58aa53485ea3c.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pharmacovigilance Analysis of Blinatumomab in Children Based on Clinical Practice Combined with FAERS Database","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eWith ongoing advancements in diagnostic techniques and therapeutic protocols for acute lymphoblastic leukemia (ALL), the long-term survival rate for pediatric patients with ALL has approached nearly 90% in numerous countries[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Nonetheless, 15\u0026ndash;20% of these patients continue to experience relapse or refractory disease. Furthermore, second-line chemotherapy not only fails to enhance prognosis but may also elevate the risk of complications and mortality[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Additionally, the high incidence of chemotherapy-related adverse events in this population frequently impedes standard treatment regimens. As a result, targeted immunotherapy has emerged as a pivotal therapeutic strategy for managing refractory and relapsed ALL.\u003c/p\u003e\u003cp\u003eBlinatumomab, marketed under the Chinese brand name Beilituo and the English brand name Blincyto, received approval from the U.S. Food and Drug Administration (FDA) in 2014 as the first bispecific antibody therapy globally, targeting CD3 and CD19 for the treatment of acute lymphoblastic leukemia (ALL). In 2017, its use was extended to include the treatment of relapsed or refractory B-cell ALL (B-ALL) in pediatric populations. The drug became available in China in 2020 and subsequently obtained approval from China's National Medical Products Administration (NMPA) in 2022 for the treatment of pediatric relapsed/refractory B-ALL. Current safety data predominantly derive from clinical trials, which are constrained by limitations such as small sample sizes and short observation periods, thereby impeding the detection of delayed and rare adverse drug events (ADEs). Consequently, continuous safety monitoring is imperative. Furthermore, the relatively brief history of clinical use in Asian pediatric populations highlights the urgent need for comprehensive safety assessments.\u003c/p\u003e\u003cp\u003eThis study integrates clinical practice with an analysis of adverse drug event (ADE) signals associated with the use of blinatumomab in pediatric populations by utilizing data mining techniques on the FDA Adverse Event Reporting System (FAERS) database. The objective is to augment the existing safety data of blinatumomab in children and to offer guidance for its safe clinical application.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Data Source\u003c/h2\u003e\u003c/div\u003e\n\u003ch3\u003e1)FAERS Database\u003c/h3\u003e\n\u003cp\u003eThe data for this study were obtained from the FAERS database. Data were extracted from the FAERS database from the first quarter of 2004 until the fourth quarter of 2024. The data were imported into a MYSQL database. After removing erroneous reports and duplicate records from the \"DEMO\" table in the Deleted folder based on case IDs, the data were filtered using the generic names \"Blinatumomab\". Generic names such as \"Blinatumomab\" were matched with the \"drugname\" field in MYSQL using fuzzy matching. Information identified as \"PS (primary suspect)\" was located in the database, and reports where the drug was not the primary suspected agent were excluded.\u003c/p\u003e\n\u003ch3\u003e2)Clinical Practice Data\u003c/h3\u003e\n\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eThe medical records of pediatric patients discharged between July 2024 and July 2025, who had been administered belinoue monoclonal antibody and met the established selection criteria, were retrieved from the hospital information system. A retrospective analysis was conducted to assess the incidence of adverse reactions.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eInclusion criteria are as follows:\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e(1)Age between 28 days and 18 years, with no gender restrictions;\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e(2)Refractory response to initial chemotherapy, characterized by an inability to continue due to severe complications during the standard induction remission protocol or consolidation therapy, or a suboptimal response to chemotherapy, indicated by minimal residual disease (MRD) levels of \u0026ge;\u0026thinsp;0.01% as determined by flow cytometry, PCR, or next-generation sequencing after two standard induction cycles; progression to the maintenance phase or bridge transplantation; relapsed B-cell acute lymphoblastic leukemia (B-ALL), defined by \u0026ge;\u0026thinsp;5% bone marrow involvement post-complete remission or extramedullary relapse; or recurrence of MRD, indicated by MRD levels of \u0026ge;\u0026thinsp;0.01% reoccurring after achieving\u0026thinsp;\u0026lt;\u0026thinsp;0.01% on standard treatment.