Enasidenib causes clinically relevant rosuvastatin accumulation leading to toxic myopathy

Enasidenib causes clinically relevant rosuvastatin accumulation leading to toxic myopathy | 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 Case Report Enasidenib causes clinically relevant rosuvastatin accumulation leading to toxic myopathy George Mason, Catelyn Cashion, Jonathon Parratt, William Stevenson This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3949825/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 A woman in her 80s developed AML while on rosuvastatin secondary prevention. IDH2 mutation was identified and Enasidenib was commenced as second line therapy and later presented with clinical, biochemical and radiographic evidence of myositis, without an alternative cause. We report the first case of enasidenib induced statin toxic myopathy, and discuss implications for AML patients most likely to receive this therapy. Enasidenib Rosuvastatin Toxic Myopathy AML Drug-Drug interaction Figures Figure 1 Figure 2 Full Text A woman in her 80s presented for investigation into a non-healing right lower leg ulcer and new neutropenia (0.7x10 9 /L) lead to a diagnosis of AML. An IDH2 c.515 G>A (p.Arg172Lys) variant was detected by digital droplet PCR. She was given low dose cytarabine and thioguanine but discontinued therapy after two cycles due to non-healing ulcers. Therapy was switched to enasidenib 100mg daily. She had been commenced on rosuvastatin 40mg daily and dabigatran 110mg twice-a-day 4 years prior due to an ischemic stroke. After 10 months of enasidenib, she experienced 3 days of lethargy, nausea and bilateral lower limb weakness. Weakness improved over a 3 week period, but worsened precipitously after enasidenib reintroduction (figure 1). At worst, examination demonstrated symmetrically reduced 2/5 hip flexion and inability to walk. Creatine kinase (CK) values were elevated alongside Creatinine. Cerebral computed tomography demonstrated evidence of prior ischemic infarction, and spinal cord magnetic resonance imaging (MRI) was unremarkable. Electromyography was consistent with myopathy, and anti-HMG-CoA reductase antibodies were not detected. MRI of the legs demonstrated abnormal proximal muscle hyperintensity (figure 2). She recommenced Enasidenib two weeks after recovery without recurrent biochemical derrangement or weakness. She passed away of AML 16 months from diagnosis. Enasidenib is an oral IDH2 inhibitor approved by the FDA for use in elderly patients with relapse or refractory IDH2 mutated AML. Oral monotherapy is aimed at achieving a balance of disease control and minimising toxicity associated with cytotoxic regimens. Enasidenib efficacy was demonstrated in a Phase 3 study [1] for patients with relapsed or refractory AML over 60 years of age, with 9% of patients over the age of 80. Our patient was intolerant of low-intensity cytotoxic therapy and enasidenib provided a targeted option for her IDH2 mutated AML given her age and comorbidities. As exhibited by this case, drug-drug interactions need to be considered as a contributor to the toxicity-benefit estimation. An off-target effect of enasidenib is inhibition of the clearance of BCRP/ABCG2 substrates [2]. Rosuvastatin is a substrate of BCRP [3], a property in which it differs notably from other commonly prescribed statins such as atorvastatin. Exclusion of other causes including HMG-CoA-directed antibody mediated necrotizing myositis and time-course of myositis resolution (figure 1) are consistent with statin toxic myopathy. Statins are ubiquitous in the older population most likely to receive oral monotherapy for AML, yet there is controversy in this age group regarding the purported benefit of statins. Indeed guidelines recommend statin use should only be considered in patients with at least 3 years life expectancy [4] due to the treatment duration required to establish benefit. This is the first published report that enasidenib can lead to overt statin toxic myopathy. Therefore initiation of enasidenib monotherapy should trigger discontinuation of rosuvastatin specifically, and potentially statin therapy altogether. Declarations Author Contributions: GM conceptualized, collected data and wrote the manuscript. CC, WS and JP revised the manuscript. The authors received no financial support for the research, authorship and publication of this article. This project did not meet the NHMRC National Statement on Ethical Conduct in Human Research 2007 (Updated 2018) definition of human research and therefore was confirmed as exempt from HREC review by the NSLHD Research Office. The authors have no relevant financial or non-financial interests to declare. Written informed consent was obtained via the next-of-kin as the subject was deceased at the time of writing. References de Botton S, Montesinos P, Schuh AC et al. Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial. Blood. 2023; 141 (2):156-167. Cheng Y, Wang X, Tong Z, et al. Assessment of transporter-mediated drug interactions for enasidenib based on a cocktail study in patients with relapse or refractory acute myeloid leukemia or myelodysplastic syndrome. J Clin Pharmacol . 2011; 62 (4):494-504. Rosuvastatin Product Information Kinoshita M, Yokote K, Arai H, et al. Committee for Epidemiology and Clinical Management of Atherosclerosis. Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017. J Atheroscler Thromb. 2018; 25 (9):846-984. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3949825","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":273481807,"identity":"13b8f11b-df78-48b4-add9-6408281b3e53","order_by":0,"name":"George Mason","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABKklEQVRIiWNgGAWjYLCCj39s6vuB9AEgZmwAC7Hh18E4syENiEnRwszbcIhxwwGofoJa5MMOP/7Mu+MAs/GN3IMHGP4clt3O3mPA8KHsMAP/jASsWgxvp5lJzj1zh83sRl7CAca2w8Y7e84YMM44d5hB4gYOLbMTzBjesD3jMbuRY3CAseFw4gYgg5m37TADA04t6Z8/8LAdljCeAdQCdFjihvtvDJj/ArXI49AiL51jIAk008BAAqSFDWQLjwEz0IUMBji0GEjnlEnOOJOWIHHmjcGBxLZ04w1n0goO9pxL5zE88wC7LbPTN3/4UGGTwN+eY/zhwx9r2Q3HD2988KPMWk7uOA5bDiDzEhiagSQHWJAHq3qQLQ2o/DogZsfuoFEwCkbBKBixAAAjo29LxxU17wAAAABJRU5ErkJggg==","orcid":"","institution":"Royal North Shore Hospital","correspondingAuthor":true,"prefix":"","firstName":"George","middleName":"","lastName":"Mason","suffix":""},{"id":273481808,"identity":"5272c25c-8b79-4949-b62b-787a871af477","order_by":1,"name":"Catelyn Cashion","email":"","orcid":"","institution":"Royal North Shore Hospital","correspondingAuthor":false,"prefix":"","firstName":"Catelyn","middleName":"","lastName":"Cashion","suffix":""},{"id":273481809,"identity":"c42a7cd7-a790-4d43-b20f-166285db7d3c","order_by":2,"name":"Jonathon Parratt","email":"","orcid":"","institution":"University of Sydney","correspondingAuthor":false,"prefix":"","firstName":"Jonathon","middleName":"","lastName":"Parratt","suffix":""},{"id":273481810,"identity":"3b8d4b83-5ef7-4713-b54d-33ccede783fa","order_by":3,"name":"William Stevenson","email":"","orcid":"","institution":"Royal North Shore Hospital","correspondingAuthor":false,"prefix":"","firstName":"William","middleName":"","lastName":"Stevenson","suffix":""}],"badges":[],"createdAt":"2024-02-12 01:18:22","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3949825/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3949825/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51389366,"identity":"e6d1ae03-b30d-4b07-a28e-c4b3fde98216","added_by":"auto","created_at":"2024-02-20 18:11:04","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":85454,"visible":true,"origin":"","legend":"\u003cp\u003eTimeline of clincal progress and biochemical results.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-3949825/v1/e9fded43b2384a071a49cdd2.png"},{"id":51389365,"identity":"5493151a-0ffa-4db9-8ee5-3f805f0d9304","added_by":"auto","created_at":"2024-02-20 18:11:04","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":223708,"visible":true,"origin":"","legend":"\u003cp\u003eMRI demonstration of myositis. Abnormal hyperintensitities seen in the bilateral iliacus (blue arrows), gluteus minimus, hamstrings with asymmetrical involvement of the left proximal muscle rectus femoris muscle (orange arrow)\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-3949825/v1/e62f0464e334ae6c10be60fb.png"},{"id":54717415,"identity":"fb102a0a-9da2-4831-afcb-c3f6aa8098df","added_by":"auto","created_at":"2024-04-15 16:15:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":458476,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3949825/v1/007937fa-1662-4498-bf49-fed95fc63256.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eEnasidenib causes clinically relevant rosuvastatin accumulation leading to toxic myopathy\u003c/p\u003e","fulltext":[{"header":"Full Text","content":"\u003cp\u003eA\u0026nbsp;woman in her 80s\u0026nbsp;presented for investigation into a non-healing right lower leg ulcer and new neutropenia (0.7x10\u003csup\u003e9\u003c/sup\u003e/L) lead to a diagnosis of AML. An IDH2 c.515 G\u0026gt;A (p.Arg172Lys) variant was detected by digital droplet PCR. She was given low dose cytarabine and thioguanine but discontinued therapy after two cycles due to non-healing ulcers. Therapy was switched to enasidenib 100mg daily. \u0026nbsp;She had been commenced on rosuvastatin 40mg daily and dabigatran 110mg twice-a-day 4 years prior due to an ischemic stroke.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;After 10 months of enasidenib, she experienced 3 days of lethargy, nausea and bilateral lower limb weakness. Weakness improved over a 3 week period, but worsened precipitously after enasidenib reintroduction (figure 1).