Adverse Events Associated with Busulfan in HSCT Pre-Transplant Conditioning: A Retrospective Pharmacovigilance Study of the FAERS Database

Adverse Events Associated with Busulfan in HSCT Pre-Transplant Conditioning: A Retrospective Pharmacovigilance Study of the FAERS Database | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Adverse Events Associated with Busulfan in HSCT Pre-Transplant Conditioning: A Retrospective Pharmacovigilance Study of the FAERS Database Xia-Wen Yang, Wen-Long Xie, Jing Fu, Jun-Feng Wang, Yi Liu, Ju-Yi Li, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6454932/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Busulfan had been approved as a pre-transplant conditioning agent for allogeneic hematopoietic stem cell transplantation (HSCT) in chronic myeloid leukemia. However, the real-world data on its safety in a large sample population is imprecise. We assessed the adverse signals associated with busulfan specifically used as a pre-transplant conditioning agent for HSCT through data mining of the FDA pharmacovigilance database. Method: This article extracted adverse events (AEs) from the FAERS database from the first quarter of 2004 to the third quarter of 2024, and determined the signal strength of AEs using Reporting Odds Ratio, Proportional Reporting Ratio, Bayesian Confidence Propagation Neural Network, and Empirical Bayesian Geometric Mean. Result: The study identified 3627 AE reports associated with busulfan limited indication for pre-transplant conditioning for HSCT, with 11489 Preferred Terms-annotated entries. The most frequently reported AEs were primarily categorized under Infections And Infestations, Injury, Poisoning And Procedural Complications. Notably, some AEs, such as Pulmonary Hypertension, Thrombotic Microangiopathy is not mentioned in the drug labeling. In the disproportionality analysis, Blood Follicle Stimulating Hormone Increased and Blood Luteinising Hormone Increased had high ROR value. We screened the concomitant medication reports with HSCT pre-conditioning as the indication and found that, in the reports of busulfan in combination with fludarabine, the AEs of Acute Graft Versus Host Disease, Infection showed positive results in the disproportionality analysis, which is different from the combination with cyclophosphamide. Conclusion: In recent years, busulfan has been mainly used for HSCT conditioning treatment rather than the initial treatment of chronic myeloid leukemia. In this study, we screened the AE reports of busulfan applied to HSCT pre-transplantation treatment in the FAERS database to demonstrate more precisely the AEs occurring in the current clinical application of busulfan. Further disproportionality analysis provides useful information for the clinical application of busulfan, which is expected to promote its safe use in clinical practice. busulfan hematopoietic stem cell transplantation the food and drug adverse event reporting system database adverse events real-world study Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 1 Introduction The pre-transplant conditioning regimens typically employ chemotherapy or radiotherapy as the initial treatment modality, followed by hematopoietic stem cell transplantation (HSCT), and have been widely utilized in the treatment of a variety of diseases. These diseases encompass hematologic malignancies (such as acute lymphoblastic leukemia and lymphoma), solid tumors, non-malignant disorders (such as hemoglobinopathies, including thalassemia and sickle cell anemia), and other genetic disorders [ 1 – 4 ]. Total body irradiation (TBI)-based conditioning regimens have been established as the standard pre-transplant conditioning approach for leukemia patients, particularly those with lymphoid malignancies [ 5 ]. However, TBI-based conditioning regimens are associated with significant adverse events (AEs), including but not limited to interstitial pneumonitis, cataracts, endocrine dysfunction, and secondary malignancies [ 6 ]. Compared with radiotherapy regimens, busulfan-based chemotherapy regimens offer the advantage of a lower risk of inhibiting lymphocyte formation while inhibiting the proliferation of bone marrow cells [ 7 ]. Therefore, in clinical practice, busulfan is also frequently used as an alternative to TBI-based regimens [ 8 ]. Busulfan, an alkylating drug approved by FDA in 1999 for the treatment of chronic myeloid leukemia [ 9 , 10 ], has evolved in its clinical application. It was initially employed as a palliative treatment for myeloproliferative disorders, but now it is widely used as a pre-transplant conditioning agent for HSCT [ 8 ]. Busulfan is commonly administered in combination with cyclophosphamide or fludarabine [ 11 ]. Clinical trials have demonstrated the significant efficacy of busulfan-based chemotherapy regimens in HSCT. Specifically, a study on the intravenous administration of busulfan in pediatric patients revealed improvements in overall survival and reductions in transplant-related mortality and relapse rates [ 12 ]. Moreover, research comparing busulfan plus cyclophosphamide regimens with TBI-based regimens indicated superior survival outcomes with busulfan-based approaches [ 13 ]. However, busulfan therapy is linked to various AEs. It can trigger AEs in multiple tissues and organs, such as bone marrow, gastrointestinal tract, liver, lungs, skin, bladder, and central nervous system[ 14 ], which include myelosuppression, diarrhea, veno-occlusive disease, pulmonary toxicity, rash, mucositis, and seizures [ 15 – 17 ]. In a study on the efficacy and safety of busulfan plus fludarabine in HSCT conditioning, the most common AEs were abnormal blood chemistry results (n = 35, 14.5%) and gastrointestinal disorders (n = 39, 16%). Cardiac toxicity, multi-organ failure infections, and hepatic veno-occlusive disease infections were also reported [ 18 ]. Busulfan was initially approved for the treatment of chronic myeloid leukemia and has now expanded its indications to HSCT pretreatment and combination chemotherapies for solid tumors. This expansion, along with evolving clinical guidelines, complicates the reflection of its AEs in real-world evidence data. Real-world data on the use of busulfan in oncology can introduce confounding factors in pharmacovigilance. The FDA Adverse Event Reporting System (FAERS) is a post-marketing surveillance database that collects and monitors AEs associated with approved drugs [ 19 , 20 ]. This database is periodically updated on a quarterly basis, available for public download via the FDA website [ 21 ]. In this study, by restricting the indications of busulfan, we further explored the AEs associated with its use in myeloablative therapy (from the first quarter of 2004 to the third quarter of 2024), offering valuable insights for clinicians when applying busulfan in myeloablative contexts. 2 Materials and methods 2.1 Data source FAERS is a publicly accessible database that aggregates and summarizes AE reports from around the world. It contains more than 9 million individual AE reports submitted by industry professionals, physicians, pharmacists, healthcare professionals, consumers, and others, making it the largest spontaneous reporting system database globally and a substantial data resource for pharmacovigilance research [ 22 ]. The FAERS database is updated quarterly and comprises seven datasets: Demographic and Administration Information (DEMO), Drug Information (DRUG), Adverse Event Information (REAC), Patient Outcome Information (OUTC), Report Source (RPSR), Drug Therapy Start and End Dates (THER), and Drug Indication (INDI). 2.2 Data Selection and Processing Given the quarterly updates, the occurrence of duplicate reports in the FAERS database is inevitable. Following the FDA's recommendations, we removed duplicate reports based on PRIMARYID and CASEID in the DEMO file to ensure data reliability. In our analysis, we included only AE reports in which busulfan was classified as the primary suspect (PS) in the DRUG file, to enhance accuracy and efficiency. AE reports were classified into System Organ Classes (SOCs) using the preferred terms (PT) from the Medical Dictionary for Regulatory Activities (MedDRA 26.0) [ 23 ]. Cases with more than three records in the FAERS database were selected, and reports with missing or duplicated patient information were excluded to obtain AE reports associated with busulfan. 2.3 Data Analysis This study employed four methods for AEs signal detection, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM) [ 24 , 25 ]. Each of the four methods has its own advantages and disadvantages in terms of applicability and feasibility. Therefore, a combination of these four methods was used in this study to identify signals with strong associations. By adopting this multi-method strategy, we aimed to overcome the limitations of a single algorithm, enhance the reliability and accuracy of data mining, and thereby provide more robust support for the objectives of this study. A signal was considered positive if the ROR ≥ 1 and 95% CI (lower limit) > 1, with three or more reports. For the PRR method, a PRR ≥ 2 and χ2 ≥ 4, with a reported number ≥ 3 indicated a statistically significant association between the drug and the target AEs. In the BCPNN method, IC025 > 0 was considered significant, while in the EBGM method, EBGM05 > 2 was deemed significant. Detailed calculations and specific procedures are presented in Supplementary Table S1 . To determine the differences between males and females after the use of busulfan, we referred to relevant literature [ 26 ], and adopted a modified ROR method, as shown in Supplementary Table S2 . 3 Results 3.1 Descriptive characteristics We screened a dataset consisting of 21,838,627 reports from the FAERS database. After removing duplicates, we analyzed a total of 18,289,374 entries. The screening time frame ranged from the first quarter of 2004 to the third quarter of 2024, Ultimately, we obtained 4,761 busulfan relevant reports, among which 3,627 AEs were caused by the use of busulfan for HSCT pretreatment (Fig. 1 ). Demographic characteristics were presented in Table 1 . AEs associated with busulfan were more frequent in males (n = 1460, 40.3%) than in females (n = 1044, 28.8%). In reports involving age information, 1232 (34%), 1128 (31.1%), and 137 (3.8%) cases were reported in the age groups < 18 years, 18-64.9 years and 65–85 years, respectively. The country with the highest proportion of recorded information was the United States, accounting for 29.00%, followed by Japan (16.30%), France (10.00%), Canada (9.10%), and China (7.40%). The primary sources of the reports were other health experts and physicians, with 2113 cases (58.3%) and 1122 cases (30.9%) respectively. Nearly half of the outcomes were other serious outcomes (48.4%), followed by death, hospitalization, and life-threatening events, with 924 cases (25.50%), 375 cases (10.30%), and 152 cases (4.20%) respectively. Figure 2 illustrated the temporal distribution of AEs associated with busulfan use in HSCT preconditioning. A marked increase in AE reports had been observed in recent years. Table 1 The overall demographic characteristics of AEs related to busulfan. Characteristics Case number Case proportion, % Gender, n (%) Female 1044 28.80% Male 1460 40.30% Unkown 1123 31.00% Age(years), n (%) 85 0 0.00% Unkown 1130 31.20% Weight 100 13 0.40% Unkown 3335 91.90% Reporters, n (%) Physician 1122 30.90% Other health professional 2113 58.30% Consumer 174 4.80% Pharmacist 29 0.80% Unkown 189 5.20% Reported Countries, n (%) United States 1053 29.00% Japan 590 16.30% France 362 10.00% Canada 331 9.10% China 270 7.40% Serious Outcome, n (%) Death 924 25.50% Hospitalization Initial or Prolonged 375 10.30% Life Threatening 152 4.20% Disability 10 0.30% Congenital Anomaly 0 0.00% Other serious outcomes 1754 48.40% Unkown 410 11.30% 3.2 Onset time of events A total of 418 cases of busulfan related reports with onset time were included for analysis. The median onset time is 21 days (interquartile range [IQR] 12–50 days). As shown in Fig. 3 A, the majority of cases clustered within the first month after treatment of busulfan (n = 260, 62.20%). Notably, even after one year of treatment with busulfan, AEs may still occur (n = 27, 6.46%). The cumulative incidence curve is presented in Fig. 3 B. Additionally, The Weibull distribution analysis revealed the patterns of early failures, with specific parameters detailed in Table 2 . Table 2 Time to onset of busulfan-associated adverse events and Weibull distribution analysis. Drug TTO(Days) Weibull distribution Case reports Median(d) (lQR) Scale parameter: α(95%Cl) Shape parameter: β(95%Cl) Type busulfan 418 21(12–50) 53.97 (44.82–63.11) 0.60 (0.56–0.64) Early failure 3.3 Signal detection at SOC level During the study period, the FAERS database recorded 11,489 AEs at PT level across 27 SOC associated with busulfan in HSCT pre-transplant treatment. Figure 4 shows the number of reported SOC cases and their corresponding ROR values (95% CI). The top five SOC by quantity were Infections and Infestations (n = 2,796, 24.34%; ROR = 1.36, 95% CI: 1.3–1.42), Injury, Poisoning and Procedural Complications (n = 1,340, 11.66%; ROR = 1.52, 95% CI: 1.43–1.61), General Disorders and Administration Site Conditions (n = 882, 7.68%; ROR = 0.77, 95% CI: 0.72–0.83), Blood and Lymphatic System Disorders (n = 840, 7.31%; ROR = 1.24, 95% CI: 1.15–1.33), and Respiratory, Thoracic and Mediastinal Disorders (n = 821, 7.15%; ROR = 1.48, 95% CI: 1.37–1.59). Supplementary Table S3 details the PRR, EBGM, and BCPNN results. 3.4 Disproportionate analysis of AEs related to the use of busulfan Four different algorithms (ROR, PRR, MGPS, and BCPNN) were used for signal detection, as shown in the Venn diagram in Supplementary Figure S1 . There were 97 PTs with positive results from all four calculation methods. The detailed analysis results are showed in Supplementary Table S4 . Table 3 summarized the top 10 SOCs with corresponding top 5 PTs and detailed values of four analysis methods. Among them, the more frequent PTs include Product Use In Unapproved Indication (n = 707), Off Label Use (n = 285), Venoocclusive Liver Disease (n = 261), Mucosal Inflammation (n = 217), Cytomegalovirus Infection (n = 192), Cytomegalovirus Infection Reactivation (n = 153), Febrile Neutropenia (n = 149), Cystitis Haemorrhagic (n = 138), Graft Versus Host Disease (n = 132), and Sepsis(n = 131). Table 3 Signal strength of the top 5 individual PTs under the top 10 SOCs of reported frequency. SOC (Top 10) PTs (Top 5 per SOC) Cases, n ROR(95%CI) PRR(χ 2 ) EBGM(EBGM05) IC(IC025) Infections And Infestations Cytomegalovirus Infection 192 1.27 (1.1–1.48) 1.27 (10.31) 1.25 (1.1) 0.32 (0.11) Cytomegalovirus Infection Reactivation 153 3.98 (3.34–4.75) 3.94 (274.29) 3.39(2.93) 1.76 (1.51) Sepsis 131 1.35 (1.13–1.61) 1.34 (10.69) 1.32 (1.13) 0.4 (0.14) Bk Virus Infection 103 2.43 (1.97–2.99) 2.41 (75.16) 2.24 (1.88) 1.16 (0.86) Pneumonia 101 0.98 (0.8–1.2) 0.98 (0.04) 0.98 (0.83) -0.03 (-0.32) Injury, Poisoning And Procedural Complications Product Use In Unapproved Indication 707 4.51 (4.15–4.91) 4.3 (1456.17) 3.64 (3.39) 1.86 (1.74) Off Label Use 285 0.86 (0.76–0.97) 0.86 (6.13) 0.87 (0.79) -0.2 (-0.38) Transplant Failure 61 2.47 (1.89–3.24) 2.46 (46.56) 2.28 (1.82) 1.19 (0.8) Toxicity To Various Agents 38 0.91 (0.66–1.26) 0.91 (0.32) 0.92 (0.7) -0.13 (-0.6) Product Use Issue 30 1.02 (0.7–1.47) 1.02 (0.01) 1.02 (0.75) 0.02 (-0.51) General Disorders And Administration Site Conditions Mucosal Inflammation 217 3.11 (2.68–3.59) 3.07 (258.3) 2.75 (2.44) 1.46 (1.25) Pyrexia 102 0.63 (0.52–0.77) 0.63 (21.23) 0.65 (0.55) -0.63 (-0.92) Multiple Organ Dysfunction Syndrome 90 1.98 (1.59–2.46) 1.97 (38.77) 1.87 (1.56) 0.9 (0.59) Drug Ineffective 65 0.43 (0.33–0.55) 0.43 (48.5) 0.44 (0.36) -1.17 (-1.53) Death 49 0.68 (0.51–0.9) 0.68 (7.29) 0.69 (0.54) -0.54 (-0.95) Blood And Lymphatic System Disorders Febrile Neutropenia 149 1.63 (1.37–1.93) 1.62 (32.49) 1.57 (1.36) 0.65 (0.4) Thrombotic Microangiopathy 129 1.67 (1.39-2) 1.66 (30.98) 1.6 (1.37) 0.68 (0.41) Thrombocytopenia 90 1.34 (1.08–1.67) 1.34 (7.32) 1.32 (1.1) 0.4 (0.08) Pancytopenia 65 1.19 (0.93–1.53) 1.19 (1.86) 1.18 (0.95) 0.24 (-0.13) Neutropenia 63 0.88 (0.68–1.13) 0.88 (0.99) 0.89 (0.72) -0.17 (-0.55) Respiratory, Thoracic And Mediastinal Disorders Respiratory Failure 127 1.87 (1.56–2.25) 1.86 (45.99) 1.78 (1.52) 0.83 (0.56) Acute Respiratory Distress Syndrome 50 1.63 (1.22–2.18) 1.63 (11.17) 1.58 (1.24) 0.66 (0.23) Pleural Effusion 47 1.5 (1.11–2.02) 1.49 (7.07) 1.45 (1.13) 0.54 (0.11) Pulmonary Hypertension 40 4.58 (3.23–6.5) 4.57 (88.27) 3.82 (2.85) 1.93 (1.44) Pulmonary Haemorrhage 37 3.33 (2.34–4.74) 3.32 (50.48) 2.95 (2.2) 1.56 (1.05) Gastrointestinal Disorders Stomatitis 118 3.52 (2.89–4.3) 3.5 (175.59) 3.08 (2.61) 1.62 (1.33) Diarrhoea 110 0.87 (0.72–1.05) 0.87 (2.08) 0.88 (0.75) -0.19 (-0.47) Nausea 77 1.2 (0.95–1.51) 1.2 (2.32) 1.18 (0.97) 0.24 (-0.1) Vomiting 51 0.78 (0.59–1.03) 0.78 (3.04) 0.79 (0.62) -0.34 (-0.75) Gastrointestinal Haemorrhage 42 2.26 (1.64–3.12) 2.26 (26.05) 2.11 (1.61) 1.08 (0.61) Immune System Disorders Graft Versus Host Disease 132 1.21 (1.02–1.45) 1.21 (4.54) 1.2 (1.03) 0.26 (0) Acute Graft Versus Host Disease 98 0.9 (0.74–1.11) 0.91 (0.94) 0.91 (0.77) -0.14 (-0.43) Haemophagocytic Lymphohistiocytosis 57 4.13 (3.09–5.52) 4.11 (108.66) 3.51 (2.76) 1.81 (1.4) Chronic Graft Versus Host Disease 55 0.74 (0.57–0.97) 0.74 (4.69) 0.75 (0.6) -0.41 (-0.8) Acute Graft Versus Host Disease In Skin 53 0.7 (0.53–0.92) 0.7 (6.58) 0.71 (0.57) -0.49 (-0.89) Hepatobiliary Disorders Venoocclusive Liver Disease 261 5.12 (4.45–5.88) 5.03 (655.34) 4.12 (3.66) 2.04 (1.84) Hepatic Failure 34 1.69 (1.19–2.4) 1.69 (8.65) 1.62 (1.21) 0.7 (0.19) Hepatic Function Abnormal 25 1.53 (1.02–2.31) 1.53 (4.21) 1.49 (1.06) 0.57 (-0.02) Liver Disorder 19 1.4 (0.87–2.23) 1.39 (1.97) 1.37 (0.92) 0.45 (-0.22) Hepatotoxicity 14 1.3 (0.75–2.24) 1.3 (0.89) 1.28 (0.81) 0.35 (-0.42) Renal And Urinary Disorders Cystitis Haemorrhagic 138 3.05 (2.54–3.66) 3.03 (159.88) 2.72 (2.34) 1.45 (1.18) Acute Kidney Injury 80 0.88 (0.7–1.1) 0.88 (1.3) 0.88 (0.73) -0.18 (-0.51) Renal Failure 55 0.87 (0.66–1.14) 0.87 (0.99) 0.88 (0.7) -0.19 (-0.58) Renal Impairment 35 0.55 (0.39–0.77) 0.55 (12.28) 0.57 (0.43) -0.82 (-1.31) Haematuria 22 1.46 (0.94–2.26) 1.46 (2.94) 1.42 (0.99) 0.51 (-0.12) Investigations Platelet Count Decreased 27 0.95 (0.64–1.4) 0.95 (0.07) 0.95 (0.69) -0.07 (-0.63) Blood Bilirubin Increased 27 1.18 (0.8–1.75) 1.18 (0.71) 1.17 (0.84) 0.23 (-0.34) Blood Follicle Stimulating Hormone Increased 24 18.86 (10.57–33.64) 18.82 (193.72) 9.52 (5.87) 3.25 (2.54) Blood Luteinising Hormone Increased 22 25.35 (13.15–48.88) 25.3 (208.23) 10.85 (6.27) 3.44 (2.68) Cytomegalovirus Test Positive 18 1.3 (0.8–2.1) 1.3 (1.16) 1.28 (0.86) 0.35 (-0.33) 3.5 Subgroup analysis In Fig. 5 , we listed the top 20 AEs in both male and female patients, including Product Use In Unapproved Indication, Mucosal Inflammation, Cytomegalovirus Infection, Venoocclusive Liver Disease and so on. We analyzed using a refined ROR method and found positive signals in PT such as Toxicity To Various Agents, Blood Follicle Stimulating Hormone Increased, Blood Luteinising Hormone Increased, Dyspnoea, and Posterior Reversible Encephalopathy Syndrome, as shown in Fig. 6 . Supplementary Figure S2 lists the top 20 AEs with the highest reporting frequencies across different age groups of patients. 3.6 Sensitivity analysis Some reports of AEs were reported by consumers. Due to potential unfamiliarity with the AEs reporting system among the consumer population, we analyzed the differences in PTs reported by health professionals compared to those reported by all type of reporter. The top 50 PTs with the most significant differences is presented in Fig. 7 . Unlike the unfiltered results, AEs such as Sepsis, Thrombocytopenia, Pleural Effusion, and Malaise did not show positive signals in the ROR and BCPNN analyses when reported by health professionals. The PT values for reports from all type of reporter and health professionals, as well as the results of the four signal detection methods, are detailed in Supplementary Table S5 and Supplementary Table S6 . Additionally, we analyzed the reports where busulfan was the only suspected drug; however, the number of cases was limited. The specific results are provided in Supplementary Table S7 . 3.7 Combination therapy analysis In clinical practice, busulfan is frequently used in combination with other agents, such as cyclophosphamide or fludarabine. We evaluated the differences in AEs between the combination of busulfan and cyclophosphamide or fludarabine. Table 4 presents the top 50 PTs identified in these analyses. Unlike the combination with cyclophosphamide, the analysis of busulfan in combination with fludarabine revealed that Acute Graft Versus Host Disease and Infection showed positive signals with higher frequencies in the disproportionality analysis. Additionally, AEs such as Venoocclusive Liver Disease, Mucosal Inflammation, Nausea, Pyrexia, and Infection were found to have higher reporting frequencies when busulfan was used in combination with fludarabine. Table 4 Combination therapy analysis and the top 50 PTs ranked by busulfan cases. PT busulfan busulfan plus cyclophosphamide busulfan plus fludarabine a ROR (95%Cl) a ROR (95%Cl) a ROR (95%Cl) Total 11489 7073 9018 Product Use In Unapproved Indication 707 4.51 (4.15–4.91) 405 3.87 (3.48–4.3) 464 3.49 (3.16–3.86) Off Label Use 285 0.86 (0.76–0.97) 165 0.82 (0.7–0.95) 250 0.98 (0.86–1.11) Venoocclusive Liver Disease 261 5.12 (4.45–5.88) 138 3.96 (3.31–4.74) 211 5.1 (4.39–5.93) Mucosal Inflammation 217 3.11 (2.68–3.59) 119 2.64 (2.18–3.19) 182 3.31 (2.83–3.87) Cytomegalovirus Infection 192 1.27 (1.1–1.48) 151 1.65 (1.4–1.95) 167 1.42 (1.22–1.67) Cytomegalovirus Infection Reactivation 153 3.98 (3.34–4.75) 103 4.28 (3.48–5.27) 127 4.25 (3.51–5.14) Febrile Neutropenia 149 1.63 (1.37–1.93) 77 1.33 (1.05–1.67) 92 1.24 (1–1.53) Cystitis Haemorrhagic 138 3.05 (2.54–3.66) 108 3.82 (3.12–4.68) 79 2.08 (1.65–2.63) Graft Versus Host Disease 132 1.21 (1.02–1.45) 134 2.05 (1.71–2.44) 107 1.24 (1.02–1.51) Sepsis 131 1.35 (1.13–1.61) 59 0.96 (0.74–1.24) 114 1.49 (1.23–1.8) Thrombotic Microangiopathy 129 1.67 (1.39–2) 72 1.48 (1.16–1.87) 94 1.52 (1.23–1.88) Respiratory Failure 127 1.87 (1.56–2.25) 82 1.94 (1.55–2.43) 91 1.68 (1.36–2.08) Stomatitis 118 3.52 (2.89–4.3) 48 2.1 (1.57–2.82) 58 2 (1.53–2.62) Venoocclusive Disease 118 3.94 (3.22–4.81) 65 3.25 (2.51–4.21) 98 4.05 (3.26–5.03) Diarrhoea 110 0.87 (0.72–1.05) 42 0.53 (0.39–0.72) 58 0.57 (0.44–0.74) Bk Virus Infection 103 2.43 (1.97–2.99) 87 3.37 (2.7–4.22) 67 1.95 (1.52–2.51) Pyrexia 102 0.63 (0.52–0.77) 76 0.77 (0.62–0.97) 105 0.84 (0.69–1.02) Pneumonia 101 0.98 (0.8–1.2) 63 0.99 (0.77–1.27) 60 0.73 (0.56–0.94) Acute Graft Versus Host Disease 98 0.9 (0.74–1.11) 46 0.68 (0.51–0.91) 125 1.51 (1.26–1.81) Thrombocytopenia 90 1.34 (1.08–1.67) 34 0.81 (0.57–1.13) 66 1.25 (0.98–1.61) Multiple Organ Dysfunction Syndrome 90 1.98 (1.59–2.46) 63 2.27 (1.75–2.93) 64 1.79 (1.38–2.31) Cytomegalovirus Viraemia 86 1.87 (1.49–2.34) 51 1.76 (1.33–2.34) 72 1.98 (1.56–2.53) Acute Kidney Injury 80 0.88 (0.7–1.1) 50 0.9 (0.68–1.19) 62 0.87 (0.67–1.12) Post Transplant Lymphoproliferative Disorder 78 1.65 (1.3–2.08) 62 2.14 (1.65–2.77) 55 1.46 (1.11–1.92) Nausea 77 1.2 (0.95–1.51) 29 0.71 (0.49–1.03) 60 1.18 (0.91–1.54) Infection 74 0.96 (0.76–1.21) 43 0.91 (0.67–1.23) 98 1.68 (1.37–2.07) Pancytopenia 65 1.19 (0.93–1.53) 51 1.54 (1.16–2.05) 59 1.4 (1.07–1.82) Drug Ineffective 65 0.43 (0.33–0.55) 67 0.74 (0.58–0.94) 76 0.65 (0.52–0.82) Septic Shock 64 1.33 (1.03–1.71) 43 1.48 (1.09–2.01) 61 1.66 (1.28–2.16) Neutropenia 63 0.88 (0.68–1.13) 27 0.62 (0.42–0.9) 55 1 (0.76–1.31) Transplant Failure 61 2.47 (1.89–3.24) 43 2.76 (2.02–3.78) 66 3.48 (2.68–4.51) Bacteraemia 58 2.52 (1.91–3.32) 38 2.61 (1.87–3.64) 35 1.85 (1.31–2.62) Haemophagocytic Lymphohistiocytosis 57 4.13 (3.09–5.52) 28 3.02 (2.04–4.46) 41 3.61 (2.6–5.03) Adenovirus Infection 56 1.32 (1.01–1.74) 36 1.39 (1–1.95) 48 1.47 (1.1–1.97) Chronic Graft Versus Host Disease 55 0.74 (0.57–0.97) 48 1.07 (0.8–1.43) 81 1.44 (1.15–1.81) Renal Failure 55 0.87 (0.66–1.14) 33 0.85 (0.6–1.2) 54 1.1 (0.84–1.45) Acute Graft Versus Host Disease In Skin 53 0.7 (0.53–0.92) 55 1.21 (0.92–1.59) 68 1.18 (0.92–1.5) Vomiting 51 0.78 (0.59–1.03) 26 0.64 (0.43–0.95) 36 0.7 (0.5–0.97) Epstein-Barr Virus Infection 50 1.04 (0.78–1.39) 27 0.92 (0.63–1.35) 53 1.45 (1.1–1.92) Acute Respiratory Distress Syndrome 50 1.63 (1.22–2.18) 23 1.18 (0.78–1.79) 27 1.08 (0.74–1.6) Death 49 0.68 (0.51–0.9) 40 0.9 (0.66–1.24) 40 0.7 (0.51–0.96) Graft Versus Host Disease In Skin 47 1.15 (0.86–1.55) 32 1.3 (0.91–1.86) 42 1.35 (0.99–1.84) Pleural Effusion 47 1.5 (1.11–2.02) 36 1.87 (1.33–2.62) 33 1.32 (0.93–1.88) Staphylococcal Infection 46 1.77 (1.31–2.41) 38 2.42 (1.74–3.38) 37 1.83 (1.3–2.55) Malaise 43 1.51 (1.1–2.06) 15 0.82 (0.49–1.38) 20 0.86 (0.55–1.35) Aplastic Anaemia 43 3.61 (2.6–5.02) 27 3.51 (2.35–5.24) 49 5.52 (4.03–7.55) Epstein-Barr Virus Infection Reactivation 43 4.13 (2.96–5.77) 35 5.65 (3.93–8.12) 29 3.51 (2.37–5.19) Gastrointestinal Haemorrhage 42 2.26 (1.64–3.12) 26 2.21 (1.48–3.3) 22 1.43 (0.93–2.21) Viral Haemorrhagic Cystitis 41 2.77 (1.99–3.85) 39 4.43 (3.16–6.21) 41 3.64 (2.62–5.07) Graft Versus Host Disease In Gastrointestinal Tract 41 0.96 (0.7–1.31) 35 1.37 (0.98–1.93) 36 1.1 (0.78–1.53) 4. Discussion As a classic alkylating agent and a cornerstone drug in HSCT conditioning regimens, the long-term safety of busulfan remains an important focus for ongoing monitoring. This study conducted an in-depth pharmacovigilance analysis of busulfan using the FAERS database. In addition to the maked AEs, we identified novel and unexpected AEs associated with busulfan. Furthermore, this study investigated the onset time, age, and gender differences of busulfan-related AEs, as well as performed sensitivity analyses. These findings may provide new evidence for updating drug labeling and for the rational and safe use of busulfan in clinical practice. 4.1 Basic information analysis In the FAERS database, busulfan-related AEs were reported more frequently in male (n = 1460, 40.3%) than female patients (n = 1044, 28.8%). This might be due to the fact that males have a higher prevalence of the disease [ 27 , 28 ]. Unfortunately, most reports (91.90%) do not include patient weight information. 34% of patients were under the age of 18; The proportion of patients aged between 18-64.9 years old was 31.1%. There were individual differences in the oral absorption and metabolic rate of busulfan. Studies had shown that age was a major factor affecting the clearance rate and distribution volume of intravenous busulfan [ 29 ]. Almost 89.2% of AE reports were recorded by healthcare professionals. Notably, serious adverse outcomes such as hospitalization, death, and life-threatening conditions accounted for approximately 40% of busulfan-related outcomes. Reports of busulfan-associated AEs have increased annually since 2015 (Fig. 2 ). These results emphasized the broad clinical utility and efficacy of busulfan and underscored the importance of improving the detection of busulfan-associated adverse drug events as it relates to serious AEs in the clinical setting. Busulfan, as an alkylating anticancer agent, is listed in the first group of "hazardous drugs" by the National Institute for Occupational Safety and Health (NIOSH) in the United States [ 30 ]. In this study, AEs were temporally analyzed using a Weibull distribution model to predict the likely time of occurrence of these events, and the type of AEs occurrence pattern was categorized as “early failure,” suggesting that AEs occurred primarily within a relatively short period of time. This result clearly demonstrated that the majority of AEs associated with busulfan occurred within the first month of the therapeutic intervention, which emphasized necessity of strengthening monitoring in the early stages of treatment to ensure better patient safety and outcomes. 4.2 AEs related to Infections And Infections In this study, the most frequently reported SOC was Infections And Infections (n = 2796, 24.34%, ROR: 1.36; 95% CI: 1.3–1.42), with the most commonly reported events under this category being Cytomegalovirus Infection, Cytomegalovirus Infection Reactivation, Sepsis, BK Virus Infection, and Pneumonia. In an open label, randomized, phase 3 trial of busulfan plus cyclophosphamide for HSCT, the most frequent AE was infection (n = 32, 32%) [ 31 ]. In another clinical trial involving busulfan conditioning, among 24 patients, 16 patients (66%) experienced infections, and five patient deaths were caused by septic shock, with sepsis being the direct cause of the septic shock [ 32 ]. This was because busulfan significantly weakens the body's immune defense capability by inhibiting bone marrow hematopoietic function and the production of immune cells (especially neutrophils and lymphocytes), thereby increasing the risk of infection [ 33 ]. BK virus is a common polyomavirus that usually reactivates under immunosuppressive conditions and may lead to severe complications such as hemorrhagic cystitis and nephropathy [ 34 ]. Therefore, it is necessary to be vigilant about the AEs related to infections caused by busulfan, as they may be accompanied by a variety of complications. 4.3 AEs related to General Disorders And Administration Site Conditions and Blood and Lymphatic System Disorders Mucosal Inflammation was the PT with the highest incidence rate among General Disorders And Administration Site Conditions (n = 217, ROR: 3.11; 95% CI: 2.68–3.59). In Blood and Lymphatic System Disorders (n = 840, 7.31%, ROR: 1.24; 95% Cl: 1.15–1.33), Febrile Neutropenia, Thrombotic Microangiopathy, Thrombocytopenia, and Pancytopenia all showed positive signals. However, Thrombotic Microangiopathy was not mentioned in the drug description of busulfan. Busulfan can produce ionic damage to the structure and function of DNA molecules that react with DNA and can cause blood and lymphatic diseases through mechanisms such as bone marrow suppression, immune suppression, and long-term toxicity. Long-term use of busulfan may lead to irreversible bone marrow damage such as bone marrow fibrosis, further increasing the incidence of blood diseases [ 35 – 37 ]. In previous studies, it was found that patients with hematologic AEs often have mucosal inflammation, although some patients have mild symptoms. In a case report on busulfan HSCT conditioning, one of the four patients developed autoimmune cytopenia, which is an important complication, while three patients had mild mucosal inflammation [ 38 ]. In a phase Ⅰ study of intravenous busulfan as a conditioning regimen for multiple myeloma, the 13 patients had a mean age of 73 years (range 68–80 years). AEs such as neutropenia and thrombocytopenia occurred frequently. In addition, grade 3 mucositis was observed in three patients [ 39 ]. Therefore, for patients who use busulfan for a long time, special attention should be paid to the occurrence of bone marrow suppression and mucosal inflammation. 4.4 AEs related to Respiratory, Thoracic and Mediating Disorders Among the AEs related to Respiratory, Thoracic And Mediastinal Disorders (n = 821, 7.15%, ROR: 1.48; 95% CI: 1.37–1.59), some AEs were described, such as Respiratory Failure (n = 127, ROR: 1.87; 95% CI: 1.56–2.25), Acute Respiratory Distress Syndrome (n = 50, ROR: 1.63; 95% CI: 1.22–2.18), Pleural Effusion (n = 47, ROR: 1.50; 95% CI: 1.11–2.02), and Pulmonary Haemorrhage (n = 37, ROR: 3.33; 95% CI: 2.34–4.74) [ 40 ]. However, descriptions of Pulmonary Hypertension (n = 40, ROR: 4.58; 95% CI: 3.23–6.5) were scarce. Busulfan has pulmonary toxicity because it can damage lung epithelial cells [ 41 ]. In a study of busulfan-associated pulmonary hypertension, four patients developed severe pulmonary hypertension 2 to 4.5 months after busulfan administration [ 42 ]. Pulmonary Hypertension is characterized by the absence, occlusion, abnormal muscularization, and perivascular inflammation of precapillary small arteries. This vascular remodeling impairs right heart function and reduces survival, with pulmonary endothelial dysfunction playing a central role [ 43 ]. Although the reporting of Pulmonary Hypertension is relatively rare, its high ROR value suggests that busulfan may be an important cause of Pulmonary Hypertension. In clinical practice, there should be enhanced monitoring of lung function indicators in patients using busulfan, and busulfan-induced lung injury needs timely diagnosis and intervention. 