Abstract
TAFRO syndrome is a newly recognized disease entity characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. The objective of this study was to investigate the effectiveness of tocilizumab, an anti-interleukin-6 receptor antibody, in patients with TAFRO syndrome. We performed a systematic literature review from inception to July 5, 2020, for articles reporting tocilizumab administration for the treatment of TAFRO syndrome. We identified 31 patients with TAFRO syndrome treated with tocilizumab. The mean age was 49.8 years, and 61.3% of the patients were male. The mean observation period was 12.6 months. Tocilizumab was used at the standard intravenous dose (8 mg/kg) weekly or every 2 weeks in combination with other immunosuppressive drugs, such as glucocorticoids, rituximab, cyclosporine, or cyclophosphamide, in most of the patients. Eighteen patients (58.1%) received tocilizumab as a first-line treatment, while it was a second-line or a third-line treatment for 13 patients with insufficient responses to the prior treatments. Sixteen patients (51.6%) obtained complete response to tocilizumab treatment, whereas 15 patients showed only partial or no response. Detailed factors of ineffectiveness included persistent thrombocytopenia (n = 7), persistent anasarca (n = 5), persistent renal dysfunction (n = 2), and persistent fever (n = 2). A total of four patients (12.9%) succumbed to the disease, while the remaining twenty-seven patients survived. Two patients achieved drug-free remission at last visit, and disease remission was maintained with tocilizumab monotherapy in five patients. No new safety signal was reported. Tocilizumab was effective in ~ 50% of the patients, suggesting it could serve as a treatment choice for TAFRO syndrome. Poor clinical response to tocilizumab observed in other patients highlights the need for the additional therapeutic treatment options.
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References
Fajgenbaum DC, Uldrick TS, Bagg A, Frank D, Wu D, Srkalovic G, Simpson D, Liu AY, Menke D, Chandrakasan S, Lechowicz MJ, Wong RSM, Pierson S, Paessler M, Rossi JF, Ide M, Ruth J, Croglio M, Suarez A, Krymskaya V, Chadburn A, Colleoni G, Nasta S, Jayanthan R, Nabel CS, Casper C, Dispenzieri A, Fosså A, Kelleher D, Kurzrock R, Voorhees P, Dogan A, Yoshizaki K, van Rhee F, Oksenhendler E, Jaffe ES, Elenitoba-Johnson KSJ, Lim MS (2017) International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood 129:1646–1657
Takai K, Nikkuni K, Momoi A, Nagai K, Igarashi N, Saeki T (2013) Thrombocytopenia with reticulin fibrosis accompanied by fever, anasarca and hepatosplenomegaly: a clinical report of five cases. J Clin Exp Hematop. 53:63–68
Kawabata H, Takai K, Kojima M, Nakamura N, Aoki S, Nakamura S, Kinoshita T, Masaki Y (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
Srkalovic G, Marijanovic I, Srkalovic MB, Fajgenbaum DC (2017) TAFRO syndrome: new subtype of idiopathic multicentric Castleman disease. Bosn J Basic Med Sci 17:81–84
Carbone A, Pantanowitz L (2016) TAFRO syndrome: an atypical variant of KSHV-negative multicentric Castleman disease. Am J Hematol 91:171–172
Iwaki N, Fajgenbaum DC, Nabel CS, Gion Y, Kondo E, Kawano M, Masunari T, Yoshida I, Moro H, Nikkuni K, Takai K, Matsue K, Kurosawa M, Hagihara M, Saito A, Okamoto M, Yokota K, Hiraiwa S, Nakamura N, Nakao S, Yoshino T, Sato Y (2016) Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease. Am J Hematol 91:220–226
Masaki Y, Kawabata H, Fujimoto S, Kawano M, Iwaki N, Kotani T, Nakashima A, Kurose N, Takai K, Suzuki R, Aoki S (2019) Epidemiological analysis of multicentric and unicentric Castleman disease and TAFRO syndrome in Japan. J Clin Exp Hematop. 59:175–178
Fujimoto S, Sakai T, Kawabata H, Kurose N, Yamada S, Takai K, Aoki S, Kuroda J, Ide M, Setoguchi K, Tsukamoto N, Iwao-Kawanami H, Kawanami T, Mizuta S, Fukushima T, Masaki Y (2019) Is TAFRO syndrome a subtype of idiopathic multicentric Castleman disease? Am J Hematol 94:975–983
Kaneko Y, Atsumi T, Tanaka Y, Inoo M, Kobayashi-Haraoka H, Amano K, Miyata M, Murakawa Y, Yasuoka H, Hirata S, Nagasawa H, Tanaka E, Miyasaka N, Yamanaka H, Yamamoto K, Takeuchi T (2016) Comparison of adding tocilizumab to methotrexate with switching to tocilizumab in patients with rheumatoid arthritis with inadequate response to methotrexate: 52-week results from a prospective, randomised, controlled study (SURPRISE study). Ann Rheum Dis 75:1917–1923
Kaneko Y, Kato M, Tanaka Y, Inoo M, Kobayashi-Haraoka H, Amano K, Miyata M, Murakawa Y, Yasuoka H, Hirata S, Tanaka E, Miyasaka N, Yamanaka H, Yamamoto K, Takeuchi T, SURPRISE study group (2018) Tocilizumab discontinuation after attaining remission in patients with rheumatoid arthritis who were treated with tocilizumab alone or in combination with methotrexate: results from a prospective randomised controlled study (the second year of the SURPRISE study). Ann Rheum Dis 77:1268–1275
Akiyama M, Kaneko Y, Kondo H, Takeuchi T (2016) Comparison of the clinical effectiveness of tumour necrosis factor inhibitors and abatacept after insufficient response to tocilizumab in patients with rheumatoid arthritis. Clin Rheumatol 35:2829–2834
Yokota S, Imagawa T, Mori M, Miyamae T, Aihara Y, Takei S, Iwata N, Umebayashi H, Murata T, Miyoshi M, Tomiita M, Nishimoto N, Kishimoto T (2008) Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial. Lancet. 371:998–1006
Kaneko Y, Kameda H, Ikeda K, Ishii T, Murakami K, Takamatsu H, Tanaka Y, Abe T, Takeuchi T (2018) Tocilizumab in patients with adult-onset still's disease refractory to glucocorticoid treatment: a randomised, double-blind, placebo-controlled phase III trial. Ann Rheum Dis 77:1720–1729
Stone JH, Tuckwell K, Dimonaco S, Klearman M, Aringer M, Blockmans D, Brouwer E, Cid MC, Dasgupta B, Rech J, Salvarani C, Schett G, Schulze-Koops H, Spiera R, Unizony SH, Collinson N (2017) Trial of tocilizumab in giant-cell arteritis. N Engl J Med 377:317–328
Nakaoka Y, Isobe M, Takei S, Tanaka Y, Ishii T, Yokota S, Nomura A, Yoshida S, Nishimoto N (2018) Efficacy and safety of tocilizumab in patients with refractory Takayasu arteritis: results from a randomised, double-blind, placebo-controlled, phase 3 trial in Japan (the TAKT study). Ann Rheum Dis 77:348–354
Akiyama M, Kaneko Y, Takeuchi T (2020) Tocilizumab in isolated polymyalgia rheumatica: a systematic literature review. Semin Arthritis Rheum 50:521–525