\u0026nbsp;\u003c/p\u003e\u003cp\u003eAt worst, examination demonstrated symmetrically reduced 2/5 hip flexion and inability to walk. Creatine kinase (CK) values were elevated alongside Creatinine. Cerebral computed tomography demonstrated evidence of prior ischemic infarction, and spinal cord magnetic resonance imaging (MRI) was unremarkable. Electromyography was consistent with myopathy, and anti-HMG-CoA reductase antibodies were not detected. MRI of the legs demonstrated abnormal proximal muscle hyperintensity (figure 2). She recommenced Enasidenib two weeks after recovery without recurrent biochemical derrangement or weakness. She passed away of AML 16 months from diagnosis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEnasidenib is an oral IDH2 inhibitor approved by the FDA for use in elderly patients with relapse or refractory IDH2 mutated AML. Oral monotherapy is aimed at achieving a balance of disease control \u0026nbsp;and minimising toxicity associated with cytotoxic regimens. Enasidenib efficacy was demonstrated in a Phase 3 study [1] for patients with relapsed or refractory AML over 60 years of age, with 9% of patients over the age of 80. Our patient was intolerant of low-intensity cytotoxic therapy and enasidenib provided a targeted option for her IDH2 mutated AML given her age and comorbidities.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAs exhibited by this case, drug-drug interactions need to be considered as a contributor to the toxicity-benefit estimation. An off-target effect of enasidenib is inhibition of the clearance of BCRP/ABCG2 substrates [2]. Rosuvastatin is a substrate of BCRP [3], a property in which it differs notably from other commonly prescribed statins such as atorvastatin. Exclusion of other causes including HMG-CoA-directed antibody mediated necrotizing myositis and time-course of myositis resolution (figure 1) are consistent with statin toxic myopathy. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eStatins are ubiquitous in the older population most likely to receive oral monotherapy for AML, yet there is controversy in this age group regarding the purported benefit of statins. Indeed guidelines recommend statin use should only be considered in patients with at least 3 years life expectancy [4] due to the treatment duration required to establish benefit.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis is the first published report that enasidenib can lead to overt statin toxic myopathy. Therefore initiation of enasidenib monotherapy should trigger discontinuation of rosuvastatin specifically, and potentially statin therapy altogether.\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u003c/strong\u003e GM conceptualized, collected data and wrote the manuscript. CC, WS and JP revised the manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors received no financial support for the research, authorship and publication of this article. This project did not meet the NHMRC National Statement on Ethical Conduct in Human Research 2007 (Updated 2018) definition of human research and therefore was confirmed as exempt from HREC review by the NSLHD Research Office. The authors have no relevant financial or non-financial interests to declare. Written informed consent was obtained via the next-of-kin as the subject was deceased at the time of writing.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ede Botton S, Montesinos P, Schuh AC et al. Enasidenib vs conventional care in older patients with late-stage mutant-IDH2 relapsed/refractory AML: a randomized phase 3 trial. Blood. 2023;\u003cstrong\u003e141\u003c/strong\u003e(2):156-167.\u003c/li\u003e\n\u003cli\u003eCheng Y, Wang X, Tong Z, et al. Assessment of transporter-mediated drug interactions for enasidenib based on a cocktail study in patients with relapse or refractory acute myeloid leukemia or myelodysplastic syndrome. \u003cem\u003eJ Clin Pharmacol\u003c/em\u003e. 2011;\u003cstrong\u003e62\u003c/strong\u003e(4):494-504.\u003c/li\u003e\n\u003cli\u003eRosuvastatin Product Information\u003c/li\u003e\n\u003cli\u003eKinoshita M, Yokote K, Arai H, et al. Committee for Epidemiology and Clinical Management of Atherosclerosis. Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017. J Atheroscler Thromb. 2018;\u003cstrong\u003e25\u003c/strong\u003e(9):846-984.\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":"Enasidenib, Rosuvastatin, Toxic Myopathy, AML, Drug-Drug interaction","lastPublishedDoi":"10.21203/rs.3.rs-3949825/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3949825/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA woman in her 80s developed AML while on rosuvastatin secondary prevention. IDH2 mutation was identified and Enasidenib was commenced as second line therapy and later presented with clinical, biochemical and radiographic evidence of myositis, without an alternative cause. 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