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Adverse events in the nervous system associated with blinatumomab: a real-world study

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Title: Adverse events in the nervous system associated with blinatumomab: a real-world study
Authors: Wen Gao, Jingwei Yu, Yifei Sun, Zheng Song, Xia Liu, Xue Han, Lanfan Li, Lihua Qiu, Shiyong Zhou, Zhengzi Qian, Xianhuo Wang, Huilai Zhang
Source: BMC Medicine, Vol 23, Iss 1, Pp 1-12 (2025)
Publisher Information: BMC, 2025.
Publication Year: 2025
Collection: LCC:Medicine
Subject Terms: Blinatumomab, Nervous system toxicity, Pharmacovigilance, FDA Adverse Event Reporting System (FAERS), Medicine
More Details: Abstract Background Nervous system toxicity (NST) is a frequent and serious adverse event (AE) associated with blinatumomab, the first bispecific antibody drug targeting CD19 and CD3. Real-world data are needed to better understand the incidence and characteristics of NST in clinical practice. Methods Data were obtained from the FDA Adverse Event Reporting System (FAERS). The reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence interval progressive neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) algorithms were utilized for data mining. Results A total of 5,962 blinatumomab-related cases were analyzed. NSTs were more frequent in males (44.01%) and younger individuals (18–45 years, 28.39%), with a higher prevalence in the USA (77.99%). Forty-three signals of NST were identified, of which neurotoxicity, neurological symptoms, agnosia, intention tremor, and immune effector cell-associated neurotoxicity syndrome had the highest ROR values. Concomitant use of medication for age, musculoskeletal system, genitourinary system, and sexual hormones were independent risk factors for NST, and age was an independent protective factor for fatal NST. The median time to onset (TTO) for neurological events was 3 days (range, 1 ~ 21). The highest fatality rate for neurological events was observed for increased intracranial pressure disorders, which also had the highest co-occurrence rate with cytokine release syndrome (CRS). Conclusions Age is an independent protective factor for fatal NST, and CRS leads to a higher fatality rate for NST patients treated with blinatumomab. Thorough medication evaluation should be conducted before administering blinatumomab, especially for high-risk patients with preexisting neurological conditions.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 1741-7015
Relation: https://doaj.org/toc/1741-7015
DOI: 10.1186/s12916-025-03913-6
Access URL: https://doaj.org/article/ea8c5f72e3944b5ba2f31de24c9b8204
Accession Number: edsdoj.8c5f72e3944b5ba2f31de24c9b8204
Database: Directory of Open Access Journals
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  Value: <anid>AN0182845009;[1ci2]06feb.25;2025Feb10.03:03;v2.2.500</anid> <title id="AN0182845009-1">Adverse events in the nervous system associated with blinatumomab: a real-world study </title> <p>Background: Nervous system toxicity (NST) is a frequent and serious adverse event (AE) associated with blinatumomab, the first bispecific antibody drug targeting CD19 and CD3. Real-world data are needed to better understand the incidence and characteristics of NST in clinical practice. Methods: Data were obtained from the FDA Adverse Event Reporting System (FAERS). The reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence interval progressive neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) algorithms were utilized for data mining. Results: A total of 5,962 blinatumomab-related cases were analyzed. NSTs were more frequent in males (44.01%) and younger individuals (18–45 years, 28.39%), with a higher prevalence in the USA (77.99%). Forty-three signals of NST were identified, of which neurotoxicity, neurological symptoms, agnosia, intention tremor, and immune effector cell-associated neurotoxicity syndrome had the highest ROR values. Concomitant use of medication for age, musculoskeletal system, genitourinary system, and sexual hormones were independent risk factors for NST, and age was an independent protective factor for fatal NST. The median time to onset (TTO) for neurological events was 3 days (range, 1 ~ 21). The highest fatality rate for neurological events was observed for increased intracranial pressure disorders, which also had the highest co-occurrence rate with cytokine release syndrome (CRS). Conclusions: Age is an independent protective factor for fatal NST, and CRS leads to a higher fatality rate for NST patients treated with blinatumomab. Thorough medication evaluation should be conducted before administering blinatumomab, especially for high-risk patients with preexisting neurological conditions.</p> <p>Highlights: ∙ Blinatumomab shows a higher incidence of NST, particularly in males and younger patients, underscoring the need for vigilant monitoring in these demographics ∙ The study identified 43 distinct signals of NST, with neurotoxicity and immune effector cell-associated neurotoxicity syndrome having the highest reporting odds ratios, indicating significant clinical concern. ∙ Specific concomitant medications related to age, musculoskeletal, and genitourinary systems, along with sexual hormones, are identified as independent risk factors for NST, emphasizing the importance of careful medication assessment. ∙ Age was found to be an independent protective factor against fatal NST, while increased intracranial pressure disorders were associated with the highest fatality rates, particularly in connection with CRS.</p> <p>Keywords: Blinatumomab; Nervous system toxicity; Pharmacovigilance; FDA Adverse Event Reporting System (FAERS)</p> <p>Supplementary Information The online version contains supplementary material available at https://doi.org/10.1186/s12916-025-03913-6.</p> <hd id="AN0182845009-2">Background</hd> <p>B-cell acute lymphoblastic leukemia (B-ALL) is a rare hematological cancer that occurs among adults and is characterized by the abnormal proliferation of B cells. Over the past 30 years, there has been a notable improvement in the prognosis of newly diagnosed ALL. By employing rigorous chemotherapy protocols, the rates of full remission have reached 85% to 90%, while the chances of long-term survival range from 30 to 50% [[<reflink idref="bib1" id="ref1">1</reflink>]]. Nevertheless, most adults with B-cell precursor ALL experience relapses and succumb to complications arising from either resistant disease or associated treatments. Among individuals who have relapsed or are unable to respond to treatment, the rates of achieving remission range from 18 to 44% when conventional salvage chemotherapy is used. However, the duration of this remission period is usually short [[<reflink idref="bib2" id="ref2">2</reflink>]]. The primary aim among this group of individuals is to initiate remission that lasts long enough to enable the transplantation of stem cells [[<reflink idref="bib3" id="ref3">3</reflink>]]. The range of overall survival for individuals with relapsed or refractory ALL is 2 ~ 6 months, while the 3 ~ 5 year survival rates are lower than 10% [[<reflink idref="bib4" id="ref4">4</reflink>]]. Thus, more effective treatments are needed for relapsed and refractory ALL among adults.</p> <p>CD-19, which is a surface antigen found in B-lineage cells, can be observed on the outer layer of more than 90% of blasts associated with B-cell precursor ALL [[<reflink idref="bib5" id="ref5">5</reflink>]]. The United States Food and Drug Administration (FDA) granted complete approval to blinatumomab, a bispecific antibody drug targeting CD19 and CD3, for adults and children with relapsed/refractory B-ALL in July 2017 [[<reflink idref="bib6" id="ref6">6</reflink>], [<reflink idref="bib7" id="ref7">7</reflink>]–[<reflink idref="bib8" id="ref8">8</reflink>]]. This decision was supported by the outcomes from the phase 3 TOWER study, which indicated that there were increased remission rates and enhanced overall survival in patients receiving blinatumomab compared with those receiving standard chemotherapy[[<reflink idref="bib9" id="ref9">9</reflink>]]. Numerous clinical trials investigating blinatumomab for various medical conditions are currently ongoing. The main adverse reactions observed include cytokine release syndrome, neurotoxicity, and hypogammaglobulinemia [[<reflink idref="bib10" id="ref10">10</reflink>]]. Nervous system toxicity (NST) and infection are particularly common in the practical use of blinatumomab [[<reflink idref="bib11" id="ref11">11</reflink>]].