4.5 AEs at other SOC levels The disproportionate analysis results indicate that AEs associated with busulfan may also affect other organs or tissues. Hepatobiliary Disorder was also a SOC with a high reporting frequency, Venoocclusive Liver Disease was the AE with the highest reported frequency and high signal strength (n = 261, ROR: 5.12; 95% CI: 4.45–5.88). Next were the Hepatic Failure, Hepatic Function Abnormal, Liver Disorder, Hepatotoxicity, all of which showed positive signals. Venoocclusive Liver Disease is the main side effect of busulfan [ 44 ], with 50% of busulfan metabolism occurring through binding to glutathione S-transferase (GST) enzyme [ 16 ]. The depletion of hepatic glutathione by busulfan can lead to oxidative stress [ 45 ]. In addition, busulfan can directly induce hepatocyte injury, trigger pro-inflammatory responses, and induce hepatotoxicity [ 46 ]. The AEs related to Renal and Urinary Disorders associated with busulfan also deserved our attention. Cystitis Haemorrhagic (n = 138, ROR: 3.05; 95% CI: 2.54–3.66) has a relatively high incidence and shows a positive signal in the disproportionality analysis. Hemorrhagic cystitis is a condition characterized by hematuria and urinary incontinence without bacterial infection [ 47 ]. In a study of 960 patients undergoing HSCT transplantation, it was found that 23.8% of patients treated with busulfan developed hemorrhagic cystitis [ 48 ]. Another study also showed that the incidence of hemorrhagic cystitis caused by busulfan was 36% [ 49 ]. In summary, patients taking busulfan need regular liver and kidney function tests to detect possible liver and kidney damage in the early stages. In addition, we observed that although the number of cases of Blood Follicle Stimulating Hormone Increased was relatively small (n = 24, ROR: 18.86; 95% CI: 10.57–33.64), the signal strength was very high, indicating a strong correlation with busulfan, However, this was not mentioned in the drug instructions. Nevertheless, a study has shown that busulfan has strong ovarian toxicity [ 50 ], which was consistent with our results. 4.6 Based on gender and age differences As described previously, in the FAERS database, AEs related to busulfan were reported more frequently in male patients than in female patients. Specifically, Blood And Lymphatic System Disorders such as Febrile Neutropenia (male: n = 74, female: n = 40) and Thrombocytopenia (male: n = 39, female: n = 26) occurred more frequently in male patients than in female patients. The differences in sex hormone levels between males and females may affect the sensitivity of drug targets. For example, androgens may enhance the toxicity of busulfan to hematopoietic stem cells by regulating the bone marrow microenvironment or immune response, leading to a higher incidence of bone marrow suppression in males [ 51 ]. This may also be due to the higher incidence of side effects such as hemorrhagic cystitis in males compared to females [ 52 , 53 ]. Estrogens might play a protective role in the bladder mucosa, resulting in a lower probability of hemorrhagic cystitis in female patients after bone marrow transplantation compared to male patients [ 54 ]. The hepatotoxicity of busulfan, such as Venoocclusive Liver Disease, was more frequent in males than in females. This might be due to genetic polymorphisms (such as gene variations in the glutathione S-transferase) that might affect the metabolism and detoxification process of busulfan, and the distribution of certain genotypes might have gender differences, making males more susceptible to toxic reactions [ 55 ]. Busulfan is one of the few anticancer agents utilized in children under the age of 3 years [ 56 ]. It is characterized by a narrow therapeutic window and substantial inter-individual metabolic variability [ 8 ]. There is a significant correlation between gender and chemotherapy related toxicity [ 57 ]. A significant correlation has been observed between sex and chemotherapy-related toxicity [24091100]. Plasma concentrations of busulfan vary markedly across different age groups. Patients with low drug exposure may experience suboptimal clinical outcomes, whereas those with elevated plasma concentrations are at an increased risk of developing Venoocclusive Liver Disease risk [ 58 ]. Therefore, the Pharmacist Committee of the European Society for Blood and Marrow Transplantation has recommended therapeutic drug monitoring for busulfan [ 59 ]. 4.7 Combination therapy analysis In clinical myeloablative conditioning regimens, busulfan is commonly administered in combination with cyclophosphamide or fludarabine. To further evaluate potential disparities in AEs associated with drug combinations, we conducted a retrospective screening of the database, specifically selecting cases where either busulfan or its combination partner (cyclophosphamide/fludarabine) was designated as the primary suspected agent, while the other drugs were classified as concomitant medications or secondary suspected agents. AEs such as Acute Graft Versus Host Disease, Infection in the busulfan combined with fludarabine regimen had positive results in the disproportionate analysis compared to busulfan combined with cyclophosphamide. This might be attributed to the fact that busulfan primarily targets myeloid cells, while fludarabine is a potent lymphocyte inhibitor. The combination of these two agents may lead to more profound T-cell depletion, thereby affecting immune reconstitution [ 60 ]. In a study based on myeloablative conditioning regimens of busulfan-fludarabine or treosulfan-fludarabine, the 2-year overall survival rate after busulfan-fludarabine conditioning was 92.7%, with the main causes of death being infection, graft-versus-host disease, and rejection [ 61 ]. However, in another study, the regimen-related toxicity and transplant-related mortality of the busulfan and fludarabine conditioning regimen were lower than those of the busulfan and cyclophosphamide regimen [ 62 ]. Leukemia recurrence remains a major issue [ 11 ]. Therefore, in clinical practice, it is essential to weigh the anti-leukemia efficacy against toxicity and optimize outcomes through individualized medication and intensified supportive treatment. 4.8 Limitations This study represents the most comprehensive real-world pharmacovigilance analysis to date, systematically evaluating the post market safety of busulfan. Firstly, the FAERS database may be subject to underreporting or incomplete reporting. For instance, less severe or common adverse events such as nausea and vomiting may be underreported, while rare events may be overreported [ 63 ]. In our collected AE reports, 91.9% lacked patient weight information. Therefore, potential biases introduced by the data should be carefully considered when interpreting the results [ 64 ]. Secondly, there is a lack of detailed clinical information regarding patients, such as comorbidities and the severity of underlying diseases, which may affect the assessment of drug interactions [ 65 ]. Thirdly, the impact of dose intensity on the incidence of adverse reactions and survival rates after transplantation was not considered [ 66 ]. Despite these limitations, which are inherent to pharmacovigilance studies using the FAERS database, the comprehensive characterization of busulfan-related AEs in this study may provide valuable insights for the safe use of the drug and further clinical research. 5. Summary In this comprehensive pharmacovigilance analysis utilizing the FAERS database, we systematically evaluated the AEs associated with busulfan use in pre-transplant conditioning for HSCT. Our findings have unveiled several key safety considerations: Age-related vulnerability: Patients under the age of 65 exhibited a higher rate of AE reporting, indicating the need for heightened vigilance in this population. Key organ toxicities: Our data underscore the importance of monitoring liver and kidney function, close hematologic surveillance of myelosuppression, and therapeutic drug monitoring. Additionally, for emerging safety signals: Clinicians should enhance their awareness of potentially serious but less frequently reported AEs, including pulmonary arterial hypertension, thrombotic microangiopathy, and endocrine disorders (elevated levels of follicle-stimulating hormone and luteinizing hormone). These findings provide important real-world evidence to guide risk assessment and monitoring strategies in clinical practice. Further prospective studies are warranted to validate these observations and elucidate the underlying mechanisms. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials The datasets involved in this study are included in the article/supplementary materials. If you have any questions, please contact the corresponding authors. Competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding This work was supported by the Research Fund of the Central Hospital of Wuhan (grant number 23YJ03). Authors' contributions X-WY: Conceptualization, Writing–original draft, Writing–review and editing, Data curation, Investigation, Methodology, Funding acquisition. W-LX: Conceptualization, Writing–review and editing, Software. JF: Writing–review and editing, Formal analysis. J-FW: Writing–review and editing. YL: Writing–review and editing. J-YL: Writing–review and editing, Validation. A-PD: Writing–review and editing, Project administration. Y-JL: Writing–review and editing, Project administration. Acknowledgements We sincerely acknowledge the support from the Department of Pharmacy at Wuhan Central Hospital. References P.A. Brown, B. Shah, A. 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W. van der Velden, E.C. de Weerd-de Jong, A.F.J. de Haan, et al., Busulfan-Dependent Hepatotoxicity of Antithymocyte Globulin Formulations During Conditioning for Hematopoietic Stem Cell Transplantation, Biol Blood Marrow Transplant. 24 (2018) 410-412. https://doi.org/10.1016/j.bbmt.2017.10.020. J. Trotman, I. Nivison-Smith, A. Dodds, Haemorrhagic cystitis: incidence and risk factors in a transplant population using hyperhydration, Bone Marrow Transplant. 23 (1999) 797-801. https://doi.org/10.1038/sj.bmt.1701644. A. Santos Carreira, M.Q. Salas, M. Remberger, et al., Interaction Between High-Dose Intravenous Busulfan and Post-Transplantation Cyclophosphamide on Hemorrhagic Cystitis After Allogeneic Hematopoietic Cell Transplantation, Transplant Cell Ther. 29 (2023) 581 e581-581 e588. https://doi.org/10.1016/j.jtct.2023.07.007. A.E. Thomas, J. Patterson, H.G. 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Fagioli, et al., Chemotherapy-related toxicity in patients with non-metastatic Ewing sarcoma: influence of sex and age, J Chemother. 26 (2014) 49-56. https://doi.org/10.1179/1973947813Y.0000000103. G.J. Veal, L. Nguyen, A. Paci, et al., Busulfan pharmacokinetics following intravenous and oral dosing regimens in children receiving high-dose myeloablative chemotherapy for high-risk neuroblastoma as part of the HR-NBL-1/SIOPEN trial, Eur J Cancer. 48 (2012) 3063-3072. https://doi.org/10.1016/j.ejca.2012.05.020. V. Domingos, K. Nezvalova-Henriksen, A. Dadkhah, et al., A practical guide to therapeutic drug monitoring in busulfan: recommendations from the Pharmacist Committee of the European Society for Blood and Marrow Transplantation (EBMT), Bone Marrow Transplant. 59 (2024) 1641-1653. https://doi.org/10.1038/s41409-024-02413-0. D. Filioglou, M. Husnain, S. Khurana, et al., Has the shortage of fludarabine altered the current paradigm of lymphodepletion in favor of bendamustine?, Front Immunol. 14 (2023) 1329850. https://doi.org/10.3389/fimmu.2023.1329850. R. Luftinger, N. Zubarovskaya, J.E. Galimard, et al., Busulfan-fludarabine- or treosulfan-fludarabine-based myeloablative conditioning for children with thalassemia major, Ann Hematol. 101 (2022) 655-665. https://doi.org/10.1007/s00277-021-04732-4. Y. Ling, L. Xuan, N. Xu, et al., Busulfan Plus Fludarabine Compared With Busulfan Plus Cyclophosphamide for AML Undergoing HLA-Haploidentical Hematopoietic Cell Transplantation: A Multicenter Randomized Phase III Trial, J Clin Oncol. 41 (2023) 4632-4642. https://doi.org/10.1200/JCO.23.00101. Y.M. Alatawi, R.A. Hansen, Empirical estimation of under-reporting in the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), Expert Opin Drug Saf. 16 (2017) 761-767. https://doi.org/10.1080/14740338.2017.1323867. Y. Wang, B. Zhao, H. Yang, et al., A real-world pharmacovigilance study of FDA adverse event reporting system events for sildenafil, Andrology. 12 (2024) 785-792. https://doi.org/10.1111/andr.13533. S.H. Lum, M. Hoenig, A.R. Gennery, et al., Conditioning Regimens for Hematopoietic Cell Transplantation in Primary Immunodeficiency, Curr Allergy Asthma Rep. 19 (2019) 52. https://doi.org/10.1007/s11882-019-0883-1. N. Gagelmann, C. Schuh, S. Flossdorf, et al., Impact of busulfan versus treosulfan dose intensity in myelofibrosis undergoing hematopoietic cell transplantation, Am J Hematol. 99 (2024) 1540-1549. https://doi.org/10.1002/ajh.27363. Additional Declarations No competing interests reported. Supplementary Files SupplementaryFigureandTableslegends.docx SupplementaryFigureS1.jpg SupplementaryFigureS2.jpg SupplementaryTableS1.docx SupplementaryTableS2.xlsx SupplementaryTableS3.xlsx SupplementaryTableS4.xlsx SupplementaryTableS5.xlsx SupplementaryTableS6.xlsx SupplementaryTableS7.xlsx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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12:57:41","extension":"xlsx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":95253,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS6.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6454932/v1/3aeb48c7ef79ba4fe258fa3d.xlsx"},{"id":83612902,"identity":"f19771dd-16e3-43a7-bbbb-3297d1a37249","added_by":"auto","created_at":"2025-05-29 12:49:41","extension":"xlsx","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":30229,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS7.