{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T15:16:03Z","timestamp":1789139763040,"version":"build-2803163510"},"reference-count":26,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T00:00:00Z","timestamp":1767657600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jilin Provincial Science and Technology Department Project","award":["YDZJ202401092ZYTS"],"award-info":[{"award-number":["YDZJ202401092ZYTS"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Cyclophosphamide(CHOP) is a widely used chemotherapeutic agent belonging to the class of alkylating agents. It primarily inhibits the proliferation of tumor cells by interfering with DNA replication and transcription. CHOP has been approved for the treatment of various types of malignant tumors. The aim of this research is to assess adverse events linked to CHOP using real-world data.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This research collected and analyzed adverse event reports associated with CHOP from the FAERS(US Food and Drug Administration Adverse Event Reporting System) database spanning from the first quarter of 2004 to the third quarter of 2024. This study leveraged the FAERS database, extracting reports submitted exclusively by healthcare professionals where CHOP was designated as the primary suspect (PS). Four risk signal detection methods were employed: Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multiitem Gamma Poisson Shrinker (MGPS), to conduct a comprehensive analysis of CHOP-related ADRs.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of 3,625 adverse event reports with CHOP as the primary suspect drug were obtained. Across 25 system organ classes (SOCs), four positive Preferred Terms(PTs) signals were detected. The most significant signal in SOCs was \u201cblood and lymphatic system disorders\u201d (ROR\u2009=\u20096.64, 95% CI 6.49\u20136.79), while the most significant PTs signal was \u201chigh grade B-cell lymphoma Burkitt-like lymphoma recurrent\u201d (ROR\u2009=\u2009613.63, 95% CI 123.85\u20133040.40).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study provides compelling evidence of the presence of CHOP seven unexpected off-label AEs were also observed, such as mucoepidermoid carcinoma, hypotelorism of orbit, breakthrough COVID-19, airway remodeling, meningitis enteroviral, acute graft versus host disease, and gastrosplenic fistula. Additionally, the combination of CHOP and radiotherapy increased the risk of several severe AEs, such as hemorrhagic cystitis. These findings highlight the importance of caution when prescribing CHOP to high-risk individuals with a history of meningitis, cystitis or airway obstruction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0339757","type":"journal-article","created":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T19:16:20Z","timestamp":1767726980000},"page":"e0339757","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":4,"title":["Adverse events associated with cyclophosphamide: A pharmacovigilance study using the FDA adverse event reporting system"],"prefix":"10.1371","volume":"21","author":[{"given":"Hui","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghao","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dexi","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9485-1839","authenticated-orcid":true,"given":"Yujuan","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,1,6]]},"reference":[{"issue":"3","key":"pone.0339757.ref001","doi-asserted-by":"crossref","first-page":"957","DOI":"10.3390\/ijms21030957","article-title":"Low dose cyclophosphamide modulates tumor microenvironment by TGF-\u03b2 signaling pathway","volume":"21","author":"H Zhong","year":"2020","journal-title":"Int J Mol Sci"},{"issue":"1","key":"pone.0339757.ref002","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/ajd.12406","article-title":"Cyclophosphamide in dermatology","volume":"58","author":"J Kim","year":"2017","journal-title":"Australas J Dermatol"},{"issue":"11","key":"pone.0339757.ref003","doi-asserted-by":"crossref","DOI":"10.1002\/pbc.29687","article-title":"Intracranial desmoplastic small round cell tumor after childhood acute myeloid leukemia treated with metronomic oral cyclophosphamide","volume":"69","author":"N S\u00e1nchez-Sierra","year":"2022","journal-title":"Pediatr Blood Cancer"},{"issue":"18","key":"pone.0339757.ref004","doi-asserted-by":"crossref","first-page":"2820","DOI":"10.1182\/blood-2014-05-573642","article-title":"Moderate-dose cyclophosphamide for severe aplastic anemia has significant toxicity and does not prevent relapse and clonal evolution","volume":"124","author":"P Scheinberg","year":"2014","journal-title":"Blood"},{"issue":"4","key":"pone.0339757.ref005","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1007\/s00280-016-3152-1","article-title":"The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy","volume":"78","author":"M Ahlmann","year":"2016","journal-title":"Cancer Chemother Pharmacol"},{"key":"pone.0339757.ref006","first-page":"4965171","article-title":"The role of antioxidants in ameliorating cyclophosphamide-induced cardiotoxicity","volume":"2020","author":"MA Ayza","year":"2020","journal-title":"Oxid Med Cell Longev"},{"key":"pone.0339757.ref007","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.bbrc.2022.03.098","article-title":"Cyclophosphamide-induced GPX4 degradation triggers parthanatos by activating AIFM1","volume":"606","author":"L Liu","year":"2022","journal-title":"Biochem Biophys Res Commun"},{"issue":"4","key":"pone.0339757.ref008","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1080\/14740338.2024.2327503","article-title":"Data