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eExclusion criteria included:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003epediatric patients presenting with extramedullary recurrence confined solely to the central nervous system;\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eindividuals who did not undergo bone marrow evaluation both prior to and following blinatumomab therapy;\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003epatients who failed to complete the prescribed course of treatment due to various reasons;\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003epatients who did not undergo assessments for cytokines, liver function, and other relevant tests during the course of blinatumomab treatment.\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Data Processing\u003c/h2\u003e\u003cp\u003e\u003cb\u003eFAERS Database\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIn this study, the System Organ Class (SOC) classification from the Medical Dictionary for Regulatory Activities (MedDRA) (version 26.0) ADE term set was used for categorical analysis. Since a single preferred term (PT) can map to multiple SOCs, to avoid duplicate counting, this study only analyzed the main SOCs related to the PTs.\u003c/p\u003e\u003cp\u003e\u003cb\u003eClinical Practice Data\u003c/b\u003e\u003c/p\u003e\u003cp\u003eStatistical analysis of all data was performed using SPSS 21.0 software. Count data is expressed as the number of occurrence cases (incidence%).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Data Mining Method\u003c/h2\u003e\u003cp\u003eThis study utilized the reporting odds ratio (ROR) and proportional reporting ratio (PRR) methods to identify the association between drugs and target ADRs [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The Reporting Odds Ratio (ROR) and the Proportional Reporting Ratio (PRR) are frequently employed signal detection methodologies in pharmacovigilance, utilized to identify potential associations between drugs and adverse events based on spontaneous reporting data. These methods are primarily intended to generate hypotheses rather than to establish causal relationships[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. By employing stratified analysis, potential confounding variables, such as age and sex, are controlled to enhance the precision of signal detection. The results of signal detection necessitate further investigation, such as epidemiological studies or clinical trials, to confirm their clinical significance[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe calculation formulas were as follows:\u003c/p\u003e\u003cp\u003eROR= (Formula 1);\u003c/p\u003e\u003cp\u003e(CI)\u0026thinsp;=\u0026thinsp;eln (ROR)\u0026thinsp;\u0026plusmn;\u0026thinsp;1.96 (Formula 2);\u003c/p\u003e\u003cp\u003eWhere ROR\u0026thinsp;\u0026gt;\u0026thinsp;1, a\u0026thinsp;\u0026ge;\u0026thinsp;3, and the lower limit of the 95% CI of ROR\u0026thinsp;\u0026gt;\u0026thinsp;1, indicating a statistically significant association between the ADE and the target drug. A higher ROR indicates a stronger association between the ADE and the drug [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePRR\u0026thinsp;=\u0026thinsp;a(c\u0026thinsp;+\u0026thinsp;d)/c(a\u0026thinsp;+\u0026thinsp;b) (Formula 3);\u003c/p\u003e\u003cp\u003e=[(ad-bc)^2](a\u0026thinsp;+\u0026thinsp;b\u0026thinsp;+\u0026thinsp;c\u0026thinsp;+\u0026thinsp;d)/[(a\u0026thinsp;+\u0026thinsp;b)(c\u0026thinsp;+\u0026thinsp;d)(a\u0026thinsp;+\u0026thinsp;c)(b\u0026thinsp;+\u0026thinsp;d)] (Formula 4);\u003c/p\u003e\u003cp\u003eWhere PRR\u0026thinsp;\u0026ge;\u0026thinsp;2, \u0026ge; 4, and a\u0026thinsp;\u0026ge;\u0026thinsp;3.