Akiyama M, Kaneko Y, Takeuchi T (2020) Effectiveness of tocilizumab in Behcet's disease: a systematic literature review. Semin Arthritis Rheum 50:797–804
van Rhee F, Voorhees P, Dispenzieri A, Fosså A, Srkalovic G, Ide M, Munshi N, Schey S, Streetly M, Pierson SK, Partridge HL, Mukherjee S, Shilling D, Stone K, Greenway A, Ruth J, Lechowicz MJ, Chandrakasan S, Jayanthan R, Jaffe ES, Leitch H, Pemmaraju N, Chadburn A, Lim MS, Elenitoba-Johnson KS, Krymskaya V, Goodman A, Hoffmann C, Zinzani PL, Ferrero S, Terriou L, Sato Y, Simpson D, Wong R, Rossi JF, Nasta S, Yoshizaki K, Kurzrock R, Uldrick TS, Casper C, Oksenhendler E, Fajgenbaum DC (2018) International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease. Blood. 132:2115–2124
Akiyama M, Yasuoka H, Takeuchi T (2017) Interleukin-6 in idiopathic multicentric Castleman’s disease after long-term tocilizumab. Ann Hematol 96:2117–2119
Simeni Njonnou SR, Deuson J, Royer-Chardon C, Vandergheynst FA, Wilde V (2020) Unexplained cause of thrombocytopenia, fever, anasarca and hypothyroidism: TAFRO syndrome with thrombotic microangiopathy renal histology. BMJ Case Rep 13:e234155
Kawabata H, Kotani S, Matsumura Y, Kondo T, Katsurada T, Haga H, Kadowaki N, Takaori-Kondo A (2013) Successful treatment of a patient with multicentric Castleman’s disease who presented with thrombocytopenia, ascites, renal failure and myelofibrosis using tocilizumab, an anti-interleukin-6 receptor antibody. Intern Med 52:1503–1507
Iwaki N, Sato Y, Takata K, Kondo E, Ohno K, Takeuchi M, Orita Y, Nakao S, Yoshino T (2013) Atypical hyaline vascular-type Castleman’s disease with thrombocytopenia, anasarca, fever, and systemic lymphadenopathy. J Clin Exp Hematop. 53:87–93
Kubokawa I, Yachie A, Hayakawa A, Hirase S, Yamamoto N, Mori T, Yanai T, Takeshima Y, Kyo E, Kageyama G, Nagai H, Uehara K, Kojima M, Iijima K (2014) The first report of adolescent TAFRO syndrome, a unique clinicopathologic variant of multicentric Castleman’s disease. BMC Pediatr 14:139
Fujiwara S, Mochinaga H, Nakata H, Ohshima K, Matsumoto M, Uchiba M, Mikami Y, Hata H, Okuno Y, Mitsuya H, Nosaka K (2016) Successful treatment of TAFRO syndrome, a variant type of multicentric Castleman disease with thrombotic microangiopathy, with anti-IL-6 receptor antibody and steroids. Int J Hematol 103:718–723
Sakashita K, Murata K, Inagaki Y, Oota S, Takamori M (2016) An anterior mediastinal lesion in TAFRO syndrome showing complete remission after glucocorticoid and tocilizumab therapy. Respirol Case Rep 4:e00173
Simons M, Apor E, Butera JN, Treaba DO (2016) TAFRO syndrome associated with EBV and successful triple therapy treatment: case report and review of the literature. Case Rep Hematol 2016:4703608
José FF, Kerbauy LN, Perini GF, Blumenschein DI, Pasqualin DD, Malheiros DM et al (2017) A life-threatening case of TAFRO syndrome with dramatic response to tocilizumab, rituximab, and pulse steroids: the first case report in Latin America. Medicine (Baltimore) 96:e6271
Fujiki T, Hirasawa S, Watanabe S, Iwamoto S, Ando R (2017) Successful treatment by tocilizumab without steroid in a very severe case of TAFRO syndrome. CEN Case Rep 6:105–110
