Effective treatment with ruxolitinib and ropeginterferon alfa-2b for refractory TAFRO- like syndrome in Polycythemia vera

Effective treatment with ruxolitinib and ropeginterferon alfa-2b for refractory TAFRO- like syndrome in Polycythemia vera | 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 Effective treatment with ruxolitinib and ropeginterferon alfa-2b for refractory TAFRO- like syndrome in Polycythemia vera Satoko Oka, Yuina Ueda-Akagi, Takaya Mituyoshi, Kazuo Ono This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6780787/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 TAFRO syndrome is a rare systemic inflammatory disease characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, and splenomegaly; however, its pathogenesis remains largely unknown. Due to the lack of appropriate treatment, TAFRO syndrome often presents with multiple organ dysfunction and fatality. The Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway has recently been shown to play an important role in the pathogenesis of inflammation in idiopathic Multicentric Castleman disease (iMCD)-TAFRO, and inhibitors of the JAK/STAT pathway may be effective as therapeutic agents for iMCD-TAFRO syndrome. Polycythemia vera (PV) is one of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), and the enhancement and modulation of immune cells may be involved in the mechanism of action of interferon (IFN)-α2 and the JAK-STAT pathway in MPNs. We herein report the successful treatment using combination therapy with ruxolitinib and ropeginterferon alfa-2b of a case of TAFRO-like syndrome with a long history of PV with JAK2 V617F refractory to several treatments. This combination therapy has potential as a new treatment option for refractory TAFRO syndrome-like symptoms. Polycythemia vera TAFRO syndrome JAK/STAT pathway ruxolitinib ropegIFNα2b Figures Figure 1 Figure 2 Figure 3 Introduction Multicentric Castleman disease (MCD) is a rare disorder that is characterized by episodes of systemic inflammation, the reactive proliferation of morphologically benign lymphocytes, multicentric lymphadenopathy, polyclonal gammaglobulinemia, microcytic anemia, hypoalbuminemia, and elevated serum inflammatory proteins, such as C-reactive protein (CRP), according to pathological hypercytokinemia ( 1 ). While human herpes virus-8 (HHV-8) drives hypercytokinemia in a cohort of immunocompromised patients, the etiology of HHV-8-negative MCD is idiopathic MCD (iMCD) ( 2 ). TAFRO syndrome identifies a subset of iMCD patients with shared manifestations, including thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, organomegaly, and typically normal immunoglobulin levels ( 3 ). The etiology of TAFRO syndrome remains unknown and a standard therapeutic strategy has not yet been established. The Janus kinase (JAK)/ signal transducers and activators of transcription (STAT) pathway was recently shown to play an important role in the pathogenesis of inflammation in iMCD-TAFRO ( 4 ), and inhibitors of the JAK/STAT pathway may be effective as therapeutic agents for iMCD-TAFRO syndrome. The interferon (IFN) receptor was identified, followed shortly by the characterization of the JAK/STAT signal transduction pathway ( 5 ). One of the main pathways by which IFN-α2 exerts its effects is the JAK/STAT pathway. Type I IFN-dependent signaling pathways are activated by human type I IFN-α receptor chains 1 and 2, e intracellular domains of which interact with JAK and are activated upon IFN-α2 binding to its receptors. JAK phosphorylate and activate STAT, which then translocate to the nucleus and activates gene expression ( 5 , 6 ). Polycythemia vera (PV) is one of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) characterized by the overproduction of red blood cells, which may lead to thrombotic and hemorrhagic events. Previous studies on MPNs suggested the involvement of the enhancement and modulation of immune cells in the mechanisms of action of IFN-α2 and the JAK-STAT pathway ( 7 ). The safety and efficacy of ruxolitinib and ropeginterferon alfa-2b (ropegIFNα2b) as treatments for patients with PV have been demonstrated ( 8 – 11 ). We herein report the first case of refractory TAFRO-like syndrome in PV that was successfully treated using combination therapy with ruxolitinib and ropegIFNα2b. Case presentation A 71-year-old Japanese female was admitted with fever and edema. The patient was diagnosed with JAK2 -mutated PV when she was 60 years old. She had been treated with hydroxyurea (HU, 500 mg daily) for 11 years. A physical examination revealed a temperature of 38.3°C, blood pressure of 100/62 mmHg, heart rate of 110 bpm, and SpO 2 of 93%. Generalized edema was present. Laboratory data showed microcytic anemia (hemoglobin, 9.3 mg/dL) and severe thrombocytopenia (platelets, 2.4 × 10 9 /L) as well as elevated levels of CRP (6.38 mg/dL, normal range: <0.3 mg/dL), alkaline phosphatase (ALP) (453 IU/L, normal range: 104–338 IU/L), and soluble interleukin-2 receptor (sIL2R) (1272 U/ml, normal range: 145–519 U/mL). Her serum IgG level was 1138 mg/dL (normal range: 870–1700 mg/dL) and monoclonal bands were not observed in immunofixation tests. Hypoalbuminemia, renal dysfunction with a creatinine level of 1.56 mg/dL (normal range: 