\u003c/p\u003e\u003cp\u003eWhen the calculated results between the target drug and the adverse reaction exceed a given threshold, an imbalance occurs, generating a signal. The strength of the signal is directly proportional to the statistical association between blinatumomab and the target ADR [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In this study, ADRs were extracted when at least one of the two indicators met the criteria. All statistical analyses were performed using Microsoft Excel 2019. The Proportional Imbalance Method is presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\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\u003eProportional Imbalance Method Table\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" 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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDrug Category\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTarget ADE Reports\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eOther ADE Reports\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTotal\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTarget Drug\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eb\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ea\u0026thinsp;+\u0026thinsp;b\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther Drugs\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ec\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ec\u0026thinsp;+\u0026thinsp;d\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ea\u0026thinsp;+\u0026thinsp;c\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eb\u0026thinsp;+\u0026thinsp;d\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ea\u0026thinsp;+\u0026thinsp;b\u0026thinsp;+\u0026thinsp;c\u0026thinsp;+\u0026thinsp;d\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eADE: Adverse Drug Event;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003ea: Number of individual reports of target ADEs for the target drug;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eb: Number of individual reports of other ADEs for the target drug;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003ec: Number of individual reports of target ADEs for other drugs; d: Number of individual reports of other ADEs for other drugs\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Basic Information for Children\u003c/h2\u003e\u003cp\u003eThe proportion of ADE reports for blinatumomab was higher among females compared to males. The United States was the leading country in reporting ADEs from FAERS. Further details are presented in Table\u0026nbsp;2.Since their inclusion in 2015, reports of ADEs related to blinatumomab have shown a steady increasing trend (Fig.\u0026nbsp;1).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe number of Blinatumomab-related ADEs reported yearly after 2015. X‐axis shows\u003c/p\u003e\u003cp\u003ethe timeline when the drug was used, and Y-axis displays the number of reports per year. ADEs, adverse drug events.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e3.2 ADE Signal Detection Results for the Blinatumomab From FAERS Database\u003c/h2\u003e\u003cp\u003eA total of 987 adverse drug event (ADE) reports were identified for blinatumomab use in children aged 0\u0026ndash;18 years, encompassing 18 System Organ Class (SOC) categories(Figure1 ).The three most frequently reported SOCs for ADEs associated with blinatumomab were neoplasms benign, malignant and unspecified (incl cysts and polyps) (N\u0026thinsp;=\u0026thinsp;228), general disorders and administration site conditions and mediastinal disorders(N\u0026thinsp;=\u0026thinsp;188), and immune system disorders(N\u0026thinsp;=\u0026thinsp;155). Additionally, 91 Preferred Terms (PTs) related to clinically and scientifically significant ADEs for doxycycline use in this pediatric population were documented (Table\u0026nbsp;3).\u003c/p\u003e\u003cp\u003eThe top ten adverse drug event (ADE) safety signals with significant and robust associations related to blinatumomab use in children are as follows: leukaemic infiltration extramedullary(ROR\u0026thinsp;=\u0026thinsp;7846.11), bone marrow leukaemic cell infiltration (ROR\u0026thinsp;=\u0026thinsp;1561.38), acute biphenotypic leukaemia (ROR\u0026thinsp;=\u0026thinsp;1169.25), acute lymphocytic leukaemia refractory (ROR\u0026thinsp;=\u0026thinsp;964.47), central nervous system leukaemia (ROR\u0026thinsp;=\u0026thinsp;848.254), tumour associated fever(ROR\u0026thinsp;=\u0026thinsp;779.497),transformation to acute myeloid leukaemia (ROR\u0026thinsp;=\u0026thinsp;463.461), ib precursor type acute leukaemia(ROR\u0026thinsp;=\u0026thinsp;411.595), malignant ascites (ROR\u0026thinsp;=\u0026thinsp;389.746), and acute lymphocytic leukaemia recurrent(ROR\u0026thinsp;=\u0026thinsp;345.835). Notably, leukaemic infiltration extramedullary exhibited the strongest signal intensity and the highest association (Table\u0026nbsp;3).