Effect of an Excess Dose of Cladribine on the Subsequent Therapeutic Regimen and Pregnancy

Effect of an Excess Dose of Cladribine on the Subsequent Therapeutic Regimen and Pregnancy | 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 Effect of an Excess Dose of Cladribine on the Subsequent Therapeutic Regimen and Pregnancy Eliza Babych, Yuliia Solodovnikova This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8712615/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 Cladribine is an oral immune reconstitution therapy approved for the treatment of highly active relapsing–remitting multiple sclerosis. It selectively reduces CD4 + and CD8 + T lymphocytes, induces an immune reconstitution effect, and enables a short treatment course with durable disease control. Although generally well tolerated, it is associated with dose-dependent adverse effects, most notably severe (grade III–IV) lymphopenia, reported in up to 40% of patients, particularly during the second treatment year. Strict adherence to weight-based dosing is therefore essential. Miscalculations of cumulative doses may lead to prolonged immunosuppression and related complications. We report a rare clinical case of excessive cumulative cladribine dosing and its subsequent clinical, hematological, and reproductive outcomes. To our knowledge, this is the first reported case describing the consequences of exceeding the cladribine dosage in multiple sclerosis. multiple sclerosis cladribine excessive dose Introduction Cladribine is an oral disease-modifying therapy (DMT) for highly active multiple sclerosis (MS) that selectively reduces CD4 + and CD8 + T lymphocytes, inducing an immune reconstitution effect and enabling a short treatment course with durable remission [1]. However, its mechanism of action carries a significant risk of lymphopenia, making precise weight-based dose calculation crucial. According to the literature, up to 40% of patients develop ≥ III grade lymphopenia usually during the second year of treatment [2–5]. We present a rare case report describing the therapeutic and pregnancy outcomes following administration of an excessive dose of cladribine in a patient with MS. Case report A 30-year-old woman with highly active relapsing-remitting MS (EDSS 5.5, disease duration 5 years) previously treated with teriflunomide and ponesimod received a first-year cladribine course at 1.75 mg/kg (body weight 40 kg). The course was followed by transient episodes of pelvic dysfunction, ataxia, oculomotor disturbances, and facial paralysis, with no changes in leukocyte counts. In the second year, she received an excessive cumulative 1-st dose of 1,33 mg/kg vs the routine 0,875 mg/kg. One month later, severe asymptomatic lymphopenia (0.2 × 10³ cells/µL) developed and persisted for six months before spontaneous recovery to 0.8 × 10³ cells/µL. Thus, the final scheduled dose was postponed and later administered per protocol, which the patient tolerated well. After 2 years of follow-up, the patient had remained clinically stable without disease progression and became pregnant. The patient’s first pregnancy was complicated by a spontaneous abortion at 14 weeks’ gestation. Ten months later, she conceived again and delivered a healthy baby by cesarean section. Discussion and Conclusion To our knowledge, this is the first reported case of excessive cumulative cladribine dosage in MS. This case highlights both the hematological risks associated with overdosing and the potential for immune recovery and sustained disease stability. Cladribine is a highly effective therapeutic option for MS patients. However, due to its profound lymphocyte-depleting effect, overdosing can lead to severe, potentially life-threatening lymphopenia and increased susceptibility to latent infection reactivation. Strict adherence to weight-based dosing and regular lymphocyte monitoring are crucial for ensuring treatment safety and optimal long-term outcomes. Declarations Conflict of interest The authors declare that they have no conflict of interest to disclose. No funds, grants, or other support were received. Ethics approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Odesa National Medical University. Consent to participate Verbal informed consent was obtained prior to the interview. Consent to publish The participant has consented to the submission of the case report to the journal. Availability of Data and Materials The data that support the findings of this study are available from the corresponding author upon reasonable request. References Zanetta, C., Rocca, M. A., Meani, A., Martinelli, V., Ferrè, L., Moiola, L., & Filippi, M. (2023). Effectiveness and safety profile of cladribine in an Italian real-life cohort of relapsing-remitting multiple sclerosis patients: a monocentric longitudinal observational study. Journal of neurology, 270(7), 3553–3564. https://doi.org/10.1007/s00415-023-11700-7 Schiavetti, I., Signori, A., Albanese, A., Frau, J., Cocco, E., Lorefice, L., di Lemme, S., Fantozzi, R., Centonze, D., Landi, D., Marfia, G., Signoriello, E., Lus, G., Zecca, C., Gobbi, C., Iodice, R., Malimpensa, L., Cordioli, C., Ferraro, D., Ruscica, F., … CladStop study group (2024). Therapeutic choices and disease activity after 2 years of treatment with cladribine: An Italian multicenter study (CladStop). European journal of neurology, 31(6), e16250. https://doi.org/10.1111/ene.16250 Rolfes, L., Pfeuffer, S., Huntemann, N., Schmidt, M., Su, C., Skuljec, J., Aslan, D., Hackert, J., Kleinschnitz, K., Hagenacker, T., Pawlitzki, M., Ruck, T., Kleinschnitz, C., Meuth, S. G., & Pul, R. (2022). Immunological consequences of cladribine treatment in multiple sclerosis: A real-world study. Multiple sclerosis and related disorders, 64, 103931. https://doi.org/10.1016/j.msard.2022.103931 Rojas, J. I., Alonso, R., Luetic, G., Patrucco, L., Casas, M., Silva, B., Miguez, J., Deri, N., Vrech, C., Liwacki, S., Piedrabuena, R., Silva, E., Tkachuk, V., Burgos, M., Tavolini, D., Zanga, G., Pinheiro, A. A., Hryb, J., Leguizamon, F., Knorre, E., … Carnero Contentti, E. (2024). Real-World Effectiveness and Safety of Cladribine in Multiple Sclerosis: Longitudinal Data From the Nationwide Registry in Argentina. Clinical neuropharmacology, 47(4), 120–127. https://doi.org/10.1097/WNF.0000000000000598 Pfeuffer, S., Rolfes, L., Hackert, J., Kleinschnitz, K., Ruck, T., Wiendl, H., Klotz, L., Kleinschnitz, C., Meuth, S. G., & Pul, R. (2022). Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres. Multiple sclerosis (Houndmills, Basingstoke, England), 28(2), 257–268. https://doi.org/10.1177/13524585211012227 Additional Declarations The authors declare no competing interests. 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-8712615","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":590994758,"identity":"b3a3f172-e825-442b-a679-56adef9f68a3","order_by":0,"name":"Eliza Babych","email":"data:image/png;base64,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","orcid":"https://orcid.org/0009-0007-3110-4186","institution":"Odesa National Medical University","correspondingAuthor":true,"prefix":"","firstName":"Eliza","middleName":"","lastName":"Babych","suffix":""},{"id":590994759,"identity":"4db0e5ad-fa67-494c-bd79-3bddf5772e57","order_by":1,"name":"Yuliia Solodovnikova","email":"","orcid":"https://orcid.org/0000-0002-2544-9766","institution":"Odesa National Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yuliia","middleName":"","lastName":"Solodovnikova","suffix":""}],"badges":[],"createdAt":"2026-01-27 16:21:55","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-8712615/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8712615/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eEffect of an Excess Dose of Cladribine on the Subsequent Therapeutic Regimen and Pregnancy\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCladribine is an oral disease-modifying therapy (DMT) for highly active multiple sclerosis (MS) that selectively reduces CD4\u0026thinsp;+\u0026thinsp;and CD8\u0026thinsp;+\u0026thinsp;T lymphocytes, inducing an immune reconstitution effect and enabling a short treatment course with durable remission [1]. However, its mechanism of action carries a significant risk of lymphopenia, making precise weight-based dose calculation crucial. According to the literature, up to 40% of patients develop\u0026thinsp;\u0026ge;\u0026thinsp;III grade lymphopenia usually during the second year of treatment [2\u0026ndash;5]. We present a rare case report describing the therapeutic and pregnancy outcomes following administration of an excessive dose of cladribine in a patient with MS.\u003c/p\u003e"},{"header":"Case report","content":"\u003cp\u003eA 30-year-old woman with highly active relapsing-remitting MS (EDSS 5.5, disease duration 5 years) previously treated with teriflunomide and ponesimod received a first-year cladribine course at 1.75 mg/kg (body weight 40 kg). The course was followed by transient episodes of pelvic dysfunction, ataxia, oculomotor disturbances, and facial paralysis, with no changes in leukocyte counts. In the second year, she received an excessive cumulative 1-st dose of 1,33 mg/kg vs the routine 0,875 mg/kg. One month later, severe asymptomatic lymphopenia (0.2 \u0026times; 10\u0026sup3; cells/\u0026micro;L) developed and persisted for six months before spontaneous recovery to 0.8 \u0026times; 10\u0026sup3; cells/\u0026micro;L. Thus, the final scheduled dose was postponed and later administered per protocol, which the patient tolerated well. After 2 years of follow-up, the patient had remained clinically stable without disease progression and became pregnant. The patient\u0026rsquo;s first pregnancy was complicated by a spontaneous abortion at 14 weeks\u0026rsquo; gestation. Ten months later, she conceived again and delivered a healthy baby by cesarean section.\u003c/p\u003e"},{"header":"Discussion and Conclusion","content":"\u003cp\u003eTo our knowledge, this is the first reported case of excessive cumulative cladribine dosage in MS. This case highlights both the hematological risks associated with overdosing and the potential for immune recovery and sustained disease stability. Cladribine is a highly effective therapeutic option for MS patients. However, due to its profound lymphocyte-depleting effect, overdosing can lead to severe, potentially life-threatening lymphopenia and increased susceptibility to latent infection reactivation. Strict adherence to weight-based dosing and regular lymphocyte monitoring are crucial for ensuring treatment safety and optimal long-term outcomes.