</p> <p>Owing to the limitations of clinical trials, including the specific populations, relatively small sample sizes, limited duration of follow‐up, and strict inclusion and exclusion criteria, the association between blinatumomab and NST is still unclear. Therefore, continuous post‐marketing surveillance of blinatumomab is necessary. Post-marketing surveillance data are crucial for evaluating the long-term safety of drugs and identifying rare or severe adverse events (AEs). Systems such as the FDA Adverse Event Reporting System (FAERS) [[<reflink idref="bib12" id="ref12">12</reflink>]] are highly valuable due to their ability to gather spontaneous reports. The utilization of the FAERS in real‐world clinical settings has become prevalent for the identification of risk signals in pharmacovigilance.</p> <p>The aim of the present study was to employ standardized data obtained from the FAERS to delineate the features of adverse event reports related to blinatumomab in terms of AEs in the nervous system. This delineation was achieved through stratification analysis, an assessment of the clinical priority of signals, an examination of the time to onset (TTO), and an evaluation of the severity of outcomes.</p> <hd id="AN0182845009-3">Methods</hd> <p></p> <hd id="AN0182845009-4">Study design and data sources</hd> <p>To evaluate the correlation between blinatumomab and AEs in the nervous system, a case/non-case study was conducted using a disproportionality analysis. The objective of the study was to determine the proportion of target AEs related to the target drug (case) versus all other drugs (non-case) [[<reflink idref="bib13" id="ref13">13</reflink>]]. If the target drug was found to cause the target adverse event more frequently than all other drugs did, this signified a significant safety signal. The relevant data for this analysis were obtained from the FAERS Quarterly Data Extract Files, which can be accessed at https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html. To ensure the inclusion of the most recent reports, we extracted all recorded reports in the FAERS from for the period from October 1, 2014, to September 30, 2023. Given that the FAERS constitutes a publicly accessible and anonymized dataset, the requirement for institutional review board approval and informed consent has been waived [[<reflink idref="bib14" id="ref14">14</reflink>]].</p> <hd id="AN0182845009-5">Data extraction and descriptive analysis</hd> <p>The FAERS database collects data through spontaneous reporting, which may result in duplicate and withdrawn/deleted reports. Therefore, the FDA official guidance document provides data deduplication rules and a list of reports that need to be deleted. We further excluded reports with missing data when counting patient information, which referred to the guidelines previously reported [[<reflink idref="bib15" id="ref15">15</reflink>]]. The present study was conducted in strict accordance with the FDA official website guidance document for data cleaning. The personnel reporting to the FAERS database are classified into five categories: physician, pharmacist, other health professionals, lawyer, and consumer. The data cleaning rules involved removing duplicate reports using the method recommended by the FDA. Specifically, we selected the PRIMARYID, CASEID, and FDA_DT fields from the DEMO table and sorted the reports using CASEID, FDA_DT, and PRIMARYID. For reports with the same CASEID, we kept the report with the largest FDA_DT value. Similarly, for both CASEID and FDA_DT, we retained the report with the largest PRIMARYID value. Additionally, starting from the first quarter of 2019, the data package for each quarter included a deletion report list. After data deduplication, reports were eliminated based on the CASEID listed in the deletion report list. Data deduplication and data cleaning were performed in accordance with the official recommended methods of the FDA.</p> <hd id="AN0182845009-6">MedDRA dictionary application</hd> <p>The Medical Dictionary for Regulatory Activities (MedDRA) dictionary is used to code the names of AEs in the FAERS database. The adverse event names in the FAERS database are described using preferred terms (PTs) from MedDRA. MedDRA contains approximately 120,000 terms, each with a unique 8-digit Arabic numeral code. The terminology is organized into five hierarchical levels: Low-Level Terms (LLTs), PTs, High-Level Terms (HLTs), High-Level Group Terms (HLGTs), and System Organ Classes (SOCs). PT is the detailed, specific term used to code individual medical events or symptoms. HLT is a mid-level grouping of related PT. HLGT is used to facilitate literature searches and safety evaluations by providing a broad overview of potential adverse event patterns.SOC is the highest level in the MedDRA and groups medical conditions based on organ systems or function. The names of the PTs were recalibrated, and the SOCs, PTs, and HLTs from the 26.1 version of the MedDRA dictionary were obtained for subsequent analysis.</p> <hd id="AN0182845009-7">Definition of NST events</hd> <p>All AEs were categorized utilizing MedDRA, and the PTs related to the SOCs for psychiatric and nervous system disorders were recognized to ascertain neurological toxicity. In our research, we included 1689 PTs, with their associations outlined in Additional file 1: Table S1. Additionally, the patient outcomes in the database are categorized into the following eight types: Death, Life-Threatening, Initial or Prolonged Hospitalization, Disability, Congenital Anomaly, Required Intervention to Prevent Permanent Impairment/Damage, and Other Serious (Important Medical Event). The outcome from the most recent version of a case is provided. If multiple outcomes are reported, they will be listed separately. Fatal NST is defined as a patient outcome of death, while all other outcomes are classified as nonfatal NST.</p> <hd id="AN0182845009-8">Statistical analysis</hd> <p>This study used various methods for detecting adverse drug event signals, including the reporting odds ratio (ROR) method, the proportional reporting ratio (PRR) method (which detects signals based on the lower limit of the PRR confidence interval), and the British Medicines and Healthcare Products Regulatory Agency (MHRA) comprehensive standard method (which is also a PRR method but with a different threshold setting). Additionally, the Bayesian confidence interval progressive neural network (BCPNN) method and polynomial gamma Poisson distribution reduction (multi-item gamma Poisson shrinker (MGPS) method) were used for signal mining (Additional file 2: Table S2 and Additional file 3: Table S3). These four methods were used to compare the occurrence rates of the target AEs associated with the target drug and the occurrence rates of AEs associated with all other drugs. If this ratio exceeded a predetermined threshold, this indicated an imbalance and the potential generation of AE signals. In the present study, a positive signal was identified when the criteria for all four algorithms were met simultaneously.</p> <p>The World Health Organization's Drug Dictionary (WHODrug) is the most important dictionary for drug coding and is widely used by pharmaceutical companies, clinical research organizations, and drug regulatory authorities. In this study, the drug classifications were based on the WHODrug B3 2024 March version (Additional file 4: Table S4). Univariate logistic regression analysis of age, sex, and drug combinations that included blinatumomab and any of 14 different agents used to treat digestive, metabolic, and cardiovascular disorders was performed to identify risk factors for blinatumomab. Variables with a <emph>p</emph>-value < 0.05 were entered into multivariate logistic regression analysis. The univariate logistic regression analysis identified significant differences across 14 variables associated with the occurrence of blinatumomab. These variables included dermatological medications, systemic corticosteroids (excluding sexual hormones and insulin), systemic anti-infective agents, musculoskeletal system medications, sensory organ system medications, antiparasitic, insecticidal, and anthelmintic drugs, digestive and metabolic system drugs, genitourinary system and sexual hormones, nervous system medications, cardiovascular system medications, respiratory system medications, and blood and hematopoietic organ medications.