\u003c/p\u003e\u003cp\u003eWithin the SOC category for General Disorders and Administration Site Conditions, there was a noted increase in the incidence of pyrexia and treatment non-response. Multiple clinical studies on blinatumomab in pediatric patients have identified fever as a prevalent adverse reaction [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Additionally, some literature documents instances of non-responsiveness to blinatumomab in pediatric patients, potentially due to drug resistance. Chitadze et al. [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] have shown that resistance to blinatumomab may be linked to the low immunogenicity of tumor cells and dysfunction of T lymphocytes.\u003c/p\u003e\u003cp\u003eWithin the SOC for general disorders and administration site conditions, cytokine release syndrome (CRS) and various graft-versus-host diseases (GVHDs) are prominent. CRS emerges as the most frequently reported condition (N\u0026thinsp;=\u0026thinsp;93), with the package insert explicitly cautioning that CRS may be life-threatening or fatal. This necessitates that healthcare professionals prioritize this potentially lethal acute disease event (ADE). Notably, the package insert does not report any instances of GVHDs, and the potential association between their occurrence and blinatumomab requires further clinical investigation for validation.\u003c/p\u003e\u003cp\u003eWithin the SOC classification of benign, malignant, and unspecified neoplasms (encompassing cysts and polyps), all categories, with the exception of central nervous system leukemia, were absent from drug labeling documentation, yet all exhibited pronounced signals. Notably, the intensity of leukemic infiltration medullary signals was the most pronounced, serving as a significant contributing factor to leukemia recurrence. Among these categories, acute lymphoblastic leukemia recurrence (N\u0026thinsp;=\u0026thinsp;96) was the most frequently observed. This phenomenon may be intrinsically linked to the pathology of the disease. Patients diagnosed with B-cell acute lymphoblastic leukemia (B-ALL) have the potential to experience relapse or develop refractory disease following systemic chemotherapy. Moreover, recurrence can occur even after hematopoietic stem cell transplantation. Therefore, in clinical practice, it is imperative to conduct long-term follow-up studies on patients receiving blinatumomab to rigorously assess and validate its sustained efficacy over time.\u003c/p\u003e\u003cp\u003eIn other SOC analyses, several unreported signals were identified in the package insert, including moderate-to-severe malignant ascites and immune effector cell-associated neurotoxicity syndrome, as well as rare cases of venoocclusive disease, hypokalemia, hemorrhagic cystitis, tinnitus, and neutropenic colitis. These signals occur infrequently and require continued monitoring, with their causal relationship to blinatumomab still needing clinical validation.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003e3.3 ADE Results for the Blinatumomab From Clinical Practice Data\u003c/h2\u003e\u003cp\u003eIn this study, a total of 11 clinical cases were documented. During the administration of belintuo monoclonal antibody, four pediatric patients experienced adverse reactions classified as grade 3 or higher according to the CTCAE 5.0 evaluation criteria [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Notably, one case involved a grade 4 adverse reaction, characterized by a severe convulsion occurring on the fourth day of belintuo monoclonal antibody infusion, which resolved spontaneously following the discontinuation of the treatment. On the fourth day of treatment, another patient discontinued blinatumomab due to the onset of neurological toxicity, characterized by sudden loss of consciousness and unresponsiveness. The patient was transitioned to levetiracetam therapy. Following a two-week course of levetiracetam, blinatumomab treatment was resumed with the concurrent administration of levetiracetam to mitigate the risk of neurological toxicity, including seizures. This therapeutic adjustment successfully prevented further neurological adverse effects.In this clinical study, the incidence of various adverse reactions was observed as follows: hematological adverse reactions occurred in 27.27% of participants, cytokine release syndrome in 63.64%, neurotoxicity in 36.36%, gastrointestinal adverse reactions in 9.09%, elevated liver enzymes in 45.45%, and musculoskeletal pain in 18.18%.\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eUpon excluding product-related issues, the 17 System Organ Classification (SOC) categories identified within the FAERS database\u0026mdash;excluding neoplasms (benign, malignant, and unspecified types, including cysts and polyps), renal and urinary disorders, and ear and labyrinth disorders\u0026mdash;were consistently referenced in drug labeling and clinical trials. Furthermore, the database revealed specific warnings regarding cytokine release syndrome (CRS) and neurotoxicity in drug instructions, alongside prevalent Adverse Drug Events (ADEs) such as fever, infections, and neutropenia. These findings underscore the reliability of the FAERS database.