The management of severe late-onset hemorrhagic cystitis (LO-HC) after allogeneic hematopoietic stem cell transplantation (HSCT) is still challenging. Because mesenchymal stromal cells (MSCs) possess anti-inflammatory and tissue repair-promoting properties, we retrospectively analyzed the efficacy and safety of MSC infusions in 7 of 33 patients with severe LO-HC after allogeneic HSCT. During treatment, each patient received at least one MSC infusion of Wharton's jelly derived from the umbilical cord of a third-party donor. In 6 patients, MSC treatment was initiated within 3 days of gross hematuria onset, while the 7th patient received an infusion 40 days later. The median dose was 1.0 (0.8-1.6) × 106/kg. Five of 7 patients responded to treatment. Notably, gross hematuria promptly disappeared in 3 patients after 1 infusion, with a time to remission not seen in patients without MSC infusion. Two patients showed no response even after several infusions. No acute or late complications were recorded. Our findings indicate that MSC transfusion might be a feasible and safe supplemental therapy for patients with severe LO-HC after allogeneic HSCT.

Tsuboi K, Kishi K, Ohmachi K, Yasuda Y, Shimizu T, Inoue H, Matsumoto M, Hattori K, Yoshiba F, Watanabe S, Ogawa Y, Kawada H, Yabe H, Yabe M, Kato S, Hotta T: Multivariate analysis of risk factors for hemorrhagic cystitis after hematopoietic stem cell transplantation. Bone Marrow Transplant 2003;32:903-907.
El-Zimaity M, Saliba R, Chan K, Shahjahan M, Carrasco A, Khorshid O, Caldera H, Couriel D, Giralt S, Khouri I, Ippoliti C, Champlin R, de Lima M: Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: donor type matters. Blood 2004;103:4674-4680.
Leung AY, Yuen KY, Kwong YL: Polyoma BK virus and haemorrhagic cystitis in haematopoietic stem cell transplantation: a changing paradigm. Bone Marrow Transplant 2005;36:929-937.
Silva Lde P, Patah PA, Saliba RM, Szewczyk NA, Gilman L, Neumann J, Han XY, Tarrand J, Ribeiro R, Gulbis A, Shpall EJ, Jones R, Popat U, Walker JA, Petropoulos D, Chiattone A, Stewart J, El-Zimaity M, Anderlini P, Giralt S, Champlin RE, de Lima M: Hemorrhagic cystitis after allogeneic hematopoietic stem cell transplants is the complex result of BK virus infection, preparative regimen intensity and donor type. Haematologica 2010;95:1183-1190.
Giraud G, Priftakis P, Bogdanovic G, Remberger M, Dubrulle M, Hau A, Gutmark R, Mattson J, Svahn BM, Ringden O, Winiarski J, Ljungman P, Dalianis T: BK-viruria and haemorrhagic cystitis are more frequent in allogeneic haematopoietic stem cell transplant patients receiving full conditioning and unrelated-HLA-mismatched grafts. Bone Marrow Transplant 2008;41:737-742.
Cesaro S, Hirsch HH, Faraci M, Owoc-Lempach J, Beltrame A, Tendas A, Baltadakis I, Dalle JH, Koc Y, Toporski J, Styczynski J, Yesilipek MA, Heinz W, Caniglia M, Rascon J, Fauser AA, Michallet M, Lopez-Corral L, Neuburger S, Tridello G, Einsele H; European Group for Blood and Marrow Transplantation: Cidofovir for BK virus-associated hemorrhagic cystitis: a retrospective study. Clin Infect Dis 2009;49:233-240.
Savva-Bordalo J, Pinho Vaz C, Sousa M, Branca R, Campilho F, Resende R, Baldaque I, Camacho O, Campos A: Clinical effectiveness of hyperbaric oxygen therapy for BK-virus-associated hemorrhagic cystitis after allogeneic bone marrow transplantation. Bone Marrow Transplant 2012;47:1095-1098.
Tirindelli MC, Flammia G, Sergi F, Cerretti R, Cudillo L, Picardi A, Postorino M, Annibali O, Greco R, Avvisati G, Arcese W: Fibrin glue for refractory hemorrhagic cystitis after unrelated marrow, cord blood, and haploidentical hematopoietic stem cell transplantation. Transfusion 2009;49:170-175.
Ashrani AA, Gabriel DA, Gajewski JL, Jacobs DR Jr, Weisdorf DJ, Key NS: Pilot study to test the efficacy and safety of activated recombinant factor VII (NovoSeven) in the treatment of refractory hemorrhagic cystitis following high-dose chemotherapy. Bone Marrow Transplant 2006;38:825-828.