</p> <p>Statistical analysis was conducted using SPSS 22.0 and Microsoft Excel 2019. The ROR method employed positive signal detection criteria, including having 3 or more reports and a lower limit of the 95% confidence interval (CI) for an ROR greater than 1. Similarly, the PRR method used positive signal detection criteria, including having 3 or more reports, a PRR greater than or equal to 2, and a chi-square value greater than or equal to 4. The BCPNN method employed a positive signal detection criterion where the lower limit (IC025) of the 95% CI for information components (IC) needs to be greater than 0. Finally, the MGPS method used a positive signal detection criterion where the lower limit (EBGM05) of the 95% CI for the empirical Bayes geometric mean (EBGM) needed to be greater than 2 and the case number needed to be greater than 0. Statistical significance was determined using the Wilcoxon two-sample test (Additional file 3: Table S3). Variables that demonstrated statistical significance in the univariate logistic regression analysis were subsequently incorporated into the multivariate logistic regression analysis. Multivariable logistic regression models were employed to examine the associations between blinatumomab and various NST, with nonfatal NST or fatal NST serving as the dependent variables. The independent variables included age, sex, and drug combinations involving blinatumomab and 14 agents from diverse systemic categories. Age was included as a continuous variable in the multivariate logistic regression analysis. Sex and drug combinations were included in the analysis as categorical variables. We also determined the time to onset of NST. Differences between groups were tested for statistical significance using the chi-square test. Continuous data that were not normally distributed were compared between groups using the Wilcoxon two-sample test. A <emph>p</emph>-value < 0.05 was considered to indicate statistical significance.</p> <hd id="AN0182845009-9">Results</hd> <p></p> <hd id="AN0182845009-10">Baseline characteristics</hd> <p>The clinical features of the cases and the baseline characteristics of the patients who received treatment with blinatumomab are summarized in Additional file 5: Table S5. Men accounted for 62.6% of the patients (<emph>N</emph> = 2396), and adults below the age of 65 accounted for 86% of the patients (<emph>N</emph> = 2873). These groups were also the most affected by neurological AEs. The most prevalent age group was between 18 and 45 years (<emph>N</emph> = 1205), and this group also experienced the highest number of fatal and nonfatal NST cases. This trend was observed for both fatal and nonfatal AEs, with men being more commonly affected than women. The majority of reports originated from the USA (3494 cases, 58.60%).</p> <hd id="AN0182845009-11">Baseline characteristics of NST in blinatumomab</hd> <p>The present study included an analysis of the clinical baseline characteristics of 1127 cases of adverse neurological and psychiatric reactions that met the criteria of four algorithms: the ROR, the PRR, the BCPNN, and the MGPS (Table 1). Among the patients with blinatumomab-related NST, 496 were male, accounting for 17.54% more cases than females (<emph>N</emph> = 409). There were 56 male individuals with fatal cases of NST, which was 26.79% greater than the number of female individuals with fatal cases of NST (<emph>N</emph> = 41). When excluding the group with missing values, the number of all NST cases was equal to or greater than 18, with the majority falling below 45. The age group in which fatal NSTs were most common was those aged 18 or younger, whereas nonfatal NSTs were most prevalent in individuals aged between 45 and 65. The median age for fatal NST adverse reactions was 23 years, whereas the median age for nonfatal NST adverse reactions was 45 years.</p> <p>Table 1 Demographic and clinical characteristics of blinatumomab-related NST reports in the FAERS database</p> <p> <ephtml> <table frame="hsides" rules="groups"><thead><tr><th align="left"><p>Clinical characteristics</p></th><th align="left"><p>Fatal</p></th><th align="left"><p>Nonfatal</p></th><th align="left"><p>Total</p></th></tr></thead><tbody><tr><td align="left" colspan="4"><p><bold>Gender</bold></p></td></tr><tr><td align="left"><p> Male</p></td><td align="left"><p>56</p></td><td align="left"><p>440</p></td><td align="left"><p>496</p></td></tr><tr><td align="left"><p> Female</p></td><td align="left"><p>41</p></td><td align="left"><p>368</p></td><td align="left"><p>409</p></td></tr><tr><td align="left"><p> Missing</p></td><td align="left"><p>33</p></td><td align="left"><p>189</p></td><td align="left"><p>222</p></td></tr><tr><td align="left" colspan="4"><p><bold>Age (year)</bold></p></td></tr><tr><td align="left"><p> Mean (SD)</p></td><td align="left"><p>32.39 (23.67)</p></td><td align="left"><p>42.73 (22.65)</p></td><td align="left"><p>41.38 (23.03)</p></td></tr><tr><td align="left"><p> Median (min, max)</p></td><td align="left"><p>23 (1.67,79)</p></td><td align="left"><p>45 (0.25,89)</p></td><td align="left"><p>43 (0.25,89)</p></td></tr><tr><td align="left" colspan="4"><p><bold>Age group</bold></p></td></tr><tr><td align="left"><p> ≤ 18</p></td><td align="left"><p>55</p></td><td align="left"><p>161</p></td><td align="left"><p>216</p></td></tr><tr><td align="left"><p> ≥ 18, < 45</p></td><td align="left"><p>36</p></td><td align="left"><p>187</p></td><td align="left"><p>320</p></td></tr><tr><td align="left"><p> ≥ 45, < 65</p></td><td align="left"><p>27</p></td><td align="left"><p>168</p></td><td align="left"><p>266</p></td></tr><tr><td align="left"><p> ≥ 65, < 75</p></td><td align="left"><p>13</p></td><td align="left"><p>106</p></td><td align="left"><p>173</p></td></tr><tr><td align="left"><p> ≥ 75</p></td><td align="left"><p>6</p></td><td align="left"><p>24</p></td><td align="left"><p>37</p></td></tr><tr><td align="left"><p> Missing</p></td><td align="left"><p>68</p></td><td align="left"><p>403</p></td><td align="left"><p>561</p></td></tr><tr><td align="left" colspan="4"><p><bold>Time to onset (day)</bold></p></td></tr><tr><td align="left"><p> Mean (SD)</p></td><td align="left"><p>20.85 (54.36)</p></td><td align="left"><p>21.40 (49.51)</p></td><td align="left"><p>21.29 (50.38)</p></td></tr><tr><td align="left"><p> Median (min, max)</p></td><td align="left"><p>3 (0,353)</p></td><td align="left"><p>3 (0,374)</p></td><td align="left"><p>3 (0,374)</p></td></tr><tr><td align="left" colspan="4"><p><bold>Country</bold></p><p>(The top 10 are listed in descending order of the total number of reports)</p></td></tr><tr><td align="left"><p> US</p></td><td align="left"><p>68</p></td><td align="left"><p>811</p></td><td align="left"><p>879</p></td></tr><tr><td align="left"><p> JP</p></td><td align="left"><p>19</p></td><td align="left"><p>99</p></td><td align="left"><p>118</p></td></tr><tr><td align="left"><p> IT</p></td><td align="left"><p>14</p></td><td align="left"><p>58</p></td><td align="left"><p>72</p></td></tr><tr><td align="left"><p> BR</p></td><td align="left"><p>6</p></td><td align="left"><p>64</p></td><td align="left"><p>70</p></td></tr><tr><td align="left"><p> FR</p></td><td align="left"><p>16</p></td><td align="left"><p>39</p></td><td align="left"><p>55</p></td></tr><tr><td align="left"><p> DE</p></td><td align="left"><p>6</p></td><td align="left"><p>26</p></td><td align="left"><p>32</p></td></tr><tr><td align="left"><p> PL</p></td><td align="left"><p>6</p></td><td align="left"><p>21</p></td><td align="left"><p>27</p></td></tr><tr><td align="left"><p> CA</p></td><td align="left"><p>2</p></td><td align="left"><p>22</p></td><td align="left"><p>24</p></td></tr><tr><td align="left"><p> RU</p></td><td align="left"><p>9</p></td><td align="left"><p>14</p></td><td align="left"><p>23</p></td></tr><tr><td align="left"><p> AU</p></td><td align="left"><p>3</p></td><td align="left"><p>19</p></td><td align="left"><p>22</p></td></tr><tr><td align="left"><p> CO</p></td><td align="left"><p>9</p></td><td align="left"><p>13</p></td><td align="left"><p>22</p></td></tr><tr><td align="left" colspan="4"><p><bold>Received year</bold></p></td></tr><tr><td align="left"><p> 2015</p></td><td align="left"><p>4</p></td><td align="left"><p>109</p></td><td align="left"><p>113</p></td></tr><tr><td align="left"><p> 2016</p></td><td align="left"><p>14</p></td><td align="left"><p>135</p></td><td align="left"><p>149</p></td></tr><tr><td align="left"><p> 2017</p></td><td align="left"><p>8</p></td><td align="left"><p>127</p></td><td align="left"><p>135</p></td></tr><tr><td align="left"><p> 2018</p></td><td align="left"><p>9</p></td><td align="left"><p>151</p></td><td align="left"><p>160</p></td></tr><tr><td align="left"><p> 2019</p></td><td align="left"><p>21</p></td><td align="left"><p>145</p></td><td align="left"><p>166</p></td></tr><tr><td align="left"><p> 2020</p></td><td align="left"><p>53</p></td><td align="left"><p>120</p></td><td align="left"><p>173</p></td></tr><tr><td align="left"><p> 2021</p></td><td align="left"><p>40</p></td><td align="left"><p>201</p></td><td align="left"><p>241</p></td></tr><tr><td align="left"><p> 2022</p></td><td align="left"><p>39</p></td><td align="left"><p>191</p></td><td align="left"><p>230</p></td></tr><tr><td align="left"><p> 2023</p></td><td align="left"><p>17</p></td><td align="left"><p>189</p></td><td align="left"><p>206</p></td></tr><tr><td align="left" colspan="4"><p><bold>Reporter type</bold></p></td></tr><tr><td align="left"><p> MD</p></td><td align="left"><p>126</p></td><td align="left"><p>676</p></td><td align="left"><p>802</p></td></tr><tr><td align="left"><p> HP</p></td><td align="left"><p>46</p></td><td align="left"><p>246</p></td><td align="left"><p>292</p></td></tr><tr><td align="left"><p> OT</p></td><td align="left"><p>12</p></td><td align="left"><p>178</p></td><td align="left"><p>190</p></td></tr><tr><td align="left"><p> CN</p></td><td align="left"><p>14</p></td><td align="left"><p>65</p></td><td align="left"><p>79</p></td></tr><tr><td align="left"><p> PH</p></td><td align="left"><p>7</p></td><td align="left"><p>201</p></td><td align="left"><p>208</p></td></tr><tr><td align="left"><p> Missing</p></td><td align="left"><p>0</p></td><td align="left"><p>2</p></td><td align="left"><p>2</p></td></tr></tbody></table> </ephtml> </p> <p> <emph>Fatal </emph>events resulting in death, <emph>nonfatal </emph>events did not result in death, <emph>US </emph>United States, <emph>JP </emph>Japan, <emph>IT </emph>Italy, <emph>BR </emph>Brazil, <emph>FR </emph>France, <emph>DE </emph>Germany, <emph>PL </emph>Poland, <emph>CA </emph>Canada, <emph>RU </emph>Russia, <emph>AU </emph>Australia, <emph>CO </emph>Colombia, <emph>MD </emph>physician, <emph>HP </emph>health professional, <emph>OT </emph>other health-professional, <emph>CN </emph>consumer; <emph>PH </emph>pharmacist</p> <hd id="AN0182845009-12">The signal spectrum of NST in blinatumomab</hd> <p>The signal values of NST associated with blinatumomab are shown in Fig. 1. In terms of the ROR intensity, the top five PTs were neurotoxicity, neurological symptoms, agnosia, intention tremor, and immune effector cell-associated neurotoxicity syndrome. The bottom five PTs were increased intracranial pressure, status epilepticus, facial paralysis, ceramic hemorrhage, and intracranial hemorrhage. In addition, more cases of tremor, delirium, and seizures were reported.</p> <p>Graph: Fig. 1 ROR values and the number of reports of high-risk signal PTs for blinatumomab-related NSTs. Note: ROR: reporting odds ratio; 95% CI: 95% confidence interval: —: The range of the 95% confidence interval; → : the value displayed exceeds the highest value on the chart</p> <hd id="AN0182845009-13">Time to onset of blinatumomab therapy-associated NST</hd> <p>Figure 2 shows the differential spectra of the TTO for the 43 neurological AEs mentioned above. In terms of neurological events, the median TTO was 3 days, with a range of 1– 21 days (Q1–Q3). NST-related AEs were observed to occur earliest in the age group, with a median time of 2 days. NST-related AEs were found to occur latest in the 18–45 and ≥ 75 years age groups, with a median TTO of 4 days. No significant difference in time to onset was observed among the different age groups or among all the patients.</p> <p>Graph: Fig. 2 Time to onset of blinatumomab-related NSTs. Note: < 18: age < 18 years old; ≥ 18, 45:age ≥ 18 and < 45 years old; ≥ 45, < 65: age ≥ 45 and < 65 years old; ≥ 65, < 75: age ≥ 65 and < 75 years old; ≥ 65, < 75: age ≥ 65 and < 75 years old; ≥ 75: age ≥ 75 years old; ALL: all blinatumomab-related cases of NST</p> <hd id="AN0182845009-14">Life-threatening AEs and non-life-threatening AEs due to blinatumomab-induced NST</hd> <p>Figure 3 shows the number of reported HLT cases of NST symptoms associated with blinatumomab, the percentages of these cases that co-occurred with cytokine release syndrome (CRS) and the ratio of fatal events to nonfatal events. Most NST cases (79%) did not overlap with CRS. Nervous system disorders were the most frequently reported AEs, with 21% of patients also experiencing CRS and 9% experiencing fatal toxicity events. The second most frequently reported neurological symptom was confusion and disorientation, which had the same co-occurrence rate with CRS (21%) as nervous system disorders but had a higher fatality rate (13%). The third and fourth most commonly reported neurological symptoms were tremor and seizures and seizure disorders, respectively. Although seizures and seizure disorders were associated with a notably higher rate of fatal neurological events at 26%, these AEs had a lower CRS co-occurrence rate of 15%. The highest rate of fatal neurological events was observed for increased intracranial pressure disorders, which also had the highest CRS co-occurrence rate of 36%. Toxic and metabolic encephalopathies also had a CRS co-occurrence rate of 36% and a comparably high rate of fatal events at 26%.</p> <p>Graph: Fig. 3 Rates of overlap between cytokine release syndrome (CRS) and fatal or non-fatal NST-related AEs induced by blinatumomab</p> <hd id="AN0182845009-15">Risk factors for blinatumomab-associated NST</hd> <p>Multivariate logistic regression analysis showed that older patients using blinatumomab were more prone to NST (Table 2). To further analyze the factors related to fatal NST induced by blinatumomab, logistic regression analysis was conducted using the same method described above. Multivariate logistic regression showed that older age was associated with a lower risk of death (Table 3).</p> <p>Table 2 Univariate and multivariate analysis of NST induced by blinatumomab</p> <p> <ephtml> <table frame="hsides" rules="groups"><thead><tr><th align="left" /><th align="left" colspan="2"><p><bold>Univariate</bold></p></th><th align="left" colspan="5"><p><bold>Multivariate</bold></p></th></tr><tr><th align="left"><p><bold>Variable</bold></p></th><th align="left"><p><bold>Wald</bold><bold><italic>χ</italic></bold><sup><bold>2</bold></sup></p></th><th align="left"><p><bold><italic>P</italic></bold><bold>-value</bold></p></th><th align="left"><p><bold><italic>β</italic></bold></p></th><th align="left"><p><bold>S.E</bold></p></th><th align="left"><p><bold>Wald</bold><bold><italic>χ</italic></bold><sup><bold>2</bold></sup></p></th><th align="left"><p><bold><italic>P</italic></bold><bold>-value</bold></p></th><th align="left"><p><bold>OR (95% CI)</bold></p></th></tr></thead><tbody><tr><td align="left"><p>Age</p></td><td align="left"><p>3.09 (<italic>t</italic>-test)</p></td><td align="left"><p><bold>0.0020</bold></p></td><td char="." align="char"><p>0.00510</p></td><td char="." align="char"><p>0.00175</p></td><td char="." align="char"><p>8.5132</p></td><td align="left"><p><bold>0.0035</bold></p></td><td align="left"><p>1.01 (1.00—1.01)</p></td></tr><tr><td align="left"><p>Gender</p></td><td align="left"><p>0.87</p></td><td align="left"><p>0.3505</p></td><td char="." align="char"><p> − 0.0537</p></td><td char="." align="char"><p>0.0781</p></td><td char="." align="char"><p>0.4733</p></td><td align="left"><p>0.4915</p></td><td align="left"><p>0.95 (0.81–1.10)</p></td></tr><tr><td align="left"><p>Dermatological medications</p></td><td align="left"><p>31.54</p></td><td align="left"><p><bold> <.0001</bold></p></td><td char="." align="char"><p>0.1965</p></td><td char="." align="char"><p>0.3053</p></td><td char="." align="char"><p>0.4143</p></td><td align="left"><p>0.5198</p></td><td align="left"><p>1.22 (0.67–2.21)</p></td></tr><tr><td align="left"><p>Systemic corticosteroids, excluding sexual hormones and insulin</p></td><td align="left"><p>25.38</p></td><td align="left"><p><bold> <.0001</bold></p></td><td char="." align="char"><p> − 0.0413</p></td><td char="." align="char"><p>0.2181</p></td><td char="." align="char"><p>0.0358</p></td><td align="left"><p>0.8498</p></td><td align="left"><p>0.96 (0.63–1.47)</p></td></tr><tr><td align="left"><p>Systemic anti-infective agents</p></td><td align="left"><p>26.21</p></td><td align="left"><p><bold> <.0001</bold></p></td><td char="." align="char"><p> − 0.0581</p></td><td char="." align="char"><p>0.1518</p></td><td char="." align="char"><p>0.1466</p></td><td align="left"><p>0.7018</p></td><td align="left"><p>0.94 (0.70–1.27)</p></td></tr><tr><td align="left"><p>Antineoplastic and immunomodulating agents</p></td><td align="left"><p>3.36</p></td><td align="left"><p><bold>0.0669</bold></p></td><td char="." align="char"><p> − 0.1717</p></td><td char="." align="char"><p>0.1091</p></td><td char="." align="char"><p>2.4754</p></td><td align="left"><p>0.1156</p></td><td align="left"><p>0.84 (0.68–1.04)</p></td></tr><tr><td align="left"><p>Musculoskeletal system medications</p></td><td align="left"><p>5.07</p></td><td align="left"><p><bold>0.0243</bold></p></td><td char="." align="char"><p> − 0.4868</p></td><td char="." align="char"><p>0.1842</p></td><td char="." align="char"><p>6.9831</p></td><td align="left"><p><bold>0.0082</bold></p></td><td align="left"><p>0.61 (0.43–0.88)</p></td></tr><tr><td align="left"><p>Sensory organ system medications</p></td><td align="left"><p>29.38</p></td><td align="left"><p><bold> <.0001</bold></p></td><td char="." align="char"><p> − 0.2119</p></td><td char="." align="char"><p>0.2984</p></td><td char="." align="char"><p>0.5040</p></td><td align="left"><p>0.4777</p></td><td align="left"><p>0.81 (0.45–1.45)</p></td></tr><tr><td align="left"><p>Antiparasitic, insecticidal, and anthelmintic drugs</p></td><td align="left"><p>14.59</p></td><td align="left"><p><bold>0.0001</bold></p></td><td char="." align="char"><p>0.4944</p></td><td char="." align="char"><p>0.3086</p></td><td char="." align="char"><p>2.5674</p></td><td align="left"><p>0.1091</p></td><td align="left"><p>1.64 (0.90–3.00)</p></td></tr><tr><td align="left"><p>Digestive and metabolic system drugs</p></td><td align="left"><p>39.62</p></td><td align="left"><p><bold> <.0001</bold></p></td><td char="." align="char"><p>0.3641</p></td><td char="." align="char"><p>0.2219</p></td><td char="." align="char"><p>2.6917</p></td><td align="left"><p>0.1009</p></td><td align="left"><p>1.44 (0.93–2.22)</p></td></tr><tr><td align="left"><p>Genitourinary system and sexual hormones</p></td><td align="left"><p>31.14</p></td><td align="left"><p><bold> <.0001</bold></p></td><td char="." align="char"><p>0.3152</p></td><td char="." align="char"><p>0.1431</p></td><td char="." align="char"><p>4.8522</p></td><td align="left"><p><bold>0.0276</bold></p></td><td align="left"><p>1.37 (1.04–1.81)</p></td></tr><tr><td align="left"><p>Nervous system medication</p></td><td align="left"><p>58.39</p></td><td align="left"><p><bold> <.0001</bold></p></td><td char="." align="char"><p>0.6644</p></td><td char="." align="char"><p>0.1544</p></td><td char="." align="char"><p>18.5095</p></td><td align="left"><p><bold> <.0001</bold></p></td><td align="left"><p>1.94 (1.44–2.63)</p></td></tr><tr><td align="left"><p>Cardiovascular system medications</p></td><td align="left"><p>30.83</p></td><td align="left"><p><bold> <.0001</bold></p></td><td char="." align="char"><p>0.0827</p></td><td char="." align="char"><p>0.2154</p></td><td char="." align="char"><p>0.1473</p></td><td align="left"><p>0.7011</p></td><td align="left"><p>1.09 (0.71–1.66)</p></td></tr><tr><td align="left"><p>Respiratory system medications</p></td><td align="left"><p>25.68</p></td><td align="left"><p><bold> <.0001</bold></p></td><td char="." align="char"><p> − 0.1240</p></td><td char="." align="char"><p>0.2189</p></td><td char="." align="char"><p>0.3207</p></td><td align="left"><p>0.5712</p></td><td align="left"><p>0.88 (0.58–1.36)</p></td></tr><tr><td align="left"><p>Blood and hematopoietic organs medication</p></td><td align="left"><p>26.48</p></td><td align="left"><p><bold> <.0001</bold></p></td><td char="." align="char"><p>0.1530</p></td><td char="." align="char"><p>0.1935</p></td><td char="." align="char"><p>0.6251</p></td><td align="left"><p>0.4292</p></td><td align="left"><p>1.17 (0.80–1.70)</p></td></tr><tr><td align="left"><p>Other miscellaneous drugs</p></td><td align="left"><p>21.03</p></td><td align="left"><p><bold> <.0001</bold></p></td><td char="." align="char"><p> − 0.1105</p></td><td char="." align="char"><p>0.2043</p></td><td char="." align="char"><p>0.2927</p></td><td align="left"><p>0.5885</p></td><td align="left"><p>0.90 (0.60–1.34)</p></td></tr></tbody></table> </ephtml> </p> <p> <emph>CI </emph>confidence interval, <emph>OR </emph>odds ratio, <emph>S.E </emph>standard error</p> <p>Table 3 Univariate and multivariate analysis of fatal NST induced by blinatumomab</p> <p> <ephtml> <table frame="hsides" rules="groups"><thead><tr><th align="left" /><th align="left" colspan="2"><p><bold>Univariate</bold></p></th><th align="left" colspan="5"><p><bold>Multivariate</bold></p></th></tr><tr><th align="left"><p><bold>Variable</bold></p></th><th align="left"><p><bold>Wald</bold><bold><italic>χ</italic></bold><sup><bold>2</bold></sup></p></th><th align="left"><p><bold><italic>P</italic></bold><bold>-value</bold></p></th><th align="left"><p><bold><italic>β</italic></bold></p></th><th align="left"><p><bold>S.E</bold></p></th><th align="left"><p><bold>Wald</bold><bold><italic>χ</italic></bold><sup><bold>2</bold></sup></p></th><th align="left"><p><bold><italic>P</italic></bold><bold>-value</bold></p></th><th align="left"><p><bold>OR (95% CI)</bold></p></th></tr></thead><tbody><tr><td align="left"><p>Age</p></td><td align="left"><p> − 2.40 (<italic>t</italic>-test)</p></td><td char="." align="char"><p><bold>0.0167</bold></p></td><td align="left"><p> − 0.00957</p></td><td char="." align="char"><p>0.00439</p></td><td char="." align="char"><p>4.7456</p></td><td char="." align="char"><p><bold>0.0294</bold></p></td><td char="–" align="char"><p>0.99 (0.98–1.00)</p></td></tr><tr><td align="left"><p>Gender</p></td><td align="left"><p>2.84</p></td><td char="." align="char"><p>0.0918</p></td><td align="left"><p>0.2554</p></td><td char="." align="char"><p>0.1932</p></td><td char="." align="char"><p>1.7481</p></td><td char="." align="char"><p>0.1861</p></td><td char="–" align="char"><p>1.29 (0.88–1.89)</p></td></tr><tr><td align="left"><p>Dermatological medications</p></td><td align="left"><p>1.00</p></td><td char="." align="char"><p>0.3181</p></td><td align="left"><p>0.4706</p></td><td char="." align="char"><p>0.7779</p></td><td char="." align="char"><p>0.3659</p></td><td char="." align="char"><p>0.5453</p></td><td char="–" align="char"><p>1.60 (0.35–7.35)</p></td></tr><tr><td align="left"><p>Systemic corticosteroids, excluding sexual hormones and insulin</p></td><td align="left"><p>0.93</p></td><td char="." align="char"><p>0.3354</p></td><td align="left"><p>0.00458</p></td><td char="." align="char"><p>0.4749</p></td><td char="." align="char"><p>0.0001</p></td><td char="." align="char"><p>0.9923</p></td><td char="–" align="char"><p>1.00 (0.40–2.55)</p></td></tr><tr><td align="left"><p>Systemic anti-infective agents</p></td><td align="left"><p>1.00</p></td><td char="." align="char"><p>0.3164</p></td><td align="left"><p> − 0.8313</p></td><td char="." align="char"><p>0.3654</p></td><td char="." align="char"><p>5.1754</p></td><td char="." align="char"><p>0.0229</p></td><td char="–" align="char"><p>0.44 (0.21–0.89)</p></td></tr><tr><td align="left"><p>Antineoplastic and immunomodulating agents</p></td><td align="left"><p>0.67</p></td><td char="." align="char"><p>0.4136</p></td><td align="left"><p>0.0700</p></td><td char="." align="char"><p>0.2621</p></td><td char="." align="char"><p>0.0712</p></td><td char="." align="char"><p>0.7896</p></td><td char="–" align="char"><p>1.07 (0.64–1.79)</p></td></tr><tr><td align="left"><p>Musculoskeletal system medications</p></td><td align="left"><p>0.81</p></td><td char="." align="char"><p>0.3669</p></td><td align="left"><p>0.3884</p></td><td char="." align="char"><p>0.4010</p></td><td char="." align="char"><p>0.9379</p></td><td char="." align="char"><p>0.3328</p></td><td char="–" align="char"><p>1.47 (0.67–3.24)</p></td></tr><tr><td align="left"><p>Sensory organ system medications</p></td><td align="left"><p>0.74</p></td><td char="." align="char"><p>0.3897</p></td><td align="left"><p>0.3141</p></td><td char="." align="char"><p>0.7446</p></td><td char="." align="char"><p>0.1779</p></td><td char="." align="char"><p>0.6732</p></td><td char="–" align="char"><p>1.37 (0.32–5.89)</p></td></tr><tr><td align="left"><p>Antiparasitic, insecticidal, and anthelmintic drugs</p></td><td align="left"><p>0.19</p></td><td char="." align="char"><p>0.6597</p></td><td align="left"><p>0.4839</p></td><td char="." align="char"><p>0.5596</p></td><td char="." align="char"><p>0.7475</p></td><td char="." align="char"><p>0.3873</p></td><td char="–" align="char"><p>1.62 (0.54–4.86)</p></td></tr><tr><td align="left"><p>Genitourinary system and sexual hormones</p></td><td align="left"><p>0.01</p></td><td char="." align="char"><p>0.9058</p></td><td align="left"><p> − 0.2863</p></td><td char="." align="char"><p>0.3216</p></td><td char="." align="char"><p>0.7928</p></td><td char="." align="char"><p>0.3733</p></td><td char="–" align="char"><p>0.75 (0.40–1.41)</p></td></tr><tr><td align="left"><p>Nervous system medication</p></td><td align="left"><p>0.48</p></td><td char="." align="char"><p>0.4888</p></td><td align="left"><p>0.2607</p></td><td char="." align="char"><p>0.3126</p></td><td char="." align="char"><p>0.6959</p></td><td char="." align="char"><p>0.4042</p></td><td char="–" align="char"><p>1.30 (0.70–2.40)</p></td></tr><tr><td align="left" /><td align="left" /><td char="." align="char" /><td align="left"><p> − 0.00002</p></td><td char="." align="char"><p>0.5272</p></td><td char="." align="char"><p>0.0000</p></td><td char="." align="char"><p>1.0000</p></td><td char="–" align="char"><p>1.00 (0.36–2.81)</p></td></tr><tr><td align="left"><p>Digestive and metabolic system drugs</p></td><td align="left"><p>0.24</p></td><td char="." align="char"><p>0.6224</p></td><td align="left"><p> − 0.4612</p></td><td char="." align="char"><p>0.5268</p></td><td char="." align="char"><p>0.7664</p></td><td char="." align="char"><p>0.3813</p></td><td char="–" align="char"><p>0.63 (0.22–1.77)</p></td></tr><tr><td align="left"><p>Respiratory system medications</p></td><td align="left"><p>0.82</p></td><td char="." align="char"><p>0.3659</p></td><td align="left"><p> − 0.00810</p></td><td char="." align="char"><p>0.5032</p></td><td char="." align="char"><p>0.0003</p></td><td char="." align="char"><p>0.9872</p></td><td char="–" align="char"><p>0.99 (0.37–2.66)</p></td></tr><tr><td align="left"><p>Blood and hematopoietic organs medication</p></td><td align="left"><p>0.05</p></td><td char="." align="char"><p>0.8239</p></td><td align="left"><p> − 0.2810</p></td><td char="." align="char"><p>0.4676</p></td><td char="." align="char"><p>0.3611</p></td><td char="." align="char"><p>0.5479</p></td><td char="–" align="char"><p>0.76 (0.30–1.89)</p></td></tr><tr><td align="left"><p>Other miscellaneous drugs</p></td><td align="left"><p>1.70</p></td><td char="." align="char"><p>0.1922</p></td><td align="left"><p>0.6322</p></td><td char="." align="char"><p>0.4518</p></td><td char="." align="char"><p>1.9579</p></td><td char="." align="char"><p>0.1617</p></td><td char="–" align="char"><p>1.88 (0.78–4.56)</p></td></tr></tbody></table> </ephtml> </p> <p> <emph>CI </emph>confidence interval, <emph>OR </emph>odds ratio, <emph>S.E </emph>standard error</p> <hd id="AN0182845009-16">Discussion</hd> <p>Blinatumomab, a bispecific T-cell engager (BiTE) antibody targeting CD19 and CD3, was approved by the FDA for the treatment of relapsed/refractory B-ALL under an accelerated approval process. Additionally, blinatumomab has received conditional authorization from the European Medicines Agency. Blinatumomab specifically targets the CD19 antigen, a cell-surface receptor that appears on B cells from the advanced pro-B-cell phase through to their differentiation into plasma cells. The present study is the most comprehensive compilation to date, as it provides information on the incidence, clinical characteristics, and outcomes of NST associated with blinatumomab in real-world settings. The assessment was conducted using data sourced from the FAERS database. The findings reveal a clear association between blinatumomab therapy and NST, as well as between blinatumomab therapy and NST combined with CRS.</p> <p>The American Society for Transplantation and Cellular Therapy (ASTCT) has classified this type of neurotoxicity as immune effector cell-associated neurotoxicity syndrome (ICANS) [[<reflink idref="bib17" id="ref16">17</reflink>]]. ICANS specifically refers to neurological toxicities associated with immune effector cells, such as chimeric antigen receptor (CAR)-T cells. Based on the definitions, NST encompasses a broader range of neurological AEs, including ICANS. Neurological AEs usually manifest following the onset of CRS, and ICANS frequently arises during the resolution of CRS. Despite ICANS typically being preceded by CRS, ICANS does not manifest in all patients with severe CRS and not all individuals with ICANS exhibit preceding CRS. In severe cases of ICANS, disruption of the blood‒brain barrier occurs, and endothelial cells undergo activation caused by a cascade of endothelial cell activation and systemic inflammation following the infusion of CAR-modified T cells. Consequently, hemorrhage and cerebral edema can occur [[<reflink idref="bib18" id="ref17">18</reflink>]]. Patients with severe ICANS show elevated levels of proinflammatory cytokines, including interleukin 2 (IL-2) and interleukin 15 (IL-15), and cytokines associated with endothelial cell activation, including interleukin 6 (IL-6), and interferon gamma [[<reflink idref="bib19" id="ref18">19</reflink>]]. In our analysis, the combination of NST and CRS was observed in only 15.35%. An examination of the accessible data obtained from six human brain donors from the Allen Brain Atlas revealed that a solitary brain presented with heightened CD19 expression in the frontal gyrus below the left hemisphere [[<reflink idref="bib21" id="ref19">21</reflink>]]. Fluctuations in CD19 manifestations within the brain may explain why neurotoxicity is only observed in a specific group of individuals. Those individuals exhibiting a particular CD19 manifestation pattern within neurons might be vulnerable to a neuroinflammatory reaction elicited by CD19-engaging T cells [[<reflink idref="bib22" id="ref20">22</reflink>]].</p> <p>According to previous studies, the median time to the first NST event associated with blinatumomab treatment was 1 week after the initiation of treatment [[<reflink idref="bib23" id="ref21">23</reflink>]]. The median occurrence time for all NSTs was 20.85 days, with the median time for fatal NST slightly longer than nonfatal NST. Hence, caution should be exercised when using blinatumomab in clinical practice, particularly within 3 weeks, as this treatment may lead to the occurrence of NST. In a retrospective study, the outcomes of blinatumomab monotherapy in five patients who were newly diagnosed with Philadelphia chromosome-negative B-ALL were analyzed. Among these patients, three developed CRS were treated with dexamethasone and/or tocilizumab, while four experienced neurotoxicity and received dexamethasone without discontinuing blinatumomab. Notably, all five patients achieved a complete response after the first cycle of treatment [[<reflink idref="bib24" id="ref22">24</reflink>]].</p> <p>According to the FAERS database, tremor was the most frequently reported neurological symptom, followed by confusion and epileptic seizures. This is consistent with previous studies [[<reflink idref="bib25" id="ref23">25</reflink>]]. The results from data mining of this database revealed that tremors were the second most frequently reported adverse event (180 cases) after neurotoxicity (358 cases). Tremors that arise because of medications are largely related to the drug's impact on the nervous system, especially the effects on dopamine, acetylcholine, and other neurotransmitter pathways, along with direct or indirect effects on neuromuscular transmission processes.</p> <p>The blinatumomab package insert does not explicitly detail episodes of confusion and epileptic seizures. However, in our study, confusion was the third common event, with 154 cases, and epileptic seizures were fourth, with 140 reported cases. In practical clinical settings, these events appear to have a relatively high incidence, necessitating increased monitoring for patients who have a prior history of neurological disorders or who possess other predisposing risk factors.</p> <p>The results of this study should prompt vigilance for NST, such as hemorrhagic cerebrovascular diseases, in patients receiving blinatumomab. In a phase 2 trial, the activity and safety of a combination of humanized anti-CD19 CAR-T cells and anti-B-cell maturation antigen (BCMA) CAR-T cells were assessed in patients with relapsed or refractory multiple myeloma [[<reflink idref="bib27" id="ref24">27</reflink>]]. However, it cannot be completely ruled out that blinatumomab may cause cerebral hemorrhage because of other factors, such as targeted neurological system toxicity. However, only limited research is available on this specific aspect.</p> <p>The FAERS database contains signals related to cerebral ischemia, such as superior sagittal sinus thrombosis and cerebral ischemia. Thrombus formation typically occurs in the superior sagittal, transverse, and sigmoid sinuses. The occurrence of an intracranial hemorrhage is often related to occlusion of the superior sagittal sinus [[<reflink idref="bib28" id="ref25">28</reflink>]]. Cerebral thrombosis may be linked to factors such as positive antiphospholipid antibodies, race, and sex [[<reflink idref="bib29" id="ref26">29</reflink>]]. In a previous study, an adolescent with refractory ALL experienced severe neurotoxicity after receiving a blinatumomab, administered according to the recommended treatment guidelines [[<reflink idref="bib30" id="ref27">30</reflink>]]. Neurologic AEs have been reported in adults receiving blinatumomab; however, research on neurologic toxicity in individuals under 18 years of age is limited. The results of the present study indicated that patients under 18 years of age had the highest number of reported cases of fatal NST, whereas those aged between 18 and 45 years had the highest number of reported cases of nonfatal NST and all NST. These findings highlight that individuals younger than 45 years have a heightened risk of experiencing neurological toxicity with blinatumomab. Therefore, monitoring neurological toxicity in patients under 45 years of age during clinical treatment with blinatumomab is crucial. Clinical trials of blinatumomab lack sufficient safety data for elderly patients. A study conducted on patients over 75 years of age revealed that fatal nonspecific toxicity NST accounted for only 4.62% of AEs, and nonfatal NST was also relatively low at 2.41%. Older patients have a lower incidence of neurotoxicity compared to younger patients.</p> <p>Several neurologic AEs have been reported in adults during blinatumomab administration [[<reflink idref="bib31" id="ref28">31</reflink>]]. Due to concerns about NST, clinical trials often exclude patients with central nervous system (CNS) disease. Previous reports have examined blinatumomab use in patients with active, or a history of CNS disease and associated toxicity [[<reflink idref="bib32" id="ref29">32</reflink>]]. This study is the first to evaluate the neurological toxicity of blinatumomab using the FAERS dataset, thus offering valuable insights into blinatumomab administration for clinicians, particularly within the first 4 days postadministration, to increase the detection of neurological toxicity. This finding is consistent with previous studies regarding the timing of the most common occurrence of NST [[<reflink idref="bib33" id="ref30">33</reflink>]].</p> <p>Our analysis of risk factors for blinatumomab-related neurologic side effects provides important insights into patient demographics and concomitant medication use. Univariate logistic regression analysis identified significant differences across various therapeutic classes, suggesting that the complexity of a patient's medication regimen can contribute to the risk of developing NST associated with blinatumomab. Specifically, the use of dermatological medications, systemic corticosteroids, and drugs targeting multiple organ systems indicates an intricate interaction that warrants further investigation. Multivariate logistic regression confirmed that older patients are more susceptible to NST [[<reflink idref="bib34" id="ref31">34</reflink>]]. This aligns with existing literature, which highlights the vulnerability of older adults to adverse drug events due to age-related physiological changes, polypharmacy, and comorbidities that may intensify the effects of immunotherapies like blinatumomab [[<reflink idref="bib23" id="ref32">23</reflink>]]. Notably, this increased risk necessitates vigilant monitoring and tailored therapeutic approaches for elderly populations undergoing treatment with blinatumomab [[<reflink idref="bib34" id="ref33">34</reflink>]].</p> <p>Contrary to initial expectations, our investigation found that older age was associated with a lower risk of fatal NST. This unexpected outcome could suggest that while older patients may experience higher rates of NST, the severity of events might not necessarily translate into fatal outcomes. It may also reflect the effectiveness of clinical management strategies implemented for older patients, who are often monitored more closely for adverse effects. Alternatively, this finding might point to inherent differences in the pathophysiology of NST across age groups, highlighting the need for more personalized risk stratification in treatment planning. The analysis of drug combinations revealed that certain therapeutic classes-including musculoskeletal system medications and systemic anti-infective agents-were notable contributors to NST in patients receiving blinatumomab. These findings underscore the importance of comprehensive medication reviews in the management of patients treated with blinatumomab, as potential interactions and cumulative effects could exacerbate neurologic toxicity.</p> <hd id="AN0182845009-17">Limitations</hd> <p>This study has several limitations. First, the FAERS database may not have included all patients with blinatumomab, leading to potential underreporting. Second, reports from nonmedical professionals may have introduced diagnostic bias. And the description and recording of NST cannot be refined and graded. Third, we recognize that causal relationships cannot be definitively established in observational studies. Further validation from independent data sources, along with insight into potential mechanisms and prevention of blinatumomab-related toxicity, are essential to confirm the causal nature of these signals.</p> <hd id="AN0182845009-18">Conclusions</hd> <p>Our study underscores the importance of recognizing and addressing risk factors for neurologic toxicities associated with blinatumomab, especially in older patients and those on complex medication regimens. Future research should focus on delineating the specific mechanisms through which drug interactions contribute to NST and developing targeted interventions to minimize these risks. Enhanced surveillance using real-world data, such as the FAERS, is crucial for improving our understanding of these AEs and enhancing patient safety in those receiving novel immunotherapies.</p> <hd id="AN0182845009-19">Acknowledgements</hd> <p>We thank American Journal Experts (AJE) (https://<ulink href="http://www.aje.cn/">www.aje.cn/</ulink>) for editing the English text of a draft of this manuscript.</p> <hd id="AN0182845009-20">Authors' contributions</hd> <p>X.H.W. and H.L.Z. designed the study. W.G. and J.W.Y. researched data, contributed to the discussion, and wrote the first draft of the manuscript. Y.F.S., Z.S. and L.H.Q. provide the code of analysis. X.L., X.H. and S.Y.Z performed the co-medication analysis. L.F.L. and Z.Z.Q. polished the language of the manuscript. All authors read and approved the final manuscript.</p> <hd id="AN0182845009-21">Funding</hd> <p>This work was supported by grants from the National Natural Science Foundation of China (W2412122, 82200208, 8247012736), State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine (QZ23-6; QZ23-4), Haihe Yingcai (Tianjin) Project (TJSJMYXYC-D2-039) and Tianjin Key Medical Discipline (Specialty) Construction Project grant (TJYXZDXK-009A), Shandong Province Medical and Health Science and Technology Development Plan (202203010420), Shandong Province Medical and Health Science and Technology Development Plan (202309030487) and the Jinan Municipal Health Commission Clinical Medicine Science and Technology Innovation Plan (2023–1-34).</p> <hd id="AN0182845009-22">Data availability</hd> <p>No datasets were generated or analysed during the current study.</p> <hd id="AN0182845009-23">Declarations</hd> <p></p> <hd id="AN0182845009-24">Ethics approval and consent to participate</hd> <p>Ethical approval was not required as the study was conducted using de-identified publicly available data.</p> <hd id="AN0182845009-25">Consent for publication</hd> <p>Not applicable.</p> <hd id="AN0182845009-26">Competing interests</hd> <p>The authors declare no competing interests.</p> <hd id="AN0182845009-27">Supplementary Information</hd> <p>Graph: Additional file 1. Table S1. Details of PTs, HLTs, and HLGTs are included in SOCs of psychiatric and nervous system disorders in MedDRA(Version 26.1).</p> <p>Graph: Additional file 2. Table S2. Four table of measure of disproportionality.</p> <p>Graph: Additional file 3. Table S3. ROR, PRR, BCPNN, and EBGM methods, formulas, and thresholds.</p> <p>Graph: Additional file 4. Table S4. Combined medication classification according to WHODrug B3 2024 March version blinatumomab-related reports.</p> <p>Graph: Additional file 5. Table S5. Demographic and clinical characteristics of blinatumomab reports in the FAERS database.