\u003c/p\u003e\u003cp\u003eThis study integrates clinical practice with an analysis of the FAERS database, demonstrating that adverse drug event (ADE) signals such as cytokine release syndrome, neurotoxicity, and fever align with the information provided in the Beilinouo monoclonal antibody package insert. However, the FAERS database also identified risk signals with increased intensity, such as leukocyte extramedullary infiltration and acute myeloid leukemia transformation, which are not mentioned in the Beilinouo package insert. These findings contribute additional insights to the post-marketing safety data of the drug. Furthermore, the FAERS database revealed additional system organ classes (SOCs) not explicitly listed in the package insert, including benign, malignant, and poorly defined tumors (such as cystic and polypoid lesions), renal/urological disorders, and ocular diseases. It is imperative for clinical practitioners to monitor pediatric patients for these potential adverse events during treatment. This study offers evidence-based support for the safety profile of Beilinouo, promoting safe and rational use of the medication in pediatric patients.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e1.Clinical trial number\u003c/p\u003e\n\u003cp\u003eClinical trial number: not applicable\u003c/p\u003e\n\u003cp\u003e2.Ethics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eThis study involved the analysis of existing, de-identified data from the FAERS database. The requirement for informed consent was waived by the The First Affiliated Hospital of Nanchang University Ethics Committee as the study posed minimal risk to the participants and the data were anonymized.\u003c/p\u003e\n\u003cp\u003e3.Consent for publication\u003c/p\u003e\n\u003cp\u003eWe hereby submit the manuscript entitled \u0026quot;Pharmacovigilance Analysis of Blinatumomab in Children Based on Clinical Practice Combined with FAERS Database\u0026quot; for exclusive consideration for publication in\u003cem\u003e\u0026nbsp;BMC Pediatrics.\u003c/em\u003e All authors have reviewed the manuscript, and we confirm that none of the material related to this submission has been previously published or is currently under consideration for publication elsewhere, including online platforms.\u003c/p\u003e\n\u003cp\u003e4.Availability of data and material\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are openly available in at OpenVigil 2.1 (http://openvigil.sourceforge.net/).\u003c/p\u003e\n\u003cp\u003e5.Competing interests\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest or financial interest in any product or service mentioned in the article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e6.Funding\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e7.Authors\u0026apos; contributions\u003c/p\u003e\n\u003cp\u003eYingqiu Tu, Xin Lai, and Nan Zhong contributed to the conception and design, as well as the analysis and interpretation of the data. Yingqiu Tu participated in drafting the manuscript and critically revising it for intellectual content, and they provided final approval of the version to be published. All authors concur with being accountable for all aspects of the work.\u003c/p\u003e\n\u003cp\u003e8.Acknowledgements\u003c/p\u003e\n\u003cp\u003eFirst and foremost, I would like to extend my sincere gratitude to all individuals who have contributed to the completion of this paper. I am particularly indebted to my colleagues for their invaluable assistance and companionship throughout the preparation process. Furthermore, I am profoundly grateful to my family for their unwavering love and steadfast support. Lastly, I wish to express my deep appreciation to those who have dedicated considerable time to reviewing this thesis and providing insightful feedback, which will undoubtedly benefit my future academic endeavors.\u003c/p\u003e\n\u003cp\u003e9.Authors\u0026apos; information (optional)\u003c/p\u003e\n\u003cp\u003eFirst author:\u003c/p\u003e\n\u003cp\u003eYingqiu Tu,First Affiliated Hospital of Nanchang University，[email protected]\u003c/p\u003e\n\u003cp\u003eOther author:\u003c/p\u003e\n\u003cp\u003eXin Lai: First Affiliated Hospital of Nanchang University，[email protected]\u003c/p\u003e\n\u003cp\u003eNan Zhong:First Affiliated Hospital of Nanchang University，[email protected]\u003c/p\u003e\n\u003cp\u003eCorresponding authors:\u003c/p\u003e\n\u003cp\u003eYingqiu Tu*,First Affiliated Hospital of Nanchang University，[email protected]\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eShahriari M, Shakibazad N, Haghpanah S, Ghasemi K. Extramedullary manifestations in acute lymphoblastic leukemia in children: a systematic review and guideline-based approach of treatment. Am J Blood Res，2020,10:360-374.\u003c/li\u003e\n\u003cli\u003eTasian SK, Hunger SP. Genomic characterization of paediatric acute lymphoblastic leukaemia: an opportunity for precision medicine therapeutics. Br J Haematol. 2017 ,176(6):867-882. \u003c/li\u003e\n\u003cli\u003ePui CH, Yang JJ, Hunger SP, Pieters R, Schrappe M, Biondi A, Vora A, Baruchel A, Silverman LB, Schmiegelow K, Escherich G, Horibe K, Benoit YC, Izraeli S, Yeoh AE, Liang DC, Downing JR, Evans WE, Relling MV, Mullighan CG. Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration. J Clin Oncol. 2015 ,33(27):2938-48.\u003c/li\u003e\n\u003cli\u003eSchmiegelow K, M\u0026uuml;ller K, Mogensen SS, Mogensen PR, Wolthers BO, Stoltze UK, Tuckuviene R, Frandsen T. Non-infectious chemotherapy-associated acute toxicities during childhood acute lymphoblastic leukemia therapy. F1000Res. 2017,6:444\u003c/li\u003e\n\u003cli\u003eLocatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, Parasole R, Linderkamp C, Flotho C, Petit A, Micalizzi C, Mergen N, Mohammad A, Kormany WN, Eckert C, M\u0026ouml;ricke A, Sartor M, Hrusak O, Peters C, Saha V, Vinti L, von Stackelberg A. Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 Mar 2;325(9):843-854. \u003c/li\u003e\n\u003cli\u003eFuster JL, Molinos-Quintana A, Fuentes C, Fern\u0026aacute;ndez JM, Velasco P, Pascual T, Rives S, Dapena JL, Sisinni L, L\u0026oacute;pez-Godino O, Palomo P, Villa-Alc\u0026aacute;zar M, Bautista F, Gonz\u0026aacute;lez-Vicent M, L\u0026oacute;pez-Duarte M, Garc\u0026iacute;a-Mor\u0026iacute;n M, Ramos-Elbal E, Ram\u0026iacute;rez M; Leukemia Working Group of the Spanish Society of Pediatric Hematology, Oncology (SEHOP). Blinatumomab and inotuzumab for B cell precursor acute lymphoblastic leukaemia in children: a retrospective study from the Leukemia Working Group of the Spanish Society of Pediatric Hematology and Oncology (SEHOP). Br J Haematol. 2020,190(5):764-771. \u003c/li\u003e\n\u003cli\u003eQueudeville M, Schlegel P, Heinz AT, Lenz T, D\u0026ouml;ring M, Holzer U, Hartmann U, Kreyenberg H, von Stackelberg A, Schrappe M, Zugmaier G, Feuchtinger T, Lang P, Handgretinger R, Ebinger M. Blinatumomab in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Eur J Haematol. 2021,106(4):473-483.\u003c/li\u003e\n\u003cli\u003eSakaeda T,Tamon A,Kadoyama K,et al.Data mining of the public version of the FDA adverse event reporting system[J].INT J MED SCI,2013,10(7):796-803.\u003c/li\u003e\n\u003cli\u003eBate A, Evans SJ. Quantitative signal detection using spontaneous ADR reporting. Pharmacoepidemiology and Drug Safety.2009,18(6), 427-436.\u003c/li\u003e\n\u003cli\u003eAlmenoff JS, Pattishall EN, Gibbs TG, DuMouchel W, Evans SJ, Yuen N. Novel statistical tools for monitoring the safety of marketed drugs. Clin Pharmacol Ther. 2007 ,82(2):157-66. \u003c/li\u003e\n\u003cli\u003eRothman KJ, Lanes S, Sacks ST. .The reporting odds ratio and its advantages over the proportional reporting ratio. Pharmacoepidemiology and Drug Safety.2004, 13(8), 519-523.\u003c/li\u003e\n\u003cli\u003eHarpaz R, DuMouchel W, LePendu P, Bauer-Mehren A, Ryan P, Shah NH. Performance of pharmacovigilance signal-detection algorithms for the FDA adverse event reporting system. Clin Pharmacol Ther. 2013 Jun;93(6):539-46. \u003c/li\u003e\n\u003cli\u003eWang Yu, Li Jia, Pan Yunyan, et al. Based on the US FDA Adverse Event Reporting System Database [J]. Journal of Adverse Drug Reactions, 2022,24 (7): 347-352.\u003c/li\u003e\n\u003cli\u003eEvans S J,Waller P C,Davis S.Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports[J].Pharmacoepidemiol Drug Saf,2001,10(6):483-486.