Han Y, Wu D, Sun A, Xie Y, Xu J, Zhou J, Zhu X, Wang Z, Ruan C: Selective embolization of the internal iliac arteries for the treatment of severe hemorrhagic cystitis following hematopoietic SCT. Bone Marrow Transplant 2008;41:881-886.
Bernardo ME, Locatelli F, Fibbe WE: Mesenchymal stromal cells. Ann NY Acad Sci 2009;1176:101-117.
English K, French A, Wood KJ: Mesenchymal stromal cells: facilitators of successful transplantation? Cell Stem Cell 2010;7:431-442.
Tolar J, Le Blanc K, Keating A, Blazar BR: Concise review: hitting the right spot with mesenchymal stromal cells. Stem Cells 2010;28:1446-1455.
Le Blanc K, Frassoni F, Ball L, Locatelli F, Roelofs H, Lewis I, Lanino E, Sundberg B, Bernardo ME, Remberger M, Dini G, Egeler RM, Bacigalupo A, Fibbe W, Ringdén O; Developmental Committee of the European Group for Blood and Marrow Transplantation: Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008;371:1579-1586.
Pérez-Simon JA, López-Villar O, Andreu EJ, Rifón J, Muntion S, Campelo MD, Sánchez-Guijo FM, Martinez C, Valcarcel D, Cañizo CD: Mesenchymal stem cells expanded in vitro with human serum for the treatment of acute and chronic graft-versus-host disease: results of a phase I/II clinical trial. Haematologica 2011;96:1072-1076.
Ringdén O, Uzunel M, Sundberg B, Lönnies L, Nava S, Gustafsson J, Henningsohn L, Le Blanc K: Tissue repair using allogeneic mesenchymal stem cells for hemorrhagic cystitis, pneumomediastinum and perforated colon. Leukemia 2007;21:2271-2276.
Ringden O, Le Blanc K: Mesenchymal stem cells for treatment of acute and chronic graft-versus-host disease, tissue toxicity and hemorrhages. Best Pract Res Clin Haematol 2011;24:65-72.
Anumanthan G, Makari JH, Honea L, Thomas JC, Wills ML, Bhowmick NA, Adams MC, Hayward SW, Matusik RJ, Brock JW 3rd, Pope JC 4th: Directed differentiation of bone marrow derived mesenchymal stem cells into bladder urothelium. J Urol 2008;180:1778-1783.
Weiss ML, Medicetty S, Bledsoe AR, Rachakatla RS, Choi M, Merchav S, Luo Y, Rao MS, Velagaleti G, Troyer D: Human umbilical cord matrix stem cells: preliminary characterization and effect of transplantation in a rodent model of Parkinson's disease. Stem Cells 2006;24:781-792.
Chen GH, Yang T, Tian H, Qiao M, Liu HW, Fu CC, Miao M, Jin ZM, Tang XW, Han Y, He GS, Zhang XH, Ma X, Chen F, Hu XH, Xue SL, Wang Y, Qiu HY, Sun AN, Chen ZZ, Wu DP: Clinical study of umbilical cord-derived mesenchymal stem cells for treatment of nineteen patients with steroid-resistant severe acute graft-versus-host disease (in Chinese). Zhonghua Xue Ye Xue Za Zhi 2012;33:303-306.
Pati S, Gerber MH, Menge TD, Wataha KA, Zhao Y, Baumgartner JA, Zhao J, Letourneau PA, Huby MP, Baer LA, Salsbury JR, Kozar RA, Wade CE, Walker PA, Dash PK, Cox CS Jr, Doursout MF, Holcomb JB: Bone marrow derived mesenchymal stem cells inhibit inflammation and preserve vascular endothelial integrity in the lungs after hemorrhagic shock. PLoS One 2011;6:e25171.
Batsali AK, Kastrinaki MC, Papadaki HA, Pontikoglou C: Mesenchymal stem cells derived from Wharton's jelly of the umbilical cord: biological properties and emerging clinical applications. Curr Stem Cell Res Ther 2013;8:144-155.
Phinney DG, Sensebé L: Mesenchymal stromal cells: misconceptions and evolving concepts. Cytotherapy 2013;15:140-145.
Kebriaei P, Robinson S: Treatment of graft-versus-host-disease with mesenchymal stromal cells. Cytotherapy 2011;13:262-268.
Tolar J, Nauta AJ, Osborn MJ, Panoskaltsis Mortari A, McElmurry RT, Bell S, Xia L, Zhou N, Riddle M, Schroeder TM, Westendorf JJ, McIvor RS, Hogendoorn PC, Szuhai K, Oseth L, Hirsch B, Yant SR, Kay MA, Peister A, Prockop DJ, Fibbe WE, Blazar BR: Sarcoma derived from cultured mesenchymal stem cells. Stem Cells 2007;25:371-379.
Ning H, