Long-term complete remission of metastatic BRAF-wild-type melanoma during ruxolitinib therapy for primary myelofibrosis

Long-term complete remission of metastatic BRAF-wild-type melanoma during ruxolitinib therapy for primary myelofibrosis | 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 Long-term complete remission of metastatic BRAF-wild-type melanoma during ruxolitinib therapy for primary myelofibrosis Francesco Mendicino, Antonella Bruzzese, Enrica Antonia Martino, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7894301/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 Durable complete remissions after immune checkpoint inhibition are rare in metastatic melanoma. The coexistence of long-term melanoma remission and concomitant myelofibrosis treated with ruxolitinib is exceptional. We describe a 73-year-old woman who achieved complete radiologic remission of metastatic BRAF-wild-type melanoma after ipilimumab and has remained disease-free for more than four years while receiving continuous ruxolitinib for primary myelofibrosis. This case highlights the long-term oncologic safety of JAK1/2 inhibition and supports that ruxolitinib does not necessarily impair immune control established by prior checkpoint blockade. Figures Figure 1 Full Text Dear Editor, durable complete remissions (CRs) after immune checkpoint inhibition (ICI) in metastatic melanoma are uncommon. The coexistence of long-term melanoma remission and concomitant myelofibrosis treated with ruxolitinib is particularly rare. We report the case of a 73-year-old woman who achieved durable CR of metastatic BRAF wild-type melanoma and has maintained remission for more than four years during continuous ruxolitinib therapy for primary myelofibrosis (PMF). The patient was diagnosed in July 2019 with lentigo-maligna melanoma of the left malar region (Breslow 3.4 mm, Clark IV, ulceration absent, BRAF wild-type). Sentinel lymph node biopsy was positive, and cervical dissection removed 46 negative nodes (pT3aN1aM0). Adjuvant pembrolizumab was started in November 2019 but stopped in February 2020 due to disease progression with new hepatic and nodal metastases (M1c). Ipilimumab (3 mg/kg every 3 weeks ×4 cycles) from September to December 2020 induced complete radiologic remission confirmed in January 2021. No further systemic therapy was administered (Figure 1). In February 2021, bone marrow biopsy revealed hypercellular marrow with grade 3 reticulin/collagen fibrosis and JAK2 V617F mutation, consistent with PMF (high-risk DIPSS-Plus). Ruxolitinib 5 mg twice daily was initiated and continued, together with erythropoietin and deferasirox. Over four years of follow-up, blood counts remained stable and spleen size decreased from 20 to 17 cm (Figure 1). Serial imaging (2021–2024) demonstrated ongoing melanoma remission without new lesions. No opportunistic infections or secondary skin cancers were observed. This case illustrates that long-term JAK1/2 inhibition does not necessarily impair antitumor immune control established by previous checkpoint therapy. Ruxolitinib exerts potent anti-inflammatory effects by downregulating proinflammatory cytokines such as IL-6, IL-23, and IFN-γ, yet its immunomodulatory balance may support stable immune homeostasis rather than systemic immunosuppression [1–3]. Data from large real-world registries (JUMP, ROMEI) confirm an increased incidence of non-melanoma skin cancers but not melanoma recurrence among ruxolitinib-treated patients [4,5]. Mechanistically, ruxolitinib modulates both innate and adaptive immunity. It can reduce NK-cell cytotoxicity via IL-2/IL-15-STAT5 inhibition and alter dendritic-cell migration, but may also attenuate tumor-promoting inflammation [6]. These context-dependent effects likely explain the benign oncologic course observed in our patient. Our observation adds to the limited evidence that JAK inhibition can coexist safely with durable melanoma remission, provided appropriate dermatologic and oncologic monitoring. Ruxolitinib’s immunomodulatory rather than broadly immunosuppressive profile may allow sustained tumor immune surveillance in select individuals with prior ICI exposure. In conclusion, this case supports the long-term safety of ruxolitinib in patients with a history of metastatic melanoma who achieved durable CR after ICI therapy. Registry-based studies collecting long-term oncologic outcomes in myelofibrosis patients treated with JAK inhibitors are warranted. Declarations Author Contributions Francesco Mendicino (FM): study conception, data collection, manuscript drafting, figure and table preparation. Antonella Bruzzese (AB), Enrica Antonia Martino (EAM), Santino Caserta (SC), Ernesto Vigna (EV), Eugenio Lucia (EL), Virginia Olivito (VO), and Caterina Labanca (CL): clinical data curation, validation, and manuscript review. Massimo Gentile (MG): final critical review and institutional supervision. All authors approved the final version of the manuscript. Conflict of interest The authors declare no conflicts of interest. Funding None. Ethics statement Written informed consent was obtained from the patient for publication. References Maschmeyer P, Sandmann S, Bach E, et al. Mechanisms underlying the anti-inflammatory and immunosuppressive activity of ruxolitinib. Front Oncol. 