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6454932/v1/38c4dc68f6403bef0b83633e.xlsx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Adverse Events Associated with Busulfan in HSCT Pre-Transplant Conditioning: A Retrospective Pharmacovigilance Study of the FAERS Database","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eThe pre-transplant conditioning regimens typically employ chemotherapy or radiotherapy as the initial treatment modality, followed by hematopoietic stem cell transplantation (HSCT), and have been widely utilized in the treatment of a variety of diseases. These diseases encompass hematologic malignancies (such as acute lymphoblastic leukemia and lymphoma), solid tumors, non-malignant disorders (such as hemoglobinopathies, including thalassemia and sickle cell anemia), and other genetic disorders [\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Total body irradiation (TBI)-based conditioning regimens have been established as the standard pre-transplant conditioning approach for leukemia patients, particularly those with lymphoid malignancies [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, TBI-based conditioning regimens are associated with significant adverse events (AEs), including but not limited to interstitial pneumonitis, cataracts, endocrine dysfunction, and secondary malignancies [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Compared with radiotherapy regimens, busulfan-based chemotherapy regimens offer the advantage of a lower risk of inhibiting lymphocyte formation while inhibiting the proliferation of bone marrow cells [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Therefore, in clinical practice, busulfan is also frequently used as an alternative to TBI-based regimens [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBusulfan, an alkylating drug approved by FDA in 1999 for the treatment of chronic myeloid leukemia [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], has evolved in its clinical application. It was initially employed as a palliative treatment for myeloproliferative disorders, but now it is widely used as a pre-transplant conditioning agent for HSCT [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Busulfan is commonly administered in combination with cyclophosphamide or fludarabine [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Clinical trials have demonstrated the significant efficacy of busulfan-based chemotherapy regimens in HSCT. Specifically, a study on the intravenous administration of busulfan in pediatric patients revealed improvements in overall survival and reductions in transplant-related mortality and relapse rates [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Moreover, research comparing busulfan plus cyclophosphamide regimens with TBI-based regimens indicated superior survival outcomes with busulfan-based approaches [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. However, busulfan therapy is linked to various AEs. It can trigger AEs in multiple tissues and organs, such as bone marrow, gastrointestinal tract, liver, lungs, skin, bladder, and central nervous system[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], which include myelosuppression, diarrhea, veno-occlusive disease, pulmonary toxicity, rash, mucositis, and seizures [\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In a study on the efficacy and safety of busulfan plus fludarabine in HSCT conditioning, the most common AEs were abnormal blood chemistry results (n\u0026thinsp;=\u0026thinsp;35, 14.5%) and gastrointestinal disorders (n\u0026thinsp;=\u0026thinsp;39, 16%). Cardiac toxicity, multi-organ failure infections, and hepatic veno-occlusive disease infections were also reported [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Busulfan was initially approved for the treatment of chronic myeloid leukemia and has now expanded its indications to HSCT pretreatment and combination chemotherapies for solid tumors. This expansion, along with evolving clinical guidelines, complicates the reflection of its AEs in real-world evidence data. Real-world data on the use of busulfan in oncology can introduce confounding factors in pharmacovigilance.\u003c/p\u003e \u003cp\u003eThe FDA Adverse Event Reporting System (FAERS) is a post-marketing surveillance database that collects and monitors AEs associated with approved drugs [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. This database is periodically updated on a quarterly basis, available for public download via the FDA website [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. In this study, by restricting the indications of busulfan, we further explored the AEs associated with its use in myeloablative therapy (from the first quarter of 2004 to the third quarter of 2024), offering valuable insights for clinicians when applying busulfan in myeloablative contexts.\u003c/p\u003e"},{"header":"2 Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Data source\u003c/h2\u003e \u003cp\u003eFAERS is a publicly accessible database that aggregates and summarizes AE reports from around the world. It contains more than 9\u0026nbsp;million individual AE reports submitted by industry professionals, physicians, pharmacists, healthcare professionals, consumers, and others, making it the largest spontaneous reporting system database globally and a substantial data resource for pharmacovigilance research [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The FAERS database is updated quarterly and comprises seven datasets: Demographic and Administration Information (DEMO), Drug Information (DRUG), Adverse Event Information (REAC), Patient Outcome Information (OUTC), Report Source (RPSR), Drug Therapy Start and End Dates (THER), and Drug Indication (INDI).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Data Selection and Processing\u003c/h2\u003e \u003cp\u003eGiven the quarterly updates, the occurrence of duplicate reports in the FAERS database is inevitable. Following the FDA's recommendations, we removed duplicate reports based on PRIMARYID and CASEID in the DEMO file to ensure data reliability. In our analysis, we included only AE reports in which busulfan was classified as the primary suspect (PS) in the DRUG file, to enhance accuracy and efficiency. AE reports were classified into System Organ Classes (SOCs) using the preferred terms (PT) from the Medical Dictionary for Regulatory Activities (MedDRA 26.0) [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Cases with more than three records in the FAERS database were selected, and reports with missing or duplicated patient information were excluded to obtain AE reports associated with busulfan.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Data Analysis\u003c/h2\u003e \u003cp\u003eThis study employed four methods for AEs signal detection, including the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Empirical Bayesian Geometric Mean (EBGM) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Each of the four methods has its own advantages and disadvantages in terms of applicability and feasibility. Therefore, a combination of these four methods was used in this study to identify signals with strong associations. By adopting this multi-method strategy, we aimed to overcome the limitations of a single algorithm, enhance the reliability and accuracy of data mining, and thereby provide more robust support for the objectives of this study. A signal was considered positive if the ROR\u0026thinsp;\u0026ge;\u0026thinsp;1 and 95% CI (lower limit)\u0026thinsp;\u0026gt;\u0026thinsp;1, with three or more reports. For the PRR method, a PRR\u0026thinsp;\u0026ge;\u0026thinsp;2 and χ2\u0026thinsp;\u0026ge;\u0026thinsp;4, with a reported number\u0026thinsp;\u0026ge;\u0026thinsp;3 indicated a statistically significant association between the drug and the target AEs. In the BCPNN method, IC025\u0026thinsp;\u0026gt;\u0026thinsp;0 was considered significant, while in the EBGM method, EBGM05\u0026thinsp;\u0026gt;\u0026thinsp;2 was deemed significant. Detailed calculations and specific procedures are presented in Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e. To determine the differences between males and females after the use of busulfan, we referred to relevant literature [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], and adopted a modified ROR method, as shown in Supplementary Table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"3 Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Descriptive characteristics\u003c/h2\u003e \u003cp\u003eWe screened a dataset consisting of 21,838,627 reports from the FAERS database. After removing duplicates, we analyzed a total of 18,289,374 entries. The screening time frame ranged from the first quarter of 2004 to the third quarter of 2024, Ultimately, we obtained 4,761 busulfan relevant reports, among which 3,627 AEs were caused by the use of busulfan for HSCT pretreatment (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Demographic characteristics were presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. AEs associated with busulfan were more frequent in males (n\u0026thinsp;=\u0026thinsp;1460, 40.3%) than in females (n\u0026thinsp;=\u0026thinsp;1044, 28.8%). In reports involving age information, 1232 (34%), 1128 (31.1%), and 137 (3.8%) cases were reported in the age groups\u0026thinsp;\u0026lt;\u0026thinsp;18 years, 18-64.9 years and 65\u0026ndash;85 years, respectively. The country with the highest proportion of recorded information was the United States, accounting for 29.00%, followed by Japan (16.30%), France (10.00%), Canada (9.10%), and China (7.40%). The primary sources of the reports were other health experts and physicians, with 2113 cases (58.3%) and 1122 cases (30.9%) respectively. Nearly half of the outcomes were other serious outcomes (48.4%), followed by death, hospitalization, and life-threatening events, with 924 cases (25.50%), 375 cases (10.30%), and 152 cases (4.20%) respectively. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e illustrated the temporal distribution of AEs associated with busulfan use in HSCT preconditioning. A marked increase in AE reports had been observed in recent years.\u003c/p\u003e \u003cp\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\u003eThe overall demographic characteristics of AEs related to busulfan.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharacteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCase number\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCase proportion, %\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender, n (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1044\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e28.80%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1460\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40.30%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnkown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1123\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31.00%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge(years), n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1232\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34.00%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e18-64.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1128\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31.10%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e65\u0026ndash;85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e137\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.80%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.00%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnkown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e31.20%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eWeight\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e153\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.20%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e50\u0026ndash;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e126\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3.50%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026gt;\u0026thinsp;100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.40%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnkown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3335\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e91.90%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReporters, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePhysician\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1122\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30.90%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther health professional\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e58.30%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConsumer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e174\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.80%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePharmacist\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.80%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnkown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e189\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5.20%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eReported Countries, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnited States\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1053\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e29.00%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJapan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e590\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16.30%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFrance\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e362\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.00%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCanada\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e331\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9.10%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e270\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7.40%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSerious Outcome, n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e924\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25.50%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospitalization Initial or Prolonged\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e375\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10.30%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLife Threatening\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e152\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.20%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDisability\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.30%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCongenital Anomaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.00%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther serious outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1754\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e48.40%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUnkown\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e410\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e11.30%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Onset time of events\u003c/h2\u003e \u003cp\u003eA total of 418 cases of busulfan related reports with onset time were included for analysis. The median onset time is 21 days (interquartile range [IQR] 12\u0026ndash;50 days). As shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA, the majority of cases clustered within the first month after treatment of busulfan (n\u0026thinsp;=\u0026thinsp;260, 62.20%). Notably, even after one year of treatment with busulfan, AEs may still occur (n\u0026thinsp;=\u0026thinsp;27, 6.46%). The cumulative incidence curve is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB. Additionally, The Weibull distribution analysis revealed the patterns of early failures, with specific parameters detailed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eTime to onset of busulfan-associated adverse events and Weibull distribution analysis.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eDrug\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e TTO(Days)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c6\" namest=\"c4\"\u003e \u003cp\u003eWeibull distribution\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eCase reports\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eMedian(d) (lQR)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eScale parameter: α(95%Cl)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003eShape parameter: β(95%Cl)\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003eType\u003c/b\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ebusulfan\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e418\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21(12\u0026ndash;50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e53.97 (44.82\u0026ndash;63.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.60 (0.56\u0026ndash;0.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEarly failure\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Signal detection at SOC level\u003c/h2\u003e \u003cp\u003eDuring the study period, the FAERS database recorded 11,489 AEs at PT level across 27 SOC associated with busulfan in HSCT pre-transplant treatment. Figure\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows the number of reported SOC cases and their corresponding ROR values (95% CI). The top five SOC by quantity were Infections and Infestations (n\u0026thinsp;=\u0026thinsp;2,796, 24.34%; ROR\u0026thinsp;=\u0026thinsp;1.36, 95% CI: 1.3\u0026ndash;1.42), Injury, Poisoning and Procedural Complications (n\u0026thinsp;=\u0026thinsp;1,340, 11.66%; ROR\u0026thinsp;=\u0026thinsp;1.52, 95% CI: 1.43\u0026ndash;1.61), General Disorders and Administration Site Conditions (n\u0026thinsp;=\u0026thinsp;882, 7.68%; ROR\u0026thinsp;=\u0026thinsp;0.77, 95% CI: 0.72\u0026ndash;0.83), Blood and Lymphatic System Disorders (n\u0026thinsp;=\u0026thinsp;840, 7.31%; ROR\u0026thinsp;=\u0026thinsp;1.24, 95% CI: 1.15\u0026ndash;1.33), and Respiratory, Thoracic and Mediastinal Disorders (n\u0026thinsp;=\u0026thinsp;821, 7.15%; ROR\u0026thinsp;=\u0026thinsp;1.48, 95% CI: 1.37\u0026ndash;1.59). Supplementary Table \u003cspan refid=\"MOESM3\" class=\"InternalRef\"\u003eS3\u003c/span\u003e details the PRR, EBGM, and BCPNN results.