Kikuchi T, Shimizu T, Toyama T, Abe R, Okamoto S (2017) Successful treatment of TAFRO syndrome with tocilizumab, prednisone, and cyclophosphamide. Intern Med 56:2205–2211
Hou T, Dhillon J, Xiao W, Jaffe ES, Sands AM, Neppalli V, Deeb G, Zhang N (2017) TAFRO syndrome: a case report and review of the literature. Hum Pathol (N Y) 10:1–4
Sakai K, Maeda T, Kuriyama A, Shimada N, Notohara K, Ueda Y (2018) TAFRO syndrome successfully treated with tocilizumab: a case report and systematic review. Mod Rheumatol 28:564–569
Takayama Y, Kubota T, Ogino Y, Ohnishi H, Togitani K, Yokoyama A (2018) TAFRO syndrome with disseminated intravascular coagulation successfully treated with tocilizumab and recombinant thrombomodulin. Intern Med 57:1291–1296
Fujiwara Y, Ito K, Takamura A, Nagata K (2018) The first case of thrombocytopenia, anasarca, fever, renal impairment or reticulin fibrosis, and organomegaly (TAFRO) syndrome with unilateral adrenal necrosis: a case report. J Med Case Rep 12:295
Suzuki K, Matsumoto T, Iwashita Y, Ishikura K, Fujioka M, Wada H, Katayama N, Imai H (2019) Clinicopathological features of TAFRO syndrome complicated by acquired hemophilia a and development of cardiopulmonary arrest that were successfully treated with VA-ECMO and tocilizumab. Int J Hematol 109:737–743
Nagayama Y, Yamano M, Yagame M, Nariyama T, Takahashi M, Kawamoto M, Matsui K (2019) TAFRO syndrome as a cause of glomerular microangiopathy: a case report and literature review. BMC Nephrol 20:375
Louis C, Vijgen S, Samii K, Chalandon Y, Terriou L, Launay D et al (2017) TAFRO syndrome in Caucasians: a case report and review of the literature. Front Med (Lausanne) 4:149
Mizuno H, Sekine A, Oguro M, Oshima Y, Kawada M, Sumida K, Yamanouchi M, Hayami N, Suwabe T, Hiramatsu R, Hasegawa E, Hoshino J, Sawa N, Fujii T, Takaichi K, Ohashi K, Ubara Y (2018) Renal histology in a patient with TAFRO syndrome: a case report. Hum Pathol 82:258–263
Nara M, Komatsuda A, Itoh F, Kaga H, Saitoh M, Togashi M, Kameoka Y, Wakui H, Takahashi N (2017) Two cases of thrombocytopenia, Anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome with high serum procalcitonin levels, including the first case complicated with adrenal hemorrhaging. Intern Med 56:1247–1252
Konishi Y, Takahashi S, Nishi K, Sakamaki T, Mitani S, Kaneko H, Mizutani C, Ukyo N, Hirata H, Tsudo M (2015) Successful treatment of TAFRO syndrome, a variant of multicentric Castleman’s disease, with cyclosporine a: possible pathogenetic contribution of interleukin-2. Tohoku J Exp Med 236:289–295
Yamaga Y, Tokuyama K, Kato T, Yamada R, Murayama M, Ikeda T, Yamakita N, Kunieda T (2016) Successful treatment with cyclosporin a in tocilizumab-resistant TAFRO syndrome. Intern Med 55:185–190
Tedesco S, Postacchini L, Manfredi L, Goteri G, Luchetti MM, Festa A, Gabrielli A, Pomponio G (2015) Successful treatment of a Caucasian case of multifocal Castleman’s disease with TAFRO syndrome with a pathophysiology targeted therapy - a case report. Exp Hematol Oncol 4:3
Tatekawa S, Umemura K, Fukuyama R, Kohno A, Taniwaki M, Kuroda J, Morishita Y (2015) Thalidomide for tocilizumab-resistant ascites with TAFRO syndrome. Clin Case Rep. 3:472–478
Awano N, Inomata M, Kondoh K, Satake K, Kamiya H, Moriya A, Ando T, Kumasaka T, Takemura T, Takeuchi K, Ikushima S (2012) Mixed-type multicentric Castleman’s disease developing during a 17-year follow-up of sarcoidosis. Intern Med 51:3061–3066
Ducoux G, Guerber A, Durel CA, Asli B, Fadlallah J, Hot A (2020) Thrombocytopenia, anasarca, fever, reticulin fibrosis/renal failure, and organomegaly (TAFRO) syndrome with bilateral adrenal hemorrhage in two Caucasian patients. Am J Case Rep 21:e919536
Minamikawa S, Matsumura O, Sato S, Nakagishi Y, Tanaka R. A pediatric case of tocilizumab-resistant TAFRO syndrome treated successfully with rituximab. Pediatr Blood Cancer. 2020:e28489
Aoki T, Wada M, Kawashima A, Hirakawa K, Nagata A, Kagawa K (2017) Tocilizumab-resistant TAFRO syndrome complicated by type II respiratory failure. Intern Med 56:3249–3254
Oka S, Ono K, Nohgawa S (2018) Successful treatment of refractory TAFRO syndrome with elevated vascular endothelial growth factor using thyroxine supplements. Clin Case Rep 6:644–650
Tadokoro A, Kanaji N, Hara T, Matsumoto K, Ishii T, Takagi T, Watanabe N, Kita N, Kawauchi M, Ueno M, Kadowaki N, Bandoh S (2016) An uncharted constellation: TAFRO syndrome. Am J Med 129:938–941
Shirai T, Onishi A, Waki D, Saegusa J, Morinobu A (2018) Successful treatment with tacrolimus in TAFRO syndrome: two case reports and literature review. Medicine (Baltimore) 97:e11045
Matsuhisa T, Takahashi N, Nakaguro M, Sato M, Inoue E, Teshigawara S, Ozawa Y, Kondo T, Nakamura S, Sato J, Ban N (2019) Fatal case of TAFRO syndrome associated with over-immunosuppression: a case report and review of the literature. Nagoya J Med Sci 81:519–528
Masaki Y, Kawabata H, Takai K, Tsukamoto N, Fujimoto S, Ishigaki Y et al (2020) 2019 updated diagnostic criteria and disease severity classification for TAFRO syndrome. Int J Hematol 111:155–158
Iwaki N, Fajgenbaum DC, Nabel CS, Gion Y, Kondo E, Kawano M, Masunari T, Yoshida I, Moro H, Nikkuni K, Takai K, Matsue K, Kurosawa M, Hagihara M, Saito A, Okamoto M, Yokota K, Hiraiwa S, Nakamura N, Nakao S, Yoshino T, Sato Y (2016) Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease. Am J Hematol 91:220–226
Ishibashi T, Kimura H, Uchida T, Kariyone S, Friese P, Burstein SA (1989) Human interleukin 6 is a direct promoter of maturation of megakaryocytes in vitro. Proc Natl Acad Sci U S A 86:5953–5957
Eddahri F, Denanglaire S, Bureau F, Spolski R, Leonard WJ, Leo O, Andris F (2009) Interleukin-6/STAT3 signaling regulates the ability of naive T cells to acquire B-cell help capacities. Blood. 113:2426–2433
Liu AY, Nabel CS, Finkelman BS, Ruth JR, Kurzrock R, Rhee F et al (2016) Idiopathic multicentric Castleman’s disease: a systematic literature review. Lancet Haematol 3:163–175
Iwaki N, Gion Y, Kondo E, Kawano M, Masunari T, Moro H, Nikkuni K, Takai K, Hagihara M, Hashimoto Y, Yokota K, Okamoto M, Nakao S, Yoshino T, Sato Y (2017) Elevated serum interferon γ-induced protein 10 kDa is associated with TAFRO syndrome. Sci Rep 7:42316
Pierson SK, Stonestrom AJ, Shilling D, Ruth J, Nabel CS, Singh A, Ren Y, Stone K, Li H, van Rhee F, Fajgenbaum DC (2018) Plasma proteomics identifies a ‘chemokine storm’ in idiopathic multicentric Castleman disease. Am J Hematol 93:902–912