2019;9:1186. Verstovsek S, Mesa RA, Gotlib J, et al. Efficacy, safety, and survival with ruxolitinib in myelofibrosis. N Engl J Med. 2012;366:799–807. Vannucchi AM, Harrison CN, Kiladjian JJ, et al. Long-term outcomes of patients with myelofibrosis treated with ruxolitinib: updated results from COMFORT studies. Leukemia. 2023;37:1809–1822. Palandri F, Breccia M, Bonifacio M, et al. Real-life experience with ruxolitinib in myelofibrosis: a study by the Rete Ematologica Lombarda (REL). Leuk Lymphoma. 2020;61:1729–1738. Guglielmelli P, Rotunno G, Mannelli L, et al. Real-world ruxolitinib discontinuation and outcomes in myelofibrosis: a multicenter study. Ann Hematol. 2022;101:1421–1431. Maschmeyer P, et al. Mechanisms underlying the anti-inflammatory and immunosuppressive activity of ruxolitinib. Front Oncol. 2019;9:1186. Additional Declarations No competing interests reported. Supplementary Files Supplementarymaterial.docx 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-7894301","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":540595042,"identity":"6366fadf-b926-4663-8e0a-90bec369e3b5","order_by":0,"name":"Francesco 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1","display":"","copyAsset":false,"role":"figure","size":74147,"visible":true,"origin":"","legend":"\u003cp\u003eIntegrated clinical timeline of melanoma (upper panel) and myelofibrosis (lower panel) courses, showing durable melanoma remission and stable hematologic response during continuous ruxolitinib therapy.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7894301/v1/391715571ed2b384263f1f6b.png"},{"id":95315815,"identity":"5c1f00fb-8094-4148-b2ac-d2895f5dc555","added_by":"auto","created_at":"2025-11-06 15:57:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":357640,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7894301/v1/d6569413-c054-4888-8179-c32ed0eccdd6.pdf"},{"id":95285728,"identity":"5762db58-9f88-4cd6-aee6-059b6b4b6d88","added_by":"auto","created_at":"2025-11-06 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The coexistence of long-term melanoma remission and concomitant myelofibrosis treated with ruxolitinib is particularly rare. We report the case of a 73-year-old woman who achieved durable CR of metastatic BRAF wild-type melanoma and has maintained remission for more than four years during continuous ruxolitinib therapy for primary myelofibrosis (PMF).\u003c/p\u003e\n\u003cp\u003eThe patient was diagnosed in July 2019 with lentigo-maligna melanoma of the left malar region (Breslow 3.4 mm, Clark IV, ulceration absent, BRAF wild-type). Sentinel lymph node biopsy was positive, and cervical dissection removed 46 negative nodes (pT3aN1aM0). Adjuvant pembrolizumab was started in November 2019 but stopped in February 2020 due to disease progression with new hepatic and nodal metastases (M1c). Ipilimumab (3 mg/kg every 3 weeks \u0026times;4 cycles) from September to December 2020 induced complete radiologic remission confirmed in January 2021. No further systemic therapy was administered (Figure 1).\u003c/p\u003e\n\u003cp\u003eIn February 2021, bone marrow biopsy revealed hypercellular marrow with grade 3 reticulin/collagen fibrosis and JAK2 V617F mutation, consistent with PMF (high-risk DIPSS-Plus). Ruxolitinib 5 mg twice daily was initiated and continued, together with erythropoietin and deferasirox. Over four years of follow-up, blood counts remained stable and spleen size decreased from 20 to 17 cm (Figure 1). Serial imaging (2021\u0026ndash;2024) demonstrated ongoing melanoma remission without new lesions. No opportunistic infections or secondary skin cancers were observed.\u003c/p\u003e\n\u003cp\u003eThis case illustrates that long-term JAK1/2 inhibition does not necessarily impair antitumor immune control established by previous checkpoint therapy. Ruxolitinib exerts potent anti-inflammatory effects by downregulating proinflammatory cytokines such as IL-6, IL-23, and IFN-\u0026gamma;, yet its immunomodulatory balance may support stable immune homeostasis rather than systemic immunosuppression [1\u0026ndash;3]. Data from large real-world registries (JUMP, ROMEI) confirm an increased incidence of non-melanoma skin cancers but not melanoma recurrence among ruxolitinib-treated patients [4,5].\u003c/p\u003e\n\u003cp\u003eMechanistically, ruxolitinib modulates both innate and adaptive immunity. It can reduce NK-cell cytotoxicity via IL-2/IL-15-STAT5 inhibition and alter dendritic-cell migration, but may also attenuate tumor-promoting inflammation [6]. These context-dependent effects likely explain the benign oncologic course observed in our patient.\u003c/p\u003e\n\u003cp\u003eOur observation adds to the limited evidence that JAK inhibition can coexist safely with durable melanoma remission, provided appropriate dermatologic and oncologic monitoring. Ruxolitinib\u0026rsquo;s immunomodulatory rather than broadly immunosuppressive profile may allow sustained tumor immune surveillance in select individuals with prior ICI exposure.\u003c/p\u003e\n\u003cp\u003eIn conclusion, this case supports the long-term safety of ruxolitinib in patients with a history of metastatic melanoma who achieved durable CR after ICI therapy. Registry-based studies collecting long-term oncologic outcomes in myelofibrosis patients treated with JAK inhibitors are warranted.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFrancesco Mendicino (FM): study conception, data collection, manuscript drafting, figure and table preparation. Antonella Bruzzese (AB), Enrica Antonia Martino (EAM), Santino Caserta (SC), Ernesto Vigna (EV), Eugenio Lucia (EL), Virginia Olivito (VO), and Caterina Labanca (CL): clinical data curation, validation, and manuscript review. Massimo Gentile (MG): final critical review and institutional supervision. All authors approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWritten informed consent was obtained from the patient for publication.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eMaschmeyer P, Sandmann S, Bach E, et al. Mechanisms underlying the anti-inflammatory and immunosuppressive activity of ruxolitinib. \u003cem\u003eFront Oncol.\u003c/em\u003e 2019;9:1186.\u003c/li\u003e\n \u003cli\u003eVerstovsek S, Mesa RA, Gotlib J, et al. Efficacy, safety, and survival with ruxolitinib in myelofibrosis. \u003cem\u003eN Engl J Med.\u003c/em\u003e 2012;366:799\u0026ndash;807.\u003c/li\u003e\n \u003cli\u003eVannucchi AM, Harrison CN, Kiladjian JJ, et al. Long-term outcomes of patients with myelofibrosis treated with ruxolitinib: updated results from COMFORT studies. \u003cem\u003eLeukemia.\u003c/em\u003e 2023;37:1809\u0026ndash;1822.\u003c/li\u003e\n \u003cli\u003ePalandri F, Breccia M, Bonifacio M, et al. Real-life experience with ruxolitinib in myelofibrosis: a study by the Rete Ematologica Lombarda (REL). \u003cem\u003eLeuk Lymphoma.\u003c/em\u003e 2020;61:1729\u0026ndash;1738.\u003c/li\u003e\n \u003cli\u003eGuglielmelli P, Rotunno G, Mannelli L, et al. Real-world ruxolitinib discontinuation and outcomes in myelofibrosis: a multicenter study. \u003cem\u003eAnn Hematol.\u003c/em\u003e 2022;101:1421\u0026ndash;1431.\u003c/li\u003e\n \u003cli\u003eMaschmeyer P, et al. Mechanisms underlying the anti-inflammatory and immunosuppressive activity of ruxolitinib. Front Oncol. 2019;9:1186.\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":true,"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":"","lastPublishedDoi":"10.21203/rs.3.rs-7894301/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7894301/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDurable complete remissions after immune checkpoint inhibition are rare in metastatic melanoma. The coexistence of long-term melanoma remission and concomitant myelofibrosis treated with ruxolitinib is exceptional. We describe a 73-year-old woman who achieved complete radiologic remission of metastatic BRAF-wild-type melanoma after ipilimumab and has remained disease-free for more than four years while receiving continuous ruxolitinib for primary myelofibrosis. This case highlights the long-term oncologic safety of JAK1/2 inhibition and supports that ruxolitinib does not necessarily impair immune control established by prior checkpoint blockade.\u003c/p\u003e","manuscriptTitle":"Long-term complete remission of metastatic BRAF-wild-type melanoma during ruxolitinib therapy for primary myelofibrosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-06 09:58:04","doi":"10.21203/rs.3.rs-7894301/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":"1dbfcc1e-307f-4c3c-a829-df64d1e2142e","owner":[],"postedDate":"November 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-06T13:23:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-06 09:58:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7894301","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7894301","identity":"rs-7894301","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}