</p> <hd id="AN0182845009-28">Abbreviations</hd> <p></p> <p>• NST</p> <p></p> <ulist> <item> Nervous system toxicity</item> <p></p> </ulist> <p>• ROR</p> <p></p> <ulist> <item> Reporting odds ratio</item> <p></p> </ulist> <p>• PRR</p> <p></p> <ulist> <item> Proportional reporting ratio</item> <p></p> </ulist> <p>• BCPNN</p> <p></p> <ulist> <item> Bayesian confidence interval progressive neural network</item> <p></p> </ulist> <p>• MGPS</p> <p></p> <ulist> <item> Multi-item gamma Poisson shrinker</item> <p></p> </ulist> <p>• LLTs</p> <p></p> <ulist> <item> Low-Level Terms</item> <p></p> </ulist> <p>• PTs</p> <p></p> <ulist> <item> Preferred terms</item> <p></p> </ulist> <p>• HLTs</p> <p></p> <ulist> <item> High-Level Terms</item> <p></p> </ulist> <p>• HLGTs</p> <p></p> <ulist> <item> High-Level Group Terms</item> <p></p> </ulist> <p>• SOCs</p> <p></p> <ulist> <item> System Organ Classes</item> <p></p> </ulist> <p>• AEs</p> <p></p> <ulist> <item> Adverse events</item> <p></p> </ulist> <p>• B-ALL</p> <p></p> <ulist> <item> B-cell acute lymphoblastic leukemia</item> <p></p> </ulist> <p>• CAR</p> <p></p> <ulist> <item> Anti-CD19 chimeric antigen receptor</item> <p></p> </ulist> <p>• CI</p> <p></p> <ulist> <item> Confidence interval</item> <p></p> </ulist> <p>• FAERS</p> <p></p> <ulist> <item> US Food and Drug Administration Adverse Event Reporting System</item> <p></p> </ulist> <p>• FDA</p> <p></p> <ulist> <item> US Food and Drug Administration</item> <p></p> </ulist> <p>• IQR</p> <p></p> <ulist> <item> Interquartile range</item> <p></p> </ulist> <p>• OR</p> <p></p> <ulist> <item> Odds ratio</item> <p></p> </ulist> <p>• TTO</p> <p></p> <ulist> <item> Time to onset</item> <p></p> </ulist> <p>• MedDRA</p> <p></p> <ulist> <item> Medical Dictionary for Regulatory Activities</item> <p></p> </ulist> <p>• WHODrug</p> <p></p> <ulist> <item> World Health Organization's Drug Dictionary</item> <p></p> </ulist> <p>• ASTCT</p> <p></p> <ulist> <item> American Society for Transplantation and Cellular Therapy</item> <p></p> </ulist> <p>• ICANS</p> <p></p> <ulist> <item> Immune effector cell-associated neurotoxicity syndrome</item> </ulist> <hd id="AN0182845009-29">Publisher's Note</hd> <p>Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.</p> <ref id="AN0182845009-30"> <title> References </title> <blist> <bibl id="bib1" idref="ref1" type="bt">1</bibl> <bibtext> Bassan R, Hoelzer D. 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Items – Name: Title
  Label: Title
  Group: Ti
  Data: Adverse events in the nervous system associated with blinatumomab: a real-world study
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Wen+Gao%22">Wen Gao</searchLink><br /><searchLink fieldCode="AR" term="%22Jingwei+Yu%22">Jingwei Yu</searchLink><br /><searchLink fieldCode="AR" term="%22Yifei+Sun%22">Yifei Sun</searchLink><br /><searchLink fieldCode="AR" term="%22Zheng+Song%22">Zheng Song</searchLink><br /><searchLink fieldCode="AR" term="%22Xia+Liu%22">Xia Liu</searchLink><br /><searchLink fieldCode="AR" term="%22Xue+Han%22">Xue Han</searchLink><br /><searchLink fieldCode="AR" term="%22Lanfan+Li%22">Lanfan Li</searchLink><br /><searchLink fieldCode="AR" term="%22Lihua+Qiu%22">Lihua Qiu</searchLink><br /><searchLink fieldCode="AR" term="%22Shiyong+Zhou%22">Shiyong Zhou</searchLink><br /><searchLink fieldCode="AR" term="%22Zhengzi+Qian%22">Zhengzi Qian</searchLink><br /><searchLink fieldCode="AR" term="%22Xianhuo+Wang%22">Xianhuo Wang</searchLink><br /><searchLink fieldCode="AR" term="%22Huilai+Zhang%22">Huilai Zhang</searchLink>
– Name: TitleSource
  Label: Source
  Group: Src
  Data: BMC Medicine, Vol 23, Iss 1, Pp 1-12 (2025)
– Name: Publisher
  Label: Publisher Information
  Group: PubInfo
  Data: BMC, 2025.
– Name: DatePubCY
  Label: Publication Year
  Group: Date
  Data: 2025
– Name: Subset
  Label: Collection
  Group: HoldingsInfo
  Data: LCC:Medicine
– Name: Subject
  Label: Subject Terms
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Blinatumomab%22">Blinatumomab</searchLink><br /><searchLink fieldCode="DE" term="%22Nervous+system+toxicity%22">Nervous system toxicity</searchLink><br /><searchLink fieldCode="DE" term="%22Pharmacovigilance%22">Pharmacovigilance</searchLink><br /><searchLink fieldCode="DE" term="%22FDA+Adverse+Event+Reporting+System+%28FAERS%29%22">FDA Adverse Event Reporting System (FAERS)</searchLink><br /><searchLink fieldCode="DE" term="%22Medicine%22">Medicine</searchLink>
– Name: Abstract
  Label: Description
  Group: Ab
  Data: Abstract Background Nervous system toxicity (NST) is a frequent and serious adverse event (AE) associated with blinatumomab, the first bispecific antibody drug targeting CD19 and CD3. Real-world data are needed to better understand the incidence and characteristics of NST in clinical practice. Methods Data were obtained from the FDA Adverse Event Reporting System (FAERS). The reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence interval progressive neural network (BCPNN), and multi-item gamma Poisson shrinker (MGPS) algorithms were utilized for data mining. Results A total of 5,962 blinatumomab-related cases were analyzed. NSTs were more frequent in males (44.01%) and younger individuals (18–45 years, 28.39%), with a higher prevalence in the USA (77.99%). Forty-three signals of NST were identified, of which neurotoxicity, neurological symptoms, agnosia, intention tremor, and immune effector cell-associated neurotoxicity syndrome had the highest ROR values. Concomitant use of medication for age, musculoskeletal system, genitourinary system, and sexual hormones were independent risk factors for NST, and age was an independent protective factor for fatal NST. The median time to onset (TTO) for neurological events was 3 days (range, 1 ~ 21). The highest fatality rate for neurological events was observed for increased intracranial pressure disorders, which also had the highest co-occurrence rate with cytokine release syndrome (CRS). Conclusions Age is an independent protective factor for fatal NST, and CRS leads to a higher fatality rate for NST patients treated with blinatumomab. Thorough medication evaluation should be conducted before administering blinatumomab, especially for high-risk patients with preexisting neurological conditions.
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  Data: electronic resource
– Name: Language
  Label: Language
  Group: Lang
  Data: English
– Name: ISSN
  Label: ISSN
  Group: ISSN
  Data: 1741-7015
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  Label: Relation
  Group: SrcInfo
  Data: https://doaj.org/toc/1741-7015
– Name: DOI
  Label: DOI
  Group: ID
  Data: 10.1186/s12916-025-03913-6
– Name: URL
  Label: Access URL
  Group: URL
  Data: <link linkTarget="URL" linkTerm="https://doaj.org/article/ea8c5f72e3944b5ba2f31de24c9b8204" linkWindow="_blank">https://doaj.org/article/ea8c5f72e3944b5ba2f31de24c9b8204</link>
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  Data: edsdoj.8c5f72e3944b5ba2f31de24c9b8204
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RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1186/s12916-025-03913-6
    Languages:
      – Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 12
        StartPage: 1
    Subjects:
      – SubjectFull: Blinatumomab
        Type: general
      – SubjectFull: Nervous system toxicity
        Type: general
      – SubjectFull: Pharmacovigilance
        Type: general
      – SubjectFull: FDA Adverse Event Reporting System (FAERS)
        Type: general
      – SubjectFull: Medicine
        Type: general
    Titles:
      – TitleFull: Adverse events in the nervous system associated with blinatumomab: a real-world study
        Type: main
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    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Wen Gao
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            NameFull: Jingwei Yu
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            NameFull: Yifei Sun
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            NameFull: Zheng Song
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            NameFull: Xia Liu
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            NameFull: Xue Han
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            NameFull: Lanfan Li
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            NameFull: Lihua Qiu
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            NameFull: Shiyong Zhou
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            NameFull: Zhengzi Qian
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            NameFull: Huilai Zhang
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            – D: 01
              M: 02
              Type: published
              Y: 2025
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              Value: 17417015
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              Value: 23
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            – TitleFull: BMC Medicine
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