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.4 Disproportionate analysis of AEs related to the use of busulfan\u003c/h2\u003e \u003cp\u003eFour different algorithms (ROR, PRR, MGPS, and BCPNN) were used for signal detection, as shown in the Venn diagram in Supplementary Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e. There were 97 PTs with positive results from all four calculation methods. The detailed analysis results are showed in Supplementary Table \u003cspan refid=\"MOESM4\" class=\"InternalRef\"\u003eS4\u003c/span\u003e. Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e summarized the top 10 SOCs with corresponding top 5 PTs and detailed values of four analysis methods. Among them, the more frequent PTs include Product Use In Unapproved Indication (n\u0026thinsp;=\u0026thinsp;707), Off Label Use (n\u0026thinsp;=\u0026thinsp;285), Venoocclusive Liver Disease (n\u0026thinsp;=\u0026thinsp;261), Mucosal Inflammation (n\u0026thinsp;=\u0026thinsp;217), Cytomegalovirus Infection (n\u0026thinsp;=\u0026thinsp;192), Cytomegalovirus Infection Reactivation (n\u0026thinsp;=\u0026thinsp;153), Febrile Neutropenia (n\u0026thinsp;=\u0026thinsp;149), Cystitis Haemorrhagic (n\u0026thinsp;=\u0026thinsp;138), Graft Versus Host Disease (n\u0026thinsp;=\u0026thinsp;132), and Sepsis(n\u0026thinsp;=\u0026thinsp;131).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSignal strength of the top 5 individual PTs under the top 10 SOCs of reported frequency.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOC (Top 10)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePTs (Top 5 per SOC)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCases, n\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eROR(95%CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePRR(χ\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eEBGM(EBGM05)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eIC(IC025)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eInfections And Infestations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCytomegalovirus Infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e192\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.27 (1.1\u0026ndash;1.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.27 (10.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.25 (1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.32 (0.11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCytomegalovirus Infection Reactivation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e153\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.98 (3.34\u0026ndash;4.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.94 (274.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.39(2.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.76 (1.51)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSepsis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e131\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.35 (1.13\u0026ndash;1.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.34 (10.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.32 (1.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.4 (0.14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBk Virus Infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.43 (1.97\u0026ndash;2.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.41 (75.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.24 (1.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.16 (0.86)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.98 (0.8\u0026ndash;1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.98 (0.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.98 (0.83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-0.03 (-0.32)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eInjury, Poisoning And Procedural Complications\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProduct Use In Unapproved Indication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e707\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.51 (4.15\u0026ndash;4.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.3 (1456.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.64 (3.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.86 (1.74)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOff Label Use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e285\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.86 (0.76\u0026ndash;0.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.86 (6.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.87 (0.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-0.2 (-0.38)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTransplant Failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.47 (1.89\u0026ndash;3.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.46 (46.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.28 (1.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.19 (0.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eToxicity To Various Agents\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.91 (0.66\u0026ndash;1.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.91 (0.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.92 (0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-0.13 (-0.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProduct Use Issue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.02 (0.7\u0026ndash;1.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.02 (0.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.02 (0.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.02 (-0.51)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eGeneral Disorders And Administration Site Conditions\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMucosal Inflammation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e217\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.11 (2.68\u0026ndash;3.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.07 (258.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.75 (2.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.46 (1.25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePyrexia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.63 (0.52\u0026ndash;0.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.63 (21.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.65 (0.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-0.63 (-0.92)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMultiple Organ Dysfunction Syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.98 (1.59\u0026ndash;2.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.97 (38.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.87 (1.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.9 (0.59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDrug Ineffective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.43 (0.33\u0026ndash;0.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.43 (48.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.44 (0.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-1.17 (-1.53)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.68 (0.51\u0026ndash;0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.68 (7.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.69 (0.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-0.54 (-0.95)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eBlood And Lymphatic System Disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFebrile Neutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e149\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.63 (1.37\u0026ndash;1.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.62 (32.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.57 (1.36)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.65 (0.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThrombotic Microangiopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e129\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.67 (1.39-2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.66 (30.98)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.6 (1.37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.68 (0.41)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.34 (1.08\u0026ndash;1.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.34 (7.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.32 (1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.4 (0.08)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePancytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.19 (0.93\u0026ndash;1.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.19 (1.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.18 (0.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.24 (-0.13)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.88 (0.68\u0026ndash;1.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.88 (0.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.89 (0.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-0.17 (-0.55)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eRespiratory, Thoracic And Mediastinal Disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRespiratory Failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e127\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.87 (1.56\u0026ndash;2.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.86 (45.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.78 (1.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.83 (0.56)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAcute Respiratory Distress Syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.63 (1.22\u0026ndash;2.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.63 (11.17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.58 (1.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.66 (0.23)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePleural Effusion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.5 (1.11\u0026ndash;2.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.49 (7.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.45 (1.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.54 (0.11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePulmonary Hypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.58 (3.23\u0026ndash;6.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.57 (88.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.82 (2.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.93 (1.44)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePulmonary Haemorrhage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.33 (2.34\u0026ndash;4.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.32 (50.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.95 (2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.56 (1.05)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eGastrointestinal Disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eStomatitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.52 (2.89\u0026ndash;4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.5 (175.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.08 (2.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.62 (1.33)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiarrhoea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.87 (0.72\u0026ndash;1.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.87 (2.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.88 (0.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-0.19 (-0.47)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.2 (0.95\u0026ndash;1.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.2 (2.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.18 (0.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.24 (-0.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.78 (0.59\u0026ndash;1.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.78 (3.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.79 (0.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-0.34 (-0.75)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGastrointestinal Haemorrhage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.26 (1.64\u0026ndash;3.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.26 (26.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.11 (1.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.08 (0.61)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eImmune System Disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGraft Versus Host Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.21 (1.02\u0026ndash;1.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.21 (4.54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.2 (1.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.26 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAcute Graft Versus Host Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.9 (0.74\u0026ndash;1.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.91 (0.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.91 (0.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-0.14 (-0.43)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHaemophagocytic Lymphohistiocytosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.13 (3.09\u0026ndash;5.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.11 (108.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.51 (2.76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.81 (1.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChronic Graft Versus Host Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.74 (0.57\u0026ndash;0.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.74 (4.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.75 (0.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-0.41 (-0.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAcute Graft Versus Host Disease In Skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.7 (0.53\u0026ndash;0.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.7 (6.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.71 (0.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-0.49 (-0.89)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eHepatobiliary Disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVenoocclusive Liver Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e261\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.12 (4.45\u0026ndash;5.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.03 (655.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4.12 (3.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.04 (1.84)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHepatic Failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.69 (1.19\u0026ndash;2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.69 (8.65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.62 (1.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.7 (0.19)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHepatic Function Abnormal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.53 (1.02\u0026ndash;2.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.53 (4.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.49 (1.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.57 (-0.02)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLiver Disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.4 (0.87\u0026ndash;2.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.39 (1.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.37 (0.