Antonelli A, Ferrari SM, Giuggioli D, Ferrannini E, Ferri C, Fallahi P (2014) Chemokine (C-X-C motif) ligand (CXCL)10 in autoimmune diseases. Autoimmun Rev 13:272–280
Galve-de Rochemonteix B, Nicod LP, Dayer JM (1996) Tumor necrosis factor soluble receptor 75: the principal receptor form released by human alveolar macrophages and monocytes in the presence of interferon gamma. Am J Respir Cell Mol Biol 14:279–287
Widner B, Wirleitner B, Baier-Bitterlich G, Weiss G, Fuchs D (2000) Cellular immune activation, neopterin production, tryptophan degradation and the development of immunodeficiency. Arch Immunol Ther Exp 48:251–258
Morita K, Fujiwara SI, Ikeda T, Kawaguchi SI, Toda Y, Ito S, Ochi SI, Nagayama T, Mashima K, Umino K, Minakata D, Nakano H, Yamasaki R, Kawasaki Y, Sugimoto M, Ashizawa M, Yamamoto C, Hatano K, Sato K, Oh I, Ohmine K, Muroi K, Ashizawa K, Yamamoto Y, Oshiro H, Kanda Y (2019) TAFRO syndrome with an anterior mediastinal mass and lethal autoantibody-mediated thrombocytopenia: an autopsy case report. Acta Haematol 141:158–163
Juskewitch JE, Norgan AP, De Goey SR, Duellman PM, Wakefield LL, Gandhi MJ et al (2017) How do I … manage the platelet transfusion-refractory patient? Transfusion. 57:2828–2835
Leurs A, Gnemmi V, Lionet A, Renaud L, Gibier JB, Copin MC et al (2019) Renal pathologic findings in TAFRO syndrome: is there a continuum between thrombotic microangiopathy and membranoproliferative glomerulonephritis? A Case Report and Literature Review Front Immunol 10:1489
Campbell L, Chen C, Bhagat SS, Parker RA, Östör AJ (2011) Risk of adverse events including serious infections in rheumatoid arthritis patients treated with tocilizumab: a systematic literature review and meta-analysis of randomized controlled trials. Rheumatology (Oxford) 50:552–562
Koike T, Harigai M, Inokuma S, Ishiguro N, Ryu J, Takeuchi T, Takei S, Tanaka Y, Sano Y, Yaguramaki H, Yamanaka H (2014) Effectiveness and safety of tocilizumab: postmarketing surveillance of 7901 patients with rheumatoid arthritis in Japan. J Rheumatol 41:15–23
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M.A. reports no conflicts of interest relevant to this article. Y.K. has received grants or speaker fees from AbbVie, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly, Hisamitsu, Jansen, Kissei, Pfizer, Sanofi, Takeda, Tanabe-Mitsubishi, and UCB. T.T. has received research grants or speaking fees from Astellas Pharma Inc., Bristol–Myers K.K., Chugai Pharmaceutical Co, Ltd., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd., AbbVie GK, Asahi Kasei Pharma Corp., Mitsubishi Tanabe Pharma, Astra Zeneca K.K., Eli Lilly Japan K.K., Novartis Pharma K.K., AbbVie GK, Nippon Kayaku Co. Ltd., Janssen Pharmaceutical K.K., Taiho Pharmaceutical Co., Ltd., and Pfizer Japan Inc.
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Akiyama, M., Kaneko, Y. & Takeuchi, T. Tocilizumab for the treatment of TAFRO syndrome: a systematic literature review. Ann Hematol 99, 2463–2475 (2020). https://doi.org/10.1007/s00277-020-04275-0
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DOI: https://doi.org/10.1007/s00277-020-04275-0