0.4–0.8 mg/dL), and proteinuria were detected. Serum rheumatoid factor and antibodies, including antinuclear, anti-SS-A, anti-SS-B, anti-DNA, anti-Sm, and anti-RNP antibodies, the perinuclear anti-neutrophil cytoplasmic antibody, and cytoplasmic anti-neutrophil cytoplasmic antibody, were all negative. Serum antibodies against hepatitis B and C viruses, HIV, human T-lymphotropic virus-1, and HHV-8 were all negative. Her serum IL-6 level was 56 pg/mL (normal range: <4.0 pg/mL). Bilateral pleural effusion, ascites, and splenomegaly were observed on computed tomography (CT) (Fig. 1 a, b and c). A bone marrow examination revealed megakaryocytic hyperplasia with grade 1 fibrosis (Fig. 2 a and b). Since her clinical features were considered to be compatible with TAFRO syndrome, steroid pulse therapy was initiated at 1 g/day of methylprednisolone for three days; however, her symptoms worsened. The administration of cyclosporine was initiated at 150 mg/day as the second-line treatment in combination with prednisolone, but did not attenuate her symptoms. The patient was administered weekly injections of the anti-IL-6 receptor antibody (tocizumab 8 mg/kg) in combination with steroids. Despite anti-IL-6 therapy with steroids, renal dysfunction, anasarca, and thrombocytopenia persisted for 2 weeks. The patient subsequently received rituximab as the fourth-line treatment; however, her symptoms worsened. JAK2 V617F was positive with an allelic burden of 99.645%. Ruxolitinib was initiated at 10 mg twice daily, and was then increased to 20 mg twice daily. Although the attenuation of anemia and renal dysfunction was observed, anasarca persisted. Eight weeks after the onset of disease, another severe relapse occurred. RopegIFNα2b add-on therapy was initiated every 2 weeks at a dose of 50 µg, and increased by 50 µg every 2 weeks. The patient’s condition and CT findings both improved (Fig. 3 a, b and c). Laboratory data showed the amelioration of anemia (hemoglobin, 10.8 mg/dL) and thrombocytopenia (platelets, 5.6 × 10 9 /L) and decreases in the levels of CRP (0.12 mg/dL), ALP (233 IU/L), and sIL2R (430 U/ml). After 6 months, JAK2 V617F remained positive with an allelic burden of 71.024%. The patient has remained stable with no recurrence for 10 months with the administration of ruxolitinib and ropegIFNα2b (250 µg every 2 weeks). Discussion TAFRO syndrome is a rare systemic inflammatory disease characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, and splenomegaly. Glucocorticoids and IL-6 inhibitors are the first-line treatment for iMCD-TAFRO ( 12 ). Cyclosporine is frequently included for refractory cases or those with an inadequate treatment response. Rituximab and cyclophosphamide are also initiated in severe cases with difficult disease control ( 13 , 14 ). Although the effectiveness of cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone therapy, lenalidomide, thalidomide, sirolimus, and siltuximab for iMCD-TAFRO has been demonstrated, an optimal treatment strategy for TAFRO syndrome has yet to be established ( 15 ). Furthermore, the mortality rate is high in cases with a poor treatment response. Although the pathogenesis of TAFRO syndrome remains largely unknown, Langan Pai et al. noted that an IFN-β stimulation increased mechanistic target of rapamycin (mTOR) activation in the monocytes and T cells of patients with iMCD-TAFRO syndrome in remission, and that type I IFN also induced mTOR activation in these patients ( 16 ). All type I IFN family members, including IFN-α and IFN-β, bind to a signal receptor complex comprising IFN-α and IFN-β receptor subunit 1 (AR1) and IFN-AR2, which activates the JAK/STAT pathway ( 17 ). The JAK/STAT pathway plays an important role in the pathogenesis of inflammation in iMCD-TAFRO, and inhibitors of the JAK/STAT pathway, such as ruxolitinib, may be effective as therapeutic agents for iMCD-TAFRO syndrome ( 18 , 19 ). In addition, since one of the main pathways by which IFN-α2 exerts its effects is the JAK/STAT pathway, it also has potential as a treatment for TAFRO syndrome. Patients with PV are at an increased risk of developing acute myeloid leukemia or myelofibrosis, which contributes to a poor prognosis in affected patients. The majority of PV cases have an acquired gain-of-function mutation in the JAK2 gene ( JAK2 V617F) ( 20 ). A high JAK2 V617F alle burden is associated with thrombotic events and transition to myelofibrosis ( 21 ). The chronic inflammatory state per se with elevated levels of several inflammatory cytokines, the deregulation of immune and inflammation genes, and/or imbalances in oxidative stress and antioxidant defense pathways may all contribute to defective tumor immune surveillance, which has the greatest impact in the advanced myelofibrosis stage. Ruxolitinib has been used as a second-line cytoreductive treatment after intolerance of or an inadequate response to HU. Five-year outcomes showed that ruxolitinib was a safe and effective long-term treatment option for PV ( 8 ). Thromboembolic events were less frequent in the ruxolitinib group than in the best-available therapy group. Moreover, recent studies indicated that an IFN-α2 treatment for PV reduced the allele burden of driver mutations, which suggests a