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.45 (-0.22)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHepatotoxicity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.3 (0.75\u0026ndash;2.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.3 (0.89)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.28 (0.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.35 (-0.42)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eRenal And Urinary Disorders\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCystitis Haemorrhagic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.05 (2.54\u0026ndash;3.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.03 (159.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.72 (2.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.45 (1.18)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAcute Kidney Injury\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.88 (0.7\u0026ndash;1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.88 (1.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.88 (0.73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-0.18 (-0.51)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRenal Failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.87 (0.66\u0026ndash;1.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.87 (0.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.88 (0.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-0.19 (-0.58)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRenal Impairment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.55 (0.39\u0026ndash;0.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.55 (12.28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.57 (0.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-0.82 (-1.31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHaematuria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.46 (0.94\u0026ndash;2.26)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.46 (2.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.42 (0.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.51 (-0.12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eInvestigations\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePlatelet Count Decreased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.95 (0.64\u0026ndash;1.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.95 (0.07)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.95 (0.69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e-0.07 (-0.63)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBlood Bilirubin Increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.18 (0.8\u0026ndash;1.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.18 (0.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.17 (0.84)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.23 (-0.34)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBlood Follicle Stimulating Hormone Increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e18.86 (10.57\u0026ndash;33.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e18.82 (193.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e9.52 (5.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.25 (2.54)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBlood Luteinising Hormone Increased\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e25.35 (13.15\u0026ndash;48.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e25.3 (208.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e10.85 (6.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e3.44 (2.68)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCytomegalovirus Test Positive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.3 (0.8\u0026ndash;2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.3 (1.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.28 (0.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.35 (-0.33)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.5 Subgroup analysis\u003c/h2\u003e \u003cp\u003eIn Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, we listed the top 20 AEs in both male and female patients, including Product Use In Unapproved Indication, Mucosal Inflammation, Cytomegalovirus Infection, Venoocclusive Liver Disease and so on. We analyzed using a refined ROR method and found positive signals in PT such as Toxicity To Various Agents, Blood Follicle Stimulating Hormone Increased, Blood Luteinising Hormone Increased, Dyspnoea, and Posterior Reversible Encephalopathy Syndrome, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e. Supplementary Figure \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e lists the top 20 AEs with the highest reporting frequencies across different age groups of patients.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.6 Sensitivity analysis\u003c/h2\u003e \u003cp\u003eSome reports of AEs were reported by consumers. Due to potential unfamiliarity with the AEs reporting system among the consumer population, we analyzed the differences in PTs reported by health professionals compared to those reported by all type of reporter. The top 50 PTs with the most significant differences is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e. Unlike the unfiltered results, AEs such as Sepsis, Thrombocytopenia, Pleural Effusion, and Malaise did not show positive signals in the ROR and BCPNN analyses when reported by health professionals. The PT values for reports from all type of reporter and health professionals, as well as the results of the four signal detection methods, are detailed in Supplementary Table \u003cspan refid=\"MOESM5\" class=\"InternalRef\"\u003eS5\u003c/span\u003e and Supplementary Table \u003cspan refid=\"MOESM6\" class=\"InternalRef\"\u003eS6\u003c/span\u003e. Additionally, we analyzed the reports where busulfan was the only suspected drug; however, the number of cases was limited. The specific results are provided in Supplementary Table \u003cspan refid=\"MOESM7\" class=\"InternalRef\"\u003eS7\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.7 Combination therapy analysis\u003c/h2\u003e \u003cp\u003eIn clinical practice, busulfan is frequently used in combination with other agents, such as cyclophosphamide or fludarabine. We evaluated the differences in AEs between the combination of busulfan and cyclophosphamide or fludarabine. Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e presents the top 50 PTs identified in these analyses. Unlike the combination with cyclophosphamide, the analysis of busulfan in combination with fludarabine revealed that Acute Graft Versus Host Disease and Infection showed positive signals with higher frequencies in the disproportionality analysis. Additionally, AEs such as Venoocclusive Liver Disease, Mucosal Inflammation, Nausea, Pyrexia, and Infection were found to have higher reporting frequencies when busulfan was used in combination with fludarabine.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCombination therapy analysis and the top 50 PTs ranked by busulfan cases.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003ebusulfan\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003ebusulfan plus cyclophosphamide\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003ebusulfan plus fludarabine\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ea\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eROR (95%Cl)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ea\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eROR (95%Cl)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ea\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eROR (95%Cl)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003e11489\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e7073\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e9018\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProduct Use In Unapproved Indication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e707\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.51 (4.15\u0026ndash;4.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e405\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.87 (3.48\u0026ndash;4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e464\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.49 (3.16\u0026ndash;3.86)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOff Label Use\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e285\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.86 (0.76\u0026ndash;0.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e165\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.82 (0.7\u0026ndash;0.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e250\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.98 (0.86\u0026ndash;1.11)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVenoocclusive Liver Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e261\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.12 (4.45\u0026ndash;5.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.96 (3.31\u0026ndash;4.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e211\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.1 (4.39\u0026ndash;5.93)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMucosal Inflammation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e217\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.11 (2.68\u0026ndash;3.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e119\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.64 (2.18\u0026ndash;3.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e182\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.31 (2.83\u0026ndash;3.87)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCytomegalovirus Infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e192\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.27 (1.1\u0026ndash;1.48)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e151\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.65 (1.4\u0026ndash;1.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e167\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.42 (1.22\u0026ndash;1.67)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCytomegalovirus Infection Reactivation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e153\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.98 (3.34\u0026ndash;4.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.28 (3.48\u0026ndash;5.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e127\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.25 (3.51\u0026ndash;5.14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFebrile Neutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e149\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.63 (1.37\u0026ndash;1.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.33 (1.05\u0026ndash;1.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.24 (1\u0026ndash;1.53)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCystitis Haemorrhagic\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e138\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.05 (2.54\u0026ndash;3.66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.82 (3.12\u0026ndash;4.68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.08 (1.65\u0026ndash;2.63)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGraft Versus Host Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.21 (1.02\u0026ndash;1.45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e134\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.05 (1.71\u0026ndash;2.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.24 (1.02\u0026ndash;1.51)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSepsis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e131\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.35 (1.13\u0026ndash;1.61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.96 (0.74\u0026ndash;1.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.49 (1.23\u0026ndash;1.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombotic Microangiopathy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e129\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.67 (1.39\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.48 (1.16\u0026ndash;1.87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.52 (1.23\u0026ndash;1.88)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRespiratory Failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e127\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.87 (1.56\u0026ndash;2.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.94 (1.55\u0026ndash;2.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.68 (1.36\u0026ndash;2.08)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStomatitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.52 (2.89\u0026ndash;4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.1 (1.57\u0026ndash;2.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2 (1.53\u0026ndash;2.62)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVenoocclusive Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.94 (3.22\u0026ndash;4.81)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.25 (2.51\u0026ndash;4.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.05 (3.26\u0026ndash;5.03)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiarrhoea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.87 (0.72\u0026ndash;1.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.53 (0.39\u0026ndash;0.72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.57 (0.44\u0026ndash;0.74)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBk Virus Infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e103\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.43 (1.97\u0026ndash;2.99)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.37 (2.7\u0026ndash;4.22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.95 (1.52\u0026ndash;2.51)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePyrexia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e102\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.63 (0.52\u0026ndash;0.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.77 (0.62\u0026ndash;0.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e105\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.84 (0.69\u0026ndash;1.02)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePneumonia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e101\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.98 (0.8\u0026ndash;1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.99 (0.77\u0026ndash;1.27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.73 (0.56\u0026ndash;0.94)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute Graft Versus Host Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.9 (0.74\u0026ndash;1.11)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.68 (0.51\u0026ndash;0.91)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e125\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.51 (1.26\u0026ndash;1.81)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThrombocytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.34 (1.08\u0026ndash;1.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.81 (0.57\u0026ndash;1.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.25 (0.98\u0026ndash;1.61)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMultiple Organ Dysfunction Syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.98 (1.59\u0026ndash;2.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.27 (1.75\u0026ndash;2.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.79 (1.38\u0026ndash;2.31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCytomegalovirus Viraemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.87 (1.49\u0026ndash;2.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.76 (1.33\u0026ndash;2.34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.98 (1.56\u0026ndash;2.53)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute Kidney Injury\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.88 (0.7\u0026ndash;1.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.9 (0.68\u0026ndash;1.