mining and safety analysis of traditional immunosuppressive drugs: a pharmacovigilance investigation based on the FAERS database","volume":"23","author":"J-J Li","year":"2024","journal-title":"Expert Opin Drug Saf"},{"key":"pone.0339757.ref009","article-title":"Assessing the risk of tumor lysis syndrome associated with the use of antineoplastic agents: a real-world pharmacovigilance study based on the FDA adverse event reporting system database","volume":"15","author":"D Li","year":"2024","journal-title":"Ther Adv Drug Saf"},{"issue":"12","key":"pone.0339757.ref010","article-title":"Urotoxicity of cyclophosphamide: a comparison across neoplastic, autoimmune, and transplant indications","volume":"16","author":"JH Gu","year":"2024","journal-title":"Cureus"},{"issue":"2","key":"pone.0339757.ref011","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1089\/bio.2021.0159","article-title":"Protective effects of antioxidants on cyclophosphamide-induced ovarian toxicity","volume":"21","author":"RS Barberino","year":"2023","journal-title":"Biopreserv Biobank"},{"key":"pone.0339757.ref012","first-page":"5096825","article-title":"Potential protective effects of antioxidants against cyclophosphamide-induced nephrotoxicity","volume":"2022","author":"MA Ayza","year":"2022","journal-title":"Int J Nephrol"},{"issue":"5","key":"pone.0339757.ref013","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1159\/000507690","article-title":"Multiple myeloma in the time of COVID-19","volume":"143","author":"AS Al Saleh","year":"2020","journal-title":"Acta Haematol"},{"key":"pone.0339757.ref014","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.intimp.2018.05.014","article-title":"Combination of 4-hydroperoxy cyclophosphamide and methotrexate inhibits IL-6\/sIL-6R-induced RANKL expression in fibroblast-like synoviocytes via suppression of the JAK2\/STAT3 and p38MAPK signaling pathway","volume":"61","author":"H-Q Niu","year":"2018","journal-title":"Int Immunopharmacol"},{"key":"pone.0339757.ref015","doi-asserted-by":"crossref","first-page":"217119","DOI":"10.1016\/j.canlet.2024.217119","article-title":"\u201cCyclophosphamide and analogues; a matter of dose and schedule for dual anticancer activities\u201d","volume":"598","author":"J Delahousse","year":"2024","journal-title":"Cancer Lett"},{"issue":"2","key":"pone.0339757.ref016","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1177\/1078155220920690","article-title":"Incidence of hemorrhagic cystitis after cyclophosphamide therapy with or without mesna: a cohort study and comprehensive literature review","volume":"27","author":"HM Almalag","year":"2021","journal-title":"J Oncol Pharm Pract"},{"issue":"3","key":"pone.0339757.ref017","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1080\/1744666X.2020.1724091","article-title":"A systematic review and meta-analysis of the gonadotoxic effects of cyclophosphamide and benefits of gonadotropin releasing hormone agonists (GnRHa) in women of child-bearing age with autoimmune rheumatic disease","volume":"16","author":"S-N Luong","year":"2020","journal-title":"Expert Rev Clin Immunol"},{"key":"pone.0339757.ref018","doi-asserted-by":"crossref","first-page":"173310","DOI":"10.1016\/j.ejphar.2020.173310","article-title":"Tropisetron ameliorates cyclophosphamide-induced hemorrhagic cystitis in rats","volume":"883","author":"MR Zirak","year":"2020","journal-title":"Eur J Pharmacol"},{"issue":"1","key":"pone.0339757.ref019","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1007\/BF00442410","article-title":"Cyclophosphamide cardiotoxicity","volume":"134","author":"G von Bernuth","year":"1980","journal-title":"Eur J Pediatr"},{"issue":"01","key":"pone.0339757.ref020","first-page":"27","article-title":"Progress in the reproductive toxicity of CHOP","volume":"5","author":"X Zhang","year":"2018","journal-title":"China Res Hosp"},{"issue":"04","key":"pone.0339757.ref021","first-page":"383","article-title":"Cardiac toxicity caused by conventional dose CHOP in childhood leukemia: a case report","volume":"6","author":"YM Yang","year":"2014","journal-title":"Chin Int Trad Chin West Med Ped"},{"issue":"06","key":"pone.0339757.ref022","first-page":"449","article-title":"Clinical application of CHOP and its toxicity prevention and treatment","volume":"40","author":"J Liu","year":"2019","journal-title":"Stud Jilin Univ Med Newspaper"},{"issue":"9","key":"pone.0339757.ref023","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1093\/rheumatology\/kez598","article-title":"Long term follow-up of Beh\u00e7et\u2019s syndrome patients treated with cyclophosphamide","volume":"59","author":"M Gurcan","year":"2020","journal-title":"Rheumatology (Oxford)"},{"issue":"6","key":"pone.0339757.ref024","first-page":"926","article-title":"A survey on gastrointestinal adverse drug reactions of doxorubicin and cyclophosphamide combination therapy","volume":"68","author":"J Jamali","year":"2018","journal-title":"J Pak Med Assoc"},{"issue":"4","key":"pone.0339757.ref025","doi-asserted-by":"crossref","first-page":"416","DOI":"10.31662\/jmaj.2021-0015","article-title":"Pattern of adverse drug reactions associated with the use of anticancer drugs in an oncology-based hospital of Nepal","volume":"5","author":"R Tamang","year":"2022","journal-title":"JMA J"},{"issue":"6","key":"pone.0339757.ref026","doi-asserted-by":"crossref","DOI":"10.1111\/aji.70014","article-title":"Cyclophosphamide-induced infertility and the impact of antioxidants","volume":"92","author":"M Abdi","year":"2024","journal-title":"Am J Reprod Immunol"}],"container-title":["PLOS 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