disease-modifying effect that is not observed with purely symptomatic treatment using aspirin and HU ( 22 ). RopegIFNα2b is a novel site-selective, monopegylated recombinant human IFN, and the PROUD-PV and CONTINUATION-PV trials showed that it was effective for and tolerated well by patients with PV ( 9 , 10 ). Furthermore, Kirito et al. demonstrated the safety and efficacy of ropegIFNα2b over 36 months in Japanese patients with PV ( 11 ). The present case had a long history of JAK2 -mutated PV and subsequently developed TAFRO-like syndrome. JAK2 V617F was detected with an almost 100% positivity rate at the onset of TAFRO-like symptoms. After combination therapy with ruxolitinib and ropegIFNα2b, the patient’s general condition improved and the allele burden of driver mutations decreased. These results and the clinical course strongly suggest that the JAK-STAT pathway is constitutively activated due to driver mutations, with the JAK2 V617F mutation being an important inflammatory driver. This is the first case of TAFRO-like syndrome in PV that was successfully treated using combination therapy with ruxolitinib and ropegIFNα2b. The JAK/STAT pathway plays an important role in the pathogenesis of inflammation in iMCD-TAFRO, and combination therapy with ropegIFNα2b and ruxolitinib may be safe and efficacious for refractory TAFRO syndrome-like symptoms. The etiology, pathology, and strategies for the optimal management of this syndrome remain largely unknown. Therefore, further studies to clarify its prognosis, pathophysiology, and appropriate treatments are needed. Declarations Statement of Ethics The patient provided her written informed consent to receive each regimen, and treatment was administered according to the principles of the Declaration of Helsinki. This study was approved by the Japanese Red Cross Society Wakayama Medical Center Ethics Committee. Conflict of Interest Statement All authors declare no conflicts of interest. Consent to participate Informed consent was obtained from the patient. Patient consent Written informed consent was obtained from this patient for her clinical information to be used for publication. Declaration of interest statement All authors declare no conflicts of interest. Funding Sources None Author Contribution SO: involved in patient care, writing the manuscript, and the conception of this study. YU-A: involved in patient care. TM: involved in patient care. KO: involved in patient care. Acknowledgement None References Iwaki N, Fajgenbaum DC, Nabel CS, et al. (2016) Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease. Am J Hematol. 91: 220-226. Liu AY, Nabel CS, Finkelman BS, et al. (2016) Idiopathic multicentric Castleman's disease: a systematic literature review. Lancet Haematol. 3: e163-175. Kawabata H, Takai K, Kojima M, et al. (2013) Castleman-Kojima disease (TAFRO syndrome) : a novel systemic inflammatory disease characterized by a constellation of symptoms, namely, thrombocytopenia, ascites (anasarca), microcytic anemia, myelofibrosis, renal dysfunction, and organomegaly : a status report and summary of Fukushima (6 June, 2012) and Nagoya meetings (22 September, 2012). J Clin Exp Hematop. 53: 57-61. Pierson SK, Shenoy S, Oromendia AB, et al. (2021) Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease.Blood Adv. 5: 3445-3456. de Weerd NA, Samarajiwa SA, Hertzog PJ. (2007) Type I interferon receptors: biochemistry and biological functions. J Biol Chem. 282: 20053-20057. Billiau A. (2006) Interferon: the pathways of discovery I. Molecular and cellular aspects. Cytokine Growth Factor Rev. 17: 381-409. Gilbert HS. (1998) Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility and efficacy. Cancer. 83:1205-1213. Kiladjian JJ, Zachee P, Hino M, Pane F, Masszi T, Harrison CN, Mesa R, Miller CB, Passamonti F, Durrant S et al (2020) Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol 7: e226–e237. Gisslinger H, Klade C, Georgiev P, Krochmalczyk D, Gercheva-Kyuchukova L, Egyed M, et al. (2020) Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol. 7: e196-e208. Gisslinger H, Klade C, Georgiev P, Krochmalczyk D, Gercheva-Kyuchukova L, Egyed M, et al. (2023) Event-free survival in patients with polycythemia vera treated with ropeginterferon alfa-2b versus best available treatment. Leukemia. 37(10):2129-2132. Kirito K, Sugimoto Y, Gotoh A, Takenaka K, Ichii M, Inano T, et al. (2024) Long-term safety and efficacy of ropeginterferon alfa-2b in Japanese patients with polycythemia vera. Int J Hematol. 120(6):675-683. Igawa T, Sato Y. (2018) TAFRO Syndrome. Hematol Oncol Clin North Am. 32(1):107-118. Wakiya R, Kameda T, Takeuchi Y, Ozaki H, Nakashima S, Shimada H, Kadowaki N, Dobashi H. (2021) Sequential change in serum VEGF levels in a case of tocilizumab-resistant TAFRO syndrome treated effectively with rituximab. Mod Rheumatol Case Rep. 5(1):145-151. Kikuchi T, Shimizu T, Toyama T, Abe R, Okamoto S.(2017) Successful Treatment of TAFRO Syndrome with Tocilizumab, Prednisone, and Cyclophosphamide..Intern Med. 56(16):2205-2211. Corinne Williams, Alexis Phillips, Vikram Aggarwal, Liron Barnea Slonim, David C Fajgenbaum, Reem Karmali. (2021) TAFRO Syndrome and Elusive Diagnosis of Idiopathic Multicentric Castleman Disease Treated with Empiric Anti-Interleukin-6 Therapy. Case Rep Oncol. 14(3):1359-1365. Langan Pai RA, Japp AS, Michael Gonzalez M, Rasheed RF, Okumura M, Arenas D, Pierson SK, Powers V, Layman AA, Kao C, Hakonarson H, van Rhee F, Betts MR, Kambayashi T, Fajgenbaum DC. (202) Type I IFN response associated with mTOR activation in the TAFRO subtype of idiopathic multicentric Castleman disease. JCI Insight. 5(9):e135031. Banerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. (2017) JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects. Drugs. 77(5):521-546. Lust H, Gong S, Remiker A, Rossoff J. Idiopathic multicentric Castleman disease with TAFRO clinical subtype responsive to IL-6/JAK inhibition: A pediatric case series. Pediatr Blood Cancer. 2021 Oct;68(10): e29261. Killian M, Viel S, Chalayer E, Forest F, Grange S, Bonnefoy PB, Oksenhendler E, Cathébras P, Paul S. (2021) JAK1/2 Inhibition in Severe TAFRO Syndrome: A Case Report. Ann Intern Med. 174(5):719-721. Regimbeau M, Mary R, Hermetet F, Girodon F. (2022) Genetic Background of Polycythemia Vera. Genes (Basel). 13(4):637. Tefferi A, Barbui T. (2023) Polycythemia vera: 2024 update on diagnosis, risk-stratification, and management. Am J Hematol. 98(9):1465-1487. Bewersdorf JP, Giri S, Wang R, Podoltsev N, Williams RT, Tallman MS, et al. (2021) Interferon alpha therapy in essential thrombocythemia and polycythemia vera-a systematic review and meta-analysis. Leukemia. 35(6):1643-1660. 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. 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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-6780787","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":466428965,"identity":"f6355e5e-6cd2-430c-b61e-ba427c86b170","order_by":0,"name":"Satoko Oka","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8ElEQVRIiWNgGAWjYDACHiD+ACKYkUUlCGhhnEGyFmYektzFz3P48WcbGTt73Xbegw8YKuzyGKSbDzBY7sCtRbK3zUw6hyc5cdthvmQDhjPJxQwyxxIYJM/g1mJwnsGMOYeHOcHsMI+ZBGPbgcQGiRwDBsk2fFrYP3+24Km3B2ox/wHRkv8Bv5azPQbSDDyHGbcBbWGA2sKAV4tkz5kyyR6e40C/8BhLJJxJTmyTSDM4gM8v/Dzpmz/87Km2Nzt/xvDDhwq7xH6J5IePJfGEGBgw9kAZCUDMBsSHJRsIaGH4gW7GR4JaRsEoGAWjYAQBANu5SP4dGdtlAAAAAElFTkSuQmCC","orcid":"","institution":"Japanese Red Cross Society Wakayama Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Satoko","middleName":"","lastName":"Oka","suffix":""},{"id":466428966,"identity":"764e81fd-05bf-4eec-8a00-87f94a631185","order_by":1,"name":"Yuina Ueda-Akagi","email":"","orcid":"","institution":"Japanese Red Cross Society Wakayama Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Yuina","middleName":"","lastName":"Ueda-Akagi","suffix":""},{"id":466428967,"identity":"12438e02-2932-4a36-b97b-43882458f789","order_by":2,"name":"Takaya Mituyoshi","email":"","orcid":"","institution":"Japanese Red Cross Society Wakayama Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Takaya","middleName":"","lastName":"Mituyoshi","suffix":""},{"id":466428968,"identity":"3148dcd9-55bf-4846-9c5f-89f3f9a2f39c","order_by":3,"name":"Kazuo Ono","email":"","orcid":"","institution":"Japanese Red Cross Society Wakayama Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Kazuo","middleName":"","lastName":"Ono","suffix":""}],"badges":[],"createdAt":"2025-05-30 04:08:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6780787/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6780787/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":84323534,"identity":"80fb85e6-eb7e-4b7d-ab46-d906afaf8520","added_by":"auto","created_at":"2025-06-10 14:45:05","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":290785,"visible":true,"origin":"","legend":"\u003cp\u003e(a, b, c) Computed tomography (CT) on admission. CT showing bilateral pleural effusion and ascites.\u003c/p\u003e","description":"","filename":"fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6780787/v1/f0b82c1076918a05cbf66d5d.jpg"},{"id":84323538,"identity":"4e157cbc-1627-4064-b483-72a81adb8a18","added_by":"auto","created_at":"2025-06-10 14:45:05","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":636533,"visible":true,"origin":"","legend":"\u003cp\u003eA bone marrow (BM) examination revealed megakaryocytic hyperplasia (a. \u003cstrong\u003eHematoxylin and eosin, \u003c/strong\u003e×\u003cstrong\u003e200\u003c/strong\u003e) with grade 1 fibrosis (b. Gomori, ×\u003cstrong\u003e200\u003c/strong\u003e)\u003c/p\u003e","description":"","filename":"fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6780787/v1/1e3e4293ad8ecf6920db987f.jpg"},{"id":84325294,"identity":"67677657-3158-430a-9ace-79d8cb5df5ba","added_by":"auto","created_at":"2025-06-10 15:01:05","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":294846,"visible":true,"origin":"","legend":"\u003cp\u003e(a, b, c) Computed tomography (CT) after treatment with ruxolitinib and ropegIFNα2b. CT showing the disappearance of bilateral pleural effusion and ascites.\u003c/p\u003e","description":"","filename":"fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6780787/v1/7a9e82466ba4e02fd9312bec.jpg"},{"id":88072662,"identity":"c8051f86-4ef2-481b-9055-9ea99322120c","added_by":"auto","created_at":"2025-08-01 06:16:54","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1596852,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6780787/v1/a6f4b7fd-be47-4200-8bc1-962a24b29062.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Effective treatment with ruxolitinib and ropeginterferon alfa-2b for refractory TAFRO- like syndrome in Polycythemia vera","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMulticentric Castleman disease (MCD) is a rare disorder that is characterized by episodes of systemic inflammation, the reactive proliferation of morphologically benign lymphocytes, multicentric lymphadenopathy, polyclonal gammaglobulinemia, microcytic anemia, hypoalbuminemia, and elevated serum inflammatory proteins, such as C-reactive protein (CRP), according to pathological hypercytokinemia (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). While human herpes virus-8 (HHV-8) drives hypercytokinemia in a cohort of immunocompromised patients, the etiology of HHV-8-negative MCD is idiopathic MCD (iMCD) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). TAFRO syndrome identifies a subset of iMCD patients with shared manifestations, including thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, organomegaly, and typically normal immunoglobulin levels (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The etiology of TAFRO syndrome remains unknown and a standard therapeutic strategy has not yet been established. The Janus kinase (JAK)/ signal transducers and activators of transcription (STAT) pathway was recently shown to play an important role in the pathogenesis of inflammation in iMCD-TAFRO (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e), and inhibitors of the JAK/STAT pathway may be effective as therapeutic agents for iMCD-TAFRO syndrome.\u003c/p\u003e \u003cp\u003eThe interferon (IFN) receptor was identified, followed shortly by the characterization of the JAK/STAT signal transduction pathway (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). One of the main pathways by which IFN-α2 exerts its effects is the JAK/STAT pathway. Type I IFN-dependent signaling pathways are activated by human type I IFN-α receptor chains 1 and 2, e intracellular domains of which interact with JAK and are activated upon IFN-α2 binding to its receptors. JAK phosphorylate and activate STAT, which then translocate to the nucleus and activates gene expression (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePolycythemia vera (PV) is one of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) characterized by the overproduction of red blood cells, which may lead to thrombotic and hemorrhagic events. Previous studies on MPNs suggested the involvement of the enhancement and modulation of immune cells in the mechanisms of action of IFN-α2 and the JAK-STAT pathway (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). The safety and efficacy of ruxolitinib and ropeginterferon alfa-2b (ropegIFNα2b) as treatments for patients with PV have been demonstrated (\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe herein report the first case of refractory TAFRO-like syndrome in PV that was successfully treated using combination therapy with ruxolitinib and ropegIFNα2b.\u003c/p\u003e"},{"header":"Case presentation","content":"\u003cp\u003eA 71-year-old Japanese female was admitted with fever and edema. The patient was diagnosed with \u003cem\u003eJAK2\u003c/em\u003e-mutated PV when she was 60 years old. She had been treated with hydroxyurea (HU, 500 mg daily) for 11 years. A physical examination revealed a temperature of 38.3\u0026deg;C, blood pressure of 100/62 mmHg, heart rate of 110 bpm, and SpO\u003csub\u003e2\u003c/sub\u003e of 93%. Generalized edema was present. Laboratory data showed microcytic anemia (hemoglobin, 9.3 mg/dL) and severe thrombocytopenia (platelets, 2.4 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L) as well as elevated levels of CRP (6.38 mg/dL, normal range: \u0026lt;0.3 mg/dL), alkaline phosphatase (ALP) (453 IU/L, normal range: 104\u0026ndash;338 IU/L), and soluble interleukin-2 receptor (sIL2R) (1272 U/ml, normal range: 145\u0026ndash;519 U/mL). Her serum IgG level was 1138 mg/dL (normal range: 870\u0026ndash;1700 mg/dL) and monoclonal bands were not observed in immunofixation tests. Hypoalbuminemia, renal dysfunction with a creatinine level of 1.56 mg/dL (normal range: 0.4\u0026ndash;0.8 mg/dL), and proteinuria were detected. Serum rheumatoid factor and antibodies, including antinuclear, anti-SS-A, anti-SS-B, anti-DNA, anti-Sm, and anti-RNP antibodies, the perinuclear anti-neutrophil cytoplasmic antibody, and cytoplasmic anti-neutrophil cytoplasmic antibody, were all negative. Serum antibodies against hepatitis B and C viruses, HIV, human T-lymphotropic virus-1, and HHV-8 were all negative. Her serum IL-6 level was 56 pg/mL (normal range: \u0026lt;4.0 pg/mL). Bilateral pleural effusion, ascites, and splenomegaly were observed on computed tomography (CT) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea, b and c). A bone marrow examination revealed megakaryocytic hyperplasia with grade 1 fibrosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea and b). Since her clinical features were considered to be compatible with TAFRO syndrome, steroid pulse therapy was initiated at 1 g/day of methylprednisolone for three days; however, her symptoms worsened. The administration of cyclosporine was initiated at 150 mg/day as the second-line treatment in combination with prednisolone, but did not attenuate her symptoms. The patient was administered weekly injections of the anti-IL-6 receptor antibody (tocizumab 8 mg/kg) in combination with steroids. Despite anti-IL-6 therapy with steroids, renal dysfunction, anasarca, and thrombocytopenia persisted for 2 weeks. The patient subsequently received rituximab as the fourth-line treatment; however, her symptoms worsened. \u003cem\u003eJAK2\u003c/em\u003e V617F was positive with an allelic burden of 99.645%. Ruxolitinib was initiated at 10 mg twice daily, and was then increased to 20 mg twice daily. Although the attenuation of anemia and renal dysfunction was observed, anasarca persisted. Eight weeks after the onset of disease, another severe relapse occurred. RopegIFNα2b add-on therapy was initiated every 2 weeks at a dose of 50 \u0026micro;g, and increased by 50 \u0026micro;g every 2 weeks. The patient\u0026rsquo;s condition and CT findings both improved (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea, b and c). Laboratory data showed the amelioration of anemia (hemoglobin, 10.8 mg/dL) and thrombocytopenia (platelets, 5.6 \u0026times; 10\u003csup\u003e9\u003c/sup\u003e/L) and decreases in the levels of CRP (0.12 mg/dL), ALP (233 IU/L), and sIL2R (430 U/ml). After 6 months, \u003cem\u003eJAK2\u003c/em\u003e V617F remained positive with an allelic burden of 71.024%. The patient has remained stable with no recurrence for 10 months with the administration of ruxolitinib and ropegIFNα2b (250 \u0026micro;g every 2 weeks).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTAFRO syndrome is a rare systemic inflammatory disease characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, and splenomegaly. Glucocorticoids and IL-6 inhibitors are the first-line treatment for iMCD-TAFRO (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Cyclosporine is frequently included for refractory cases or those with an inadequate treatment response. Rituximab and cyclophosphamide are also initiated in severe cases with difficult disease control (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Although the effectiveness of cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone therapy, lenalidomide, thalidomide, sirolimus, and siltuximab for iMCD-TAFRO has been demonstrated, an optimal treatment strategy for TAFRO syndrome has yet to be established (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). Furthermore, the mortality rate is high in cases with a poor treatment response.\u003c/p\u003e \u003cp\u003eAlthough the pathogenesis of TAFRO syndrome remains largely unknown, Langan Pai et al. noted that an IFN-β stimulation increased mechanistic target of rapamycin (mTOR) activation in the monocytes and T cells of patients with iMCD-TAFRO syndrome in remission, and that type I IFN also induced mTOR activation in these patients (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). All type I IFN family members, including IFN-α and IFN-β, bind to a signal receptor complex comprising IFN-α and IFN-β receptor subunit 1 (AR1) and IFN-AR2, which activates the JAK/STAT pathway (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e). The JAK/STAT pathway plays an important role in the pathogenesis of inflammation in iMCD-TAFRO, and inhibitors of the JAK/STAT pathway, such as ruxolitinib, may be effective as therapeutic agents for iMCD-TAFRO syndrome (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). In addition, since one of the main pathways by which IFN-α2 exerts its effects is the JAK/STAT pathway, it also has potential as a treatment for TAFRO syndrome.\u003c/p\u003e \u003cp\u003ePatients with PV are at an increased risk of developing acute myeloid leukemia or myelofibrosis, which contributes to a poor prognosis in affected patients. The majority of PV cases have an acquired gain-of-function mutation in the \u003cem\u003eJAK2\u003c/em\u003e gene (\u003cem\u003eJAK2\u003c/em\u003e V617F) (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). A high \u003cem\u003eJAK2\u003c/em\u003e V617F alle burden is associated with thrombotic events and transition to myelofibrosis (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e). The chronic inflammatory state \u003cem\u003eper se\u003c/em\u003e with elevated levels of several inflammatory cytokines, the deregulation of immune and inflammation genes, and/or imbalances in oxidative stress and antioxidant defense pathways may all contribute to defective tumor immune surveillance, which has the greatest impact in the advanced myelofibrosis stage. Ruxolitinib has been used as a second-line cytoreductive treatment after intolerance of or an inadequate response to HU. Five-year outcomes showed that ruxolitinib was a safe and effective long-term treatment option for PV (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Thromboembolic events were less frequent in the ruxolitinib group than in the best-available therapy group. Moreover, recent studies indicated that an IFN-α2 treatment for PV reduced the allele burden of driver mutations, which suggests a disease-modifying effect that is not observed with purely symptomatic treatment using aspirin and HU (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). RopegIFNα2b is a novel site-selective, monopegylated recombinant human IFN, and the PROUD-PV and CONTINUATION-PV trials showed that it was effective for and tolerated well by patients with PV (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Furthermore, Kirito et al. demonstrated the safety and efficacy of ropegIFNα2b over 36 months in Japanese patients with PV (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe present case had a long history of \u003cem\u003eJAK2\u003c/em\u003e-mutated PV and subsequently developed TAFRO-like syndrome. \u003cem\u003eJAK2\u003c/em\u003e V617F was detected with an almost 100% positivity rate at the onset of TAFRO-like symptoms. After combination therapy with ruxolitinib and ropegIFNα2b, the patient\u0026rsquo;s general condition improved and the allele burden of driver mutations decreased. These results and the clinical course strongly suggest that the JAK-STAT pathway is constitutively activated due to driver mutations, with the \u003cem\u003eJAK2\u003c/em\u003e V617F mutation being an important inflammatory driver.\u003c/p\u003e \u003cp\u003eThis is the first case of TAFRO-like syndrome in PV that was successfully treated using combination therapy with ruxolitinib and ropegIFNα2b. The JAK/STAT pathway plays an important role in the pathogenesis of inflammation in iMCD-TAFRO, and combination therapy with ropegIFNα2b and ruxolitinib may be safe and efficacious for refractory TAFRO syndrome-like symptoms. The etiology, pathology, and strategies for the optimal management of this syndrome remain largely unknown. Therefore, further studies to clarify its prognosis, pathophysiology, and appropriate treatments are needed.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eStatement of Ethics\u003c/h2\u003e \u003cp\u003eThe patient provided her written informed consent to receive each regimen, and treatment was administered according to the principles of the Declaration of Helsinki. This study was approved by the Japanese Red Cross Society Wakayama Medical Center Ethics Committee.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eConflict of Interest Statement\u003c/h2\u003e \u003cp\u003eAll authors declare no conflicts of interest.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eConsent to participate\u003c/h2\u003e \u003cp\u003e Informed consent was obtained from the patient.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003ePatient consent\u003c/h2\u003e \u003cp\u003e Written informed consent was obtained from this patient for her clinical information to be used for publication.\u003c/p\u003e \u003cp\u003e\u003cstrong\u003eDeclaration of interest statement\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll authors declare no conflicts of interest.\u003c/p\u003e\u003ch2\u003eFunding Sources\u003c/h2\u003e \u003cp\u003eNone\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eSO: involved in patient care, writing the manuscript, and the conception of this study. YU-A: involved in patient care. TM: involved in patient care. KO: involved in patient care.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eNone\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eIwaki N, Fajgenbaum DC, Nabel CS, et al. (2016) Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease. Am J Hematol. 91: 220-226.\u003c/li\u003e\n\u003cli\u003eLiu AY, Nabel CS, Finkelman BS, et al. (2016) Idiopathic multicentric Castleman\u0026apos;s disease: a systematic literature review. Lancet Haematol. 3: e163-175.\u003c/li\u003e\n\u003cli\u003eKawabata H, Takai K, Kojima M, et al. (2013) Castleman-Kojima disease (TAFRO syndrome) : a novel systemic inflammatory disease characterized by a constellation of symptoms, namely, thrombocytopenia, ascites (anasarca), microcytic anemia, myelofibrosis, renal dysfunction, and organomegaly : a status report and summary of Fukushima (6 June, 2012) and Nagoya meetings (22 September, 2012). J Clin Exp Hematop. 53: 57-61. \u003c/li\u003e\n\u003cli\u003ePierson SK, Shenoy S, Oromendia AB, et al. (2021) Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease.Blood Adv. 5: 3445-3456. \u003c/li\u003e\n\u003cli\u003ede Weerd NA, Samarajiwa SA, Hertzog PJ. (2007) Type I interferon receptors: biochemistry and biological functions. J Biol Chem. 282: 20053-20057. \u003c/li\u003e\n\u003cli\u003eBilliau A. (2006) Interferon: the pathways of discovery I. Molecular and cellular aspects. Cytokine Growth Factor Rev. 17: 381-409. \u003c/li\u003e\n\u003cli\u003eGilbert HS. (1998) Long term treatment of myeloproliferative disease with interferon-alpha-2b: feasibility and efficacy. Cancer. 83:1205-1213.\u003c/li\u003e\n\u003cli\u003eKiladjian JJ, Zachee P, Hino M, Pane F, Masszi T, Harrison CN, Mesa R, Miller CB, Passamonti F, Durrant S et al (2020) Long-term efficacy and safety of ruxolitinib versus best available therapy in polycythaemia vera (RESPONSE): 5-year follow up of a phase 3 study. Lancet Haematol 7: e226\u0026ndash;e237.\u003c/li\u003e\n\u003cli\u003eGisslinger H, Klade C, Georgiev P, Krochmalczyk D, Gercheva-Kyuchukova L, Egyed M, et al. (2020) Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study. Lancet Haematol. 7: e196-e208.