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.87 (0.67\u0026ndash;1.12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePost Transplant Lymphoproliferative Disorder\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.65 (1.3\u0026ndash;2.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.14 (1.65\u0026ndash;2.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.46 (1.11\u0026ndash;1.92)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNausea\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.2 (0.95\u0026ndash;1.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.71 (0.49\u0026ndash;1.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.18 (0.91\u0026ndash;1.54)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.96 (0.76\u0026ndash;1.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.91 (0.67\u0026ndash;1.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.68 (1.37\u0026ndash;2.07)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePancytopenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.19 (0.93\u0026ndash;1.53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.54 (1.16\u0026ndash;2.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.4 (1.07\u0026ndash;1.82)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDrug Ineffective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.43 (0.33\u0026ndash;0.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.74 (0.58\u0026ndash;0.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.65 (0.52\u0026ndash;0.82)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeptic Shock\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.33 (1.03\u0026ndash;1.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.48 (1.09\u0026ndash;2.01)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.66 (1.28\u0026ndash;2.16)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutropenia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.88 (0.68\u0026ndash;1.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.62 (0.42\u0026ndash;0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1 (0.76\u0026ndash;1.31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTransplant Failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.47 (1.89\u0026ndash;3.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.76 (2.02\u0026ndash;3.78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.48 (2.68\u0026ndash;4.51)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBacteraemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.52 (1.91\u0026ndash;3.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.61 (1.87\u0026ndash;3.64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.85 (1.31\u0026ndash;2.62)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHaemophagocytic Lymphohistiocytosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.13 (3.09\u0026ndash;5.52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.02 (2.04\u0026ndash;4.46)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.61 (2.6\u0026ndash;5.03)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenovirus Infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.32 (1.01\u0026ndash;1.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.39 (1\u0026ndash;1.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.47 (1.1\u0026ndash;1.97)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic Graft Versus Host Disease\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.74 (0.57\u0026ndash;0.97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.07 (0.8\u0026ndash;1.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.44 (1.15\u0026ndash;1.81)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal Failure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.87 (0.66\u0026ndash;1.14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.85 (0.6\u0026ndash;1.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.1 (0.84\u0026ndash;1.45)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute Graft Versus Host Disease In Skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.7 (0.53\u0026ndash;0.92)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.21 (0.92\u0026ndash;1.59)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.18 (0.92\u0026ndash;1.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVomiting\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.78 (0.59\u0026ndash;1.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.64 (0.43\u0026ndash;0.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.7 (0.5\u0026ndash;0.97)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpstein-Barr Virus Infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.04 (0.78\u0026ndash;1.39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.92 (0.63\u0026ndash;1.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.45 (1.1\u0026ndash;1.92)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute Respiratory Distress Syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.63 (1.22\u0026ndash;2.18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.18 (0.78\u0026ndash;1.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.08 (0.74\u0026ndash;1.6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDeath\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.68 (0.51\u0026ndash;0.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.9 (0.66\u0026ndash;1.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.7 (0.51\u0026ndash;0.96)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGraft Versus Host Disease In Skin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.15 (0.86\u0026ndash;1.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.3 (0.91\u0026ndash;1.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.35 (0.99\u0026ndash;1.84)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePleural Effusion\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.5 (1.11\u0026ndash;2.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.87 (1.33\u0026ndash;2.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.32 (0.93\u0026ndash;1.88)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStaphylococcal Infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.77 (1.31\u0026ndash;2.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.42 (1.74\u0026ndash;3.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.83 (1.3\u0026ndash;2.55)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMalaise\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.51 (1.1\u0026ndash;2.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.82 (0.49\u0026ndash;1.38)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.86 (0.55\u0026ndash;1.35)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAplastic Anaemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.61 (2.6\u0026ndash;5.02)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.51 (2.35\u0026ndash;5.24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5.52 (4.03\u0026ndash;7.55)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEpstein-Barr Virus Infection Reactivation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.13 (2.96\u0026ndash;5.77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.65 (3.93\u0026ndash;8.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.51 (2.37\u0026ndash;5.19)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrointestinal Haemorrhage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.26 (1.64\u0026ndash;3.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.21 (1.48\u0026ndash;3.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.43 (0.93\u0026ndash;2.21)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eViral Haemorrhagic Cystitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.77 (1.99\u0026ndash;3.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.43 (3.16\u0026ndash;6.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.64 (2.62\u0026ndash;5.07)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGraft Versus Host Disease In Gastrointestinal Tract\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e41\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.96 (0.7\u0026ndash;1.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.37 (0.98\u0026ndash;1.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.1 (0.78\u0026ndash;1.53)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eAs a classic alkylating agent and a cornerstone drug in HSCT conditioning regimens, the long-term safety of busulfan remains an important focus for ongoing monitoring. This study conducted an in-depth pharmacovigilance analysis of busulfan using the FAERS database. In addition to the maked AEs, we identified novel and unexpected AEs associated with busulfan. Furthermore, this study investigated the onset time, age, and gender differences of busulfan-related AEs, as well as performed sensitivity analyses. These findings may provide new evidence for updating drug labeling and for the rational and safe use of busulfan in clinical practice.\u003c/p\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e4.1 Basic information analysis\u003c/h2\u003e \u003cp\u003eIn the FAERS database, busulfan-related AEs were reported more frequently in male (n\u0026thinsp;=\u0026thinsp;1460, 40.3%) than female patients (n\u0026thinsp;=\u0026thinsp;1044, 28.8%). This might be due to the fact that males have a higher prevalence of the disease [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Unfortunately, most reports (91.90%) do not include patient weight information. 34% of patients were under the age of 18; The proportion of patients aged between 18-64.9 years old was 31.1%. There were individual differences in the oral absorption and metabolic rate of busulfan. Studies had shown that age was a major factor affecting the clearance rate and distribution volume of intravenous busulfan [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Almost 89.2% of AE reports were recorded by healthcare professionals. Notably, serious adverse outcomes such as hospitalization, death, and life-threatening conditions accounted for approximately 40% of busulfan-related outcomes. Reports of busulfan-associated AEs have increased annually since 2015 (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). These results emphasized the broad clinical utility and efficacy of busulfan and underscored the importance of improving the detection of busulfan-associated adverse drug events as it relates to serious AEs in the clinical setting. Busulfan, as an alkylating anticancer agent, is listed in the first group of \"hazardous drugs\" by the National Institute for Occupational Safety and Health (NIOSH) in the United States [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn this study, AEs were temporally analyzed using a Weibull distribution model to predict the likely time of occurrence of these events, and the type of AEs occurrence pattern was categorized as \u0026ldquo;early failure,\u0026rdquo; suggesting that AEs occurred primarily within a relatively short period of time. This result clearly demonstrated that the majority of AEs associated with busulfan occurred within the first month of the therapeutic intervention, which emphasized necessity of strengthening monitoring in the early stages of treatment to ensure better patient safety and outcomes.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003e4.2 AEs related to Infections And Infections\u003c/h2\u003e \u003cp\u003eIn this study, the most frequently reported SOC was Infections And Infections (n\u0026thinsp;=\u0026thinsp;2796, 24.34%, ROR: 1.36; 95% CI: 1.3\u0026ndash;1.42), with the most commonly reported events under this category being Cytomegalovirus Infection, Cytomegalovirus Infection Reactivation, Sepsis, BK Virus Infection, and Pneumonia. In an open label, randomized, phase 3 trial of busulfan plus cyclophosphamide for HSCT, the most frequent AE was infection (n\u0026thinsp;=\u0026thinsp;32, 32%) [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. In another clinical trial involving busulfan conditioning, among 24 patients, 16 patients (66%) experienced infections, and five patient deaths were caused by septic shock, with sepsis being the direct cause of the septic shock [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. This was because busulfan significantly weakens the body's immune defense capability by inhibiting bone marrow hematopoietic function and the production of immune cells (especially neutrophils and lymphocytes), thereby increasing the risk of infection [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. BK virus is a common polyomavirus that usually reactivates under immunosuppressive conditions and may lead to severe complications such as hemorrhagic cystitis and nephropathy [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Therefore, it is necessary to be vigilant about the AEs related to infections caused by busulfan, as they may be accompanied by a variety of complications.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003e4.3 AEs related to General Disorders And Administration Site Conditions and Blood and Lymphatic System Disorders\u003c/h2\u003e \u003cp\u003eMucosal Inflammation was the PT with the highest incidence rate among General Disorders And Administration Site Conditions (n\u0026thinsp;=\u0026thinsp;217, ROR: 3.11; 95% CI: 2.68\u0026ndash;3.59). In Blood and Lymphatic System Disorders (n\u0026thinsp;=\u0026thinsp;840, 7.31%, ROR: 1.24; 95% Cl: 1.15\u0026ndash;1.33), Febrile Neutropenia, Thrombotic Microangiopathy, Thrombocytopenia, and Pancytopenia all showed positive signals. However, Thrombotic Microangiopathy was not mentioned in the drug description of busulfan. Busulfan can produce ionic damage to the structure and function of DNA molecules that react with DNA and can cause blood and lymphatic diseases through mechanisms such as bone marrow suppression, immune suppression, and long-term toxicity. Long-term use of busulfan may lead to irreversible bone marrow damage such as bone marrow fibrosis, further increasing the incidence of blood diseases [\u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. In previous studies, it was found that patients with hematologic AEs often have mucosal inflammation, although some patients have mild symptoms. In a case report on busulfan HSCT conditioning, one of the four patients developed autoimmune cytopenia, which is an important complication, while three patients had mild mucosal inflammation [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. In a phase Ⅰ study of intravenous busulfan as a conditioning regimen for multiple myeloma, the 13 patients had a mean age of 73 years (range 68\u0026ndash;80 years). AEs such as neutropenia and thrombocytopenia occurred frequently. In addition, grade 3 mucositis was observed in three patients [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Therefore, for patients who use busulfan for a long time, special attention should be paid to the occurrence of bone marrow suppression and mucosal inflammation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e4.4 AEs related to Respiratory, Thoracic and Mediating Disorders\u003c/h2\u003e \u003cp\u003eAmong the AEs related to Respiratory, Thoracic And Mediastinal Disorders (n\u0026thinsp;=\u0026thinsp;821, 7.15%, ROR: 1.48; 95% CI: 1.37\u0026ndash;1.59), some AEs were described, such as Respiratory Failure (n\u0026thinsp;=\u0026thinsp;127, ROR: 1.87; 95% CI: 1.56\u0026ndash;2.25), Acute Respiratory Distress Syndrome (n\u0026thinsp;=\u0026thinsp;50, ROR: 1.63; 95% CI: 1.22\u0026ndash;2.18), Pleural Effusion (n\u0026thinsp;=\u0026thinsp;47, ROR: 1.50; 95% CI: 1.11\u0026ndash;2.02), and Pulmonary Haemorrhage (n\u0026thinsp;=\u0026thinsp;37, ROR: 3.33; 95% CI: 2.34\u0026ndash;4.74) [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. However, descriptions of Pulmonary Hypertension (n\u0026thinsp;=\u0026thinsp;40, ROR: 4.58; 95% CI: 3.23\u0026ndash;6.5) were scarce. Busulfan has pulmonary toxicity because it can damage lung epithelial cells [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. In a study of busulfan-associated pulmonary hypertension, four patients developed severe pulmonary hypertension 2 to 4.5 months after busulfan administration [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Pulmonary Hypertension is characterized by the absence, occlusion, abnormal muscularization, and perivascular inflammation of precapillary small arteries. This vascular remodeling impairs right heart function and reduces survival, with pulmonary endothelial dysfunction playing a central role [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Although the reporting of Pulmonary Hypertension is relatively rare, its high ROR value suggests that busulfan may be an important cause of Pulmonary Hypertension. In clinical practice, there should be enhanced monitoring of lung function indicators in patients using busulfan, and busulfan-induced lung injury needs timely diagnosis and intervention.