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":" \u003cp\u003e \u003cstrong\u003eConflict of interest\u003c/strong\u003e \u003cp\u003eThe authors declare that they have no conflict of interest to disclose. No funds, grants, or other support were received.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eEthics approval\u003c/h2\u003e \u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Odesa National Medical University.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent to participate\u003c/strong\u003e \u003cp\u003e Verbal informed consent was obtained prior to the interview.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eConsent to publish\u003c/strong\u003e \u003cp\u003e The participant has consented to the submission of the case report to the journal.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAvailability of Data and Materials\u003c/h2\u003e \u003cp\u003eThe data that support the findings of this study are available from the corresponding author upon reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZanetta, C., Rocca, M. A., Meani, A., Martinelli, V., Ferrè, L., Moiola, L., \u0026amp; Filippi, M. (2023). Effectiveness and safety profile of cladribine in an Italian real-life cohort of relapsing-remitting multiple sclerosis patients: a monocentric longitudinal observational study. Journal of neurology, 270(7), 3553–3564. https://doi.org/10.1007/s00415-023-11700-7\u003c/li\u003e\n\u003cli\u003eSchiavetti, I., Signori, A., Albanese, A., Frau, J., Cocco, E., Lorefice, L., di Lemme, S., Fantozzi, R., Centonze, D., Landi, D., Marfia, G., Signoriello, E., Lus, G., Zecca, C., Gobbi, C., Iodice, R., Malimpensa, L., Cordioli, C., Ferraro, D., Ruscica, F., … CladStop study group (2024). Therapeutic choices and disease activity after 2 years of treatment with cladribine: An Italian multicenter study (CladStop). European journal of neurology, 31(6), e16250. https://doi.org/10.1111/ene.16250\u003c/li\u003e\n\u003cli\u003eRolfes, L., Pfeuffer, S., Huntemann, N., Schmidt, M., Su, C., Skuljec, J., Aslan, D., Hackert, J., Kleinschnitz, K., Hagenacker, T., Pawlitzki, M., Ruck, T., Kleinschnitz, C., Meuth, S. G., \u0026amp; Pul, R. (2022). Immunological consequences of cladribine treatment in multiple sclerosis: A real-world study. Multiple sclerosis and related disorders, 64, 103931. https://doi.org/10.1016/j.msard.2022.103931\u003c/li\u003e\n\u003cli\u003eRojas, J. I., Alonso, R., Luetic, G., Patrucco, L., Casas, M., Silva, B., Miguez, J., Deri, N., Vrech, C., Liwacki, S., Piedrabuena, R., Silva, E., Tkachuk, V., Burgos, M., Tavolini, D., Zanga, G., Pinheiro, A. A., Hryb, J., Leguizamon, F., Knorre, E., … Carnero Contentti, E. (2024). Real-World Effectiveness and Safety of Cladribine in Multiple Sclerosis: Longitudinal Data From the Nationwide Registry in Argentina. Clinical neuropharmacology, 47(4), 120–127. https://doi.org/10.1097/WNF.0000000000000598\u003c/li\u003e\n\u003cli\u003ePfeuffer, S., Rolfes, L., Hackert, J., Kleinschnitz, K., Ruck, T., Wiendl, H., Klotz, L., Kleinschnitz, C., Meuth, S. G., \u0026amp; Pul, R. (2022). Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres. Multiple sclerosis (Houndmills, Basingstoke, England), 28(2), 257–268. https://doi.org/10.1177/13524585211012227\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"multiple sclerosis, cladribine, excessive dose","lastPublishedDoi":"10.21203/rs.3.rs-8712615/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8712615/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eCladribine is an oral immune reconstitution therapy approved for the treatment of highly active relapsing\u0026ndash;remitting multiple sclerosis. It selectively reduces CD4\u0026thinsp;+\u0026thinsp;and CD8\u0026thinsp;+\u0026thinsp;T lymphocytes, induces an immune reconstitution effect, and enables a short treatment course with durable disease control. Although generally well tolerated, it is associated with dose-dependent adverse effects, most notably severe (grade III\u0026ndash;IV) lymphopenia, reported in up to 40% of patients, particularly during the second treatment year. Strict adherence to weight-based dosing is therefore essential. Miscalculations of cumulative doses may lead to prolonged immunosuppression and related complications. We report a rare clinical case of excessive cumulative cladribine dosing and its subsequent clinical, hematological, and reproductive outcomes. To our knowledge, this is the first reported case describing the consequences of exceeding the cladribine dosage in multiple sclerosis.\u003c/p\u003e","manuscriptTitle":"Effect of an Excess Dose of Cladribine on the Subsequent Therapeutic Regimen and Pregnancy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-17 06:55:35","doi":"10.21203/rs.3.rs-8712615/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":"bf00dd55-e49b-461a-a80d-b1cf6cad88b7","owner":[],"postedDate":"February 17th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-17T06:55:35+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-17 06:55:35","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8712615","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8712615","identity":"rs-8712615","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}