\u003c/li\u003e\n\u003cli\u003eBrown PA, Ji L, Xu X, Devidas M, Hogan LE, Borowitz MJ, Raetz EA, Zugmaier G, Sharon E, Bernhardt MB, Terezakis SA, Gore L, Whitlock JA, Pulsipher MA, Hunger SP, Loh ML. Effect of Postreinduction Therapy Consolidation With Blinatumomab vs Chemotherapy on Disease-Free Survival in Children, Adolescents, and Young Adults With First Relapse of B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021 ,325(9):833-842. \u003c/li\u003e\n\u003cli\u003eLocatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, Parasole R, Linderkamp C, Flotho C, Petit A, Micalizzi C, Mergen N, Mohammad A, Kormany WN, Eckert C, M\u0026ouml;ricke A, Sartor M, Hrusak O, Peters C, Saha V, Vinti L, von Stackelberg A. Effect of Blinatumomab vs Chemotherapy on Event-Free Survival Among Children With High-risk First-Relapse B-Cell Acute Lymphoblastic Leukemia: A Randomized Clinical Trial. JAMA. 2021,325(9):843-854. \u003c/li\u003e\n\u003cli\u003eLocatelli F, Zugmaier G, Mergen N, Bader P, Jeha S, Schlegel PG, Bourquin JP, Handgretinger R, Brethon B, R\u0026ouml;ssig C, Kormany WN, Viswagnachar P, Chen-Santel C. Blinatumomab in pediatric relapsed/refractory B-cell acute lymphoblastic leukemia: RIALTO expanded access study final analysis. Blood Adv. 2022,6(3):1004-1014.\u003c/li\u003e\n\u003cli\u003eChitadze G, Laqua A, Lettau M, Baldus CD, Br\u0026uuml;ggemann M. Bispecific antibodies in acute lymphoblastic leukemia therapy. Expert Rev Hematol. 2020,13(11):1211-1233.\u003c/li\u003e\n\u003cli\u003eU.S. Department of Health and Human Services,National Institutes of Health,National Cancer Institute.Common Terminology Criteria for Adverse Events (CTCAE）Version 5.0[EB/OL][2022.08.25](2017.11.27)\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 2 to 4 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"blinatumomab, signal detection, adverse drug events, pharmacovigilance Analysis","lastPublishedDoi":"10.21203/rs.3.rs-7875023/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7875023/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: This study aimed to analyze adverse drug events (ADEs) of blinatumomab monotherapy using the Food and Drug Administration Adverse Event Reporting System (FAERS) database, providing a valuable reference for clinical drug safety.\u003c/p\u003e\n\u003cp\u003eResearch design and methods: FAERS data for blinatumomab from their market approval in the United States until the fourth quarter of 2024 were retrieved. Signal detection was performed using the reporting odds ratio (ROR) and proportional reporting ratio (PRR) methods. ADEs were classified according to the System Organ Class (SOC) in the Medical Dictionary for Regulatory Activities (MedDRA) version 26.0.\u003c/p\u003e\n\u003cp\u003eResults: A total of 987 ADE reports were retrieved for blinatumomab , respectively, involving 18 SOC categories. blinatumomab marboxil demonstrated a strong association with leukaemic infiltration extramedullary, bone marrow leukaemic cell infiltration , acute biphenotypic leukaemia, acute lymphocytic leukaemia refractory , central nervous system leukaemia, tumour associated fever, transformation to acute myeloid leukaemia, ib precursor type acute leukaemia, malignant ascites, and acute lymphocytic leukaemia recurrent. In our hospital, there were 11 instances of blinatumomab administration in children, with reported adverse effects including hematological adverse reactions, cytokine release syndrome ,neurotoxicity, gastrointestinal adverse reactions, elevated liver enzymes and musculoskeletal pain.\u003c/p\u003e\n\u003cp\u003eConclusions: When using blinatumomab clinically, attention should be paid not only to common ADEs but also to those not mentioned on the drug label.\u003c/p\u003e","manuscriptTitle":"Pharmacovigilance Analysis of Blinatumomab in Children Based on Clinical Practice Combined with FAERS Database","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-25 16:13:07","doi":"10.21203/rs.3.rs-7875023/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2025-11-23T03:31:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"128873947243039296800559720987513584100","date":"2025-11-16T02:49:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-14T08:53:58+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-21T08:38:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-21T07:54:20+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-21T07:53:27+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Pediatrics","date":"2025-10-16T08:04:41+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bped","sideBox":"Learn more about [BMC Pediatrics](http://bmcpediatr.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bped/default.aspx","title":"BMC Pediatrics","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2be4fc65-e4af-4a6f-b75b-61b2bcd909cc","owner":[],"postedDate":"November 25th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-11-25T16:13:07+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-25 16:13:07","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7875023","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7875023","identity":"rs-7875023","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}