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003e4.5 AEs at other SOC levels\u003c/h2\u003e \u003cp\u003eThe disproportionate analysis results indicate that AEs associated with busulfan may also affect other organs or tissues. Hepatobiliary Disorder was also a SOC with a high reporting frequency, Venoocclusive Liver Disease was the AE with the highest reported frequency and high signal strength (n\u0026thinsp;=\u0026thinsp;261, ROR: 5.12; 95% CI: 4.45\u0026ndash;5.88). Next were the Hepatic Failure, Hepatic Function Abnormal, Liver Disorder, Hepatotoxicity, all of which showed positive signals. Venoocclusive Liver Disease is the main side effect of busulfan [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e], with 50% of busulfan metabolism occurring through binding to glutathione S-transferase (GST) enzyme [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The depletion of hepatic glutathione by busulfan can lead to oxidative stress [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. In addition, busulfan can directly induce hepatocyte injury, trigger pro-inflammatory responses, and induce hepatotoxicity [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe AEs related to Renal and Urinary Disorders associated with busulfan also deserved our attention. Cystitis Haemorrhagic (n\u0026thinsp;=\u0026thinsp;138, ROR: 3.05; 95% CI: 2.54\u0026ndash;3.66) has a relatively high incidence and shows a positive signal in the disproportionality analysis. Hemorrhagic cystitis is a condition characterized by hematuria and urinary incontinence without bacterial infection [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. In a study of 960 patients undergoing HSCT transplantation, it was found that 23.8% of patients treated with busulfan developed hemorrhagic cystitis [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. Another study also showed that the incidence of hemorrhagic cystitis caused by busulfan was 36% [\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. In summary, patients taking busulfan need regular liver and kidney function tests to detect possible liver and kidney damage in the early stages.\u003c/p\u003e \u003cp\u003eIn addition, we observed that although the number of cases of Blood Follicle Stimulating Hormone Increased was relatively small (n\u0026thinsp;=\u0026thinsp;24, ROR: 18.86; 95% CI: 10.57\u0026ndash;33.64), the signal strength was very high, indicating a strong correlation with busulfan, However, this was not mentioned in the drug instructions. Nevertheless, a study has shown that busulfan has strong ovarian toxicity [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e], which was consistent with our results.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003e4.6 Based on gender and age differences\u003c/h2\u003e \u003cp\u003eAs described previously, in the FAERS database, AEs related to busulfan were reported more frequently in male patients than in female patients. Specifically, Blood And Lymphatic System Disorders such as Febrile Neutropenia (male: n\u0026thinsp;=\u0026thinsp;74, female: n\u0026thinsp;=\u0026thinsp;40) and Thrombocytopenia (male: n\u0026thinsp;=\u0026thinsp;39, female: n\u0026thinsp;=\u0026thinsp;26) occurred more frequently in male patients than in female patients. The differences in sex hormone levels between males and females may affect the sensitivity of drug targets. For example, androgens may enhance the toxicity of busulfan to hematopoietic stem cells by regulating the bone marrow microenvironment or immune response, leading to a higher incidence of bone marrow suppression in males [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. This may also be due to the higher incidence of side effects such as hemorrhagic cystitis in males compared to females [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. Estrogens might play a protective role in the bladder mucosa, resulting in a lower probability of hemorrhagic cystitis in female patients after bone marrow transplantation compared to male patients [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. The hepatotoxicity of busulfan, such as Venoocclusive Liver Disease, was more frequent in males than in females. This might be due to genetic polymorphisms (such as gene variations in the glutathione S-transferase) that might affect the metabolism and detoxification process of busulfan, and the distribution of certain genotypes might have gender differences, making males more susceptible to toxic reactions [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eBusulfan is one of the few anticancer agents utilized in children under the age of 3 years [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. It is characterized by a narrow therapeutic window and substantial inter-individual metabolic variability [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. There is a significant correlation between gender and chemotherapy related toxicity [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. A significant correlation has been observed between sex and chemotherapy-related toxicity [24091100]. Plasma concentrations of busulfan vary markedly across different age groups. Patients with low drug exposure may experience suboptimal clinical outcomes, whereas those with elevated plasma concentrations are at an increased risk of developing Venoocclusive Liver Disease risk [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. Therefore, the Pharmacist Committee of the European Society for Blood and Marrow Transplantation has recommended therapeutic drug monitoring for busulfan [\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003e4.7 Combination therapy analysis\u003c/h2\u003e \u003cp\u003eIn clinical myeloablative conditioning regimens, busulfan is commonly administered in combination with cyclophosphamide or fludarabine. To further evaluate potential disparities in AEs associated with drug combinations, we conducted a retrospective screening of the database, specifically selecting cases where either busulfan or its combination partner (cyclophosphamide/fludarabine) was designated as the primary suspected agent, while the other drugs were classified as concomitant medications or secondary suspected agents. AEs such as Acute Graft Versus Host Disease, Infection in the busulfan combined with fludarabine regimen had positive results in the disproportionate analysis compared to busulfan combined with cyclophosphamide. This might be attributed to the fact that busulfan primarily targets myeloid cells, while fludarabine is a potent lymphocyte inhibitor. The combination of these two agents may lead to more profound T-cell depletion, thereby affecting immune reconstitution [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]. In a study based on myeloablative conditioning regimens of busulfan-fludarabine or treosulfan-fludarabine, the 2-year overall survival rate after busulfan-fludarabine conditioning was 92.7%, with the main causes of death being infection, graft-versus-host disease, and rejection [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]. However, in another study, the regimen-related toxicity and transplant-related mortality of the busulfan and fludarabine conditioning regimen were lower than those of the busulfan and cyclophosphamide regimen [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e]. Leukemia recurrence remains a major issue [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Therefore, in clinical practice, it is essential to weigh the anti-leukemia efficacy against toxicity and optimize outcomes through individualized medication and intensified supportive treatment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003e4.8 Limitations\u003c/h2\u003e \u003cp\u003eThis study represents the most comprehensive real-world pharmacovigilance analysis to date, systematically evaluating the post market safety of busulfan. Firstly, the FAERS database may be subject to underreporting or incomplete reporting. For instance, less severe or common adverse events such as nausea and vomiting may be underreported, while rare events may be overreported [\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]. In our collected AE reports, 91.9% lacked patient weight information. Therefore, potential biases introduced by the data should be carefully considered when interpreting the results [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e]. Secondly, there is a lack of detailed clinical information regarding patients, such as comorbidities and the severity of underlying diseases, which may affect the assessment of drug interactions [\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e]. Thirdly, the impact of dose intensity on the incidence of adverse reactions and survival rates after transplantation was not considered [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e]. Despite these limitations, which are inherent to pharmacovigilance studies using the FAERS database, the comprehensive characterization of busulfan-related AEs in this study may provide valuable insights for the safe use of the drug and further clinical research.\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Summary","content":"\u003cp\u003eIn this comprehensive pharmacovigilance analysis utilizing the FAERS database, we systematically evaluated the AEs associated with busulfan use in pre-transplant conditioning for HSCT. Our findings have unveiled several key safety considerations:\u003c/p\u003e \u003cp\u003eAge-related vulnerability: Patients under the age of 65 exhibited a higher rate of AE reporting, indicating the need for heightened vigilance in this population. Key organ toxicities: Our data underscore the importance of monitoring liver and kidney function, close hematologic surveillance of myelosuppression, and therapeutic drug monitoring. Additionally, for emerging safety signals: Clinicians should enhance their awareness of potentially serious but less frequently reported AEs, including pulmonary arterial hypertension, thrombotic microangiopathy, and endocrine disorders (elevated levels of follicle-stimulating hormone and luteinizing hormone). These findings provide important real-world evidence to guide risk assessment and monitoring strategies in clinical practice. Further prospective studies are warranted to validate these observations and elucidate the underlying mechanisms.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets involved in this study are included in the article/supplementary materials. If you have any questions, please contact the corresponding authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Research Fund of the Central Hospital of Wuhan (grant number 23YJ03).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eX-WY: Conceptualization, Writing\u0026ndash;original draft, Writing\u0026ndash;review and editing, Data curation, Investigation, Methodology, Funding acquisition. W-LX: Conceptualization, Writing\u0026ndash;review and editing, Software. JF: Writing\u0026ndash;review and editing, Formal analysis. J-FW: Writing\u0026ndash;review and editing. YL: Writing\u0026ndash;review and editing. J-YL: Writing\u0026ndash;review and editing, Validation. A-PD: Writing\u0026ndash;review and editing, Project administration. Y-JL: Writing\u0026ndash;review and editing, Project administration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe sincerely acknowledge the support from the Department of Pharmacy at Wuhan Central Hospital.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eP.A. Brown, B. Shah, A. Advani, et al., Acute Lymphoblastic Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology, J Natl Compr Canc Netw. 19 (2021) 1079-1109. https://doi.org/10.6004/jnccn.2021.0042.\u003c/li\u003e\n\u003cli\u003eX.H. Zhang, J. Chen, M.Z. 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Flossdorf, et al., Impact of busulfan versus treosulfan dose intensity in myelofibrosis undergoing hematopoietic cell transplantation, Am J Hematol. 99 (2024) 1540-1549. https://doi.org/10.1002/ajh.27363.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"busulfan, hematopoietic stem cell transplantation, the food and drug adverse event reporting system, database, adverse events, real-world study","lastPublishedDoi":"10.21203/rs.3.rs-6454932/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6454932/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground:\u003c/h2\u003e \u003cp\u003e Busulfan had been approved as a pre-transplant conditioning agent for allogeneic hematopoietic stem cell transplantation (HSCT) in chronic myeloid leukemia. However, the real-world data on its safety in a large sample population is imprecise. We assessed the adverse signals associated with busulfan specifically used as a pre-transplant conditioning agent for HSCT through data mining of the FDA pharmacovigilance database.\u003c/p\u003e\u003ch2\u003eMethod:\u003c/h2\u003e \u003cp\u003eThis article extracted adverse events (AEs) from the FAERS database from the first quarter of 2004 to the third quarter of 2024, and determined the signal strength of AEs using Reporting Odds Ratio, Proportional Reporting Ratio, Bayesian Confidence Propagation Neural Network, and Empirical Bayesian Geometric Mean.\u003c/p\u003e\u003ch2\u003eResult:\u003c/h2\u003e \u003cp\u003eThe study identified 3627 AE reports associated with busulfan limited indication for pre-transplant conditioning for HSCT, with 11489 Preferred Terms-annotated entries. The most frequently reported AEs were primarily categorized under Infections And Infestations, Injury, Poisoning And Procedural Complications. Notably, some AEs, such as Pulmonary Hypertension, Thrombotic Microangiopathy is not mentioned in the drug labeling. In the disproportionality analysis, Blood Follicle Stimulating Hormone Increased and Blood Luteinising Hormone Increased had high ROR value. We screened the concomitant medication reports with HSCT pre-conditioning as the indication and found that, in the reports of busulfan in combination with fludarabine, the AEs of Acute Graft Versus Host Disease, Infection showed positive results in the disproportionality analysis, which is different from the combination with cyclophosphamide.\u003c/p\u003e\u003ch2\u003eConclusion:\u003c/h2\u003e \u003cp\u003eIn recent years, busulfan has been mainly used for HSCT conditioning treatment rather than the initial treatment of chronic myeloid leukemia. In this study, we screened the AE reports of busulfan applied to HSCT pre-transplantation treatment in the FAERS database to demonstrate more precisely the AEs occurring in the current clinical application of busulfan. Further disproportionality analysis provides useful information for the clinical application of busulfan, which is expected to promote its safe use in clinical practice.\u003c/p\u003e","manuscriptTitle":"Adverse Events Associated with Busulfan in HSCT Pre-Transplant Conditioning: A Retrospective Pharmacovigilance Study of the FAERS Database","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-29 12:49:36","doi":"10.21203/rs.3.rs-6454932/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"239a9c33-d17e-424f-b798-d182a58feaa5","owner":[],"postedDate":"May 29th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-17T20:24:32+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-29 12:49:36","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6454932","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6454932","identity":"rs-6454932","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}