\u003c/li\u003e\n\u003cli\u003eGisslinger H, Klade C, Georgiev P, Krochmalczyk D, Gercheva-Kyuchukova L, Egyed M, et al. (2023) Event-free survival in patients with polycythemia vera treated with ropeginterferon alfa-2b versus best available treatment. Leukemia. 37(10):2129-2132. \u003c/li\u003e\n\u003cli\u003eKirito K, Sugimoto Y, Gotoh A, Takenaka K, Ichii M, Inano T, et al. (2024) Long-term safety and efficacy of ropeginterferon alfa-2b in Japanese patients with polycythemia vera. Int J Hematol. 120(6):675-683.\u003c/li\u003e\n\u003cli\u003eIgawa T, Sato Y. (2018) TAFRO Syndrome. Hematol Oncol Clin North Am. 32(1):107-118.\u003c/li\u003e\n\u003cli\u003eWakiya R, Kameda T, Takeuchi Y, Ozaki H, Nakashima S, Shimada H, Kadowaki N, Dobashi H. (2021) Sequential change in serum VEGF levels in a case of tocilizumab-resistant TAFRO syndrome treated effectively with rituximab. Mod Rheumatol Case Rep. 5(1):145-151. \u003c/li\u003e\n\u003cli\u003eKikuchi T, Shimizu T, Toyama T, Abe R, Okamoto S.(2017) Successful Treatment of TAFRO Syndrome with Tocilizumab, Prednisone, and Cyclophosphamide..Intern Med. 56(16):2205-2211. \u003c/li\u003e\n\u003cli\u003eCorinne Williams, Alexis Phillips, Vikram Aggarwal, Liron Barnea Slonim, David C Fajgenbaum, Reem Karmali. (2021) TAFRO Syndrome and Elusive Diagnosis of Idiopathic Multicentric Castleman Disease Treated with Empiric Anti-Interleukin-6 Therapy. Case Rep Oncol. 14(3):1359-1365. \u003c/li\u003e\n\u003cli\u003eLangan Pai RA, Japp AS, Michael Gonzalez M, Rasheed RF, Okumura M, Arenas D, Pierson SK, Powers V, Layman AA, Kao C, Hakonarson H, van Rhee F, Betts MR, Kambayashi T, Fajgenbaum DC. (202) Type I IFN response associated with mTOR activation in the TAFRO subtype of idiopathic multicentric Castleman disease. JCI Insight. 5(9):e135031.\u003c/li\u003e\n\u003cli\u003eBanerjee S, Biehl A, Gadina M, Hasni S, Schwartz DM. (2017) JAK-STAT Signaling as a Target for Inflammatory and Autoimmune Diseases: Current and Future Prospects. Drugs. 77(5):521-546. \u003c/li\u003e\n\u003cli\u003eLust H, Gong S, Remiker A, Rossoff J. Idiopathic multicentric Castleman disease with TAFRO clinical subtype responsive to IL-6/JAK inhibition: A pediatric case series. Pediatr Blood Cancer. 2021 Oct;68(10): e29261. \u003c/li\u003e\n\u003cli\u003eKillian M, Viel S, Chalayer E, Forest F, Grange S, Bonnefoy PB, Oksenhendler E, Cath\u0026eacute;bras P, Paul S. (2021) JAK1/2 Inhibition in Severe TAFRO Syndrome: A Case Report. Ann Intern Med. 174(5):719-721. \u003c/li\u003e\n\u003cli\u003eRegimbeau M, Mary R, Hermetet F, Girodon F. (2022) Genetic Background of Polycythemia Vera. Genes (Basel). 13(4):637. \u003c/li\u003e\n\u003cli\u003eTefferi A, Barbui T. (2023) Polycythemia vera: 2024 update on diagnosis, risk-stratification, and management. Am J Hematol. 98(9):1465-1487. \u003c/li\u003e\n\u003cli\u003eBewersdorf JP, Giri S, Wang R, Podoltsev N, Williams RT, Tallman MS, et al. (2021) Interferon alpha therapy in essential thrombocythemia and polycythemia vera-a systematic review and meta-analysis. Leukemia. 35(6):1643-1660.\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":"Polycythemia vera, TAFRO syndrome, JAK/STAT pathway, ruxolitinib, ropegIFNα2b","lastPublishedDoi":"10.21203/rs.3.rs-6780787/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6780787/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTAFRO syndrome is a rare systemic inflammatory disease characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, and splenomegaly; however, its pathogenesis remains largely unknown. Due to the lack of appropriate treatment, TAFRO syndrome often presents with multiple organ dysfunction and fatality. The Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway has recently been shown to play an important role in the pathogenesis of inflammation in idiopathic Multicentric Castleman disease (iMCD)-TAFRO, and inhibitors of the JAK/STAT pathway may be effective as therapeutic agents for iMCD-TAFRO syndrome. Polycythemia vera (PV) is one of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), and the enhancement and modulation of immune cells may be involved in the mechanism of action of interferon (IFN)-α2 and the JAK-STAT pathway in MPNs. We herein report the successful treatment using combination therapy with ruxolitinib and ropeginterferon alfa-2b of a case of TAFRO-like syndrome with a long history of PV with \u003cem\u003eJAK2\u003c/em\u003e V617F refractory to several treatments. This combination therapy has potential as a new treatment option for refractory TAFRO syndrome-like symptoms.\u003c/p\u003e","manuscriptTitle":"Effective treatment with ruxolitinib and ropeginterferon alfa-2b for refractory TAFRO- like syndrome in Polycythemia vera","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-10 14:45:01","doi":"10.21203/rs.3.rs-6780787/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":"d519cbcd-df21-41a5-9c95-0759bb07fe38","owner":[],"postedDate":"June 10th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-08-01T06:08:46+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-10 14:45:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6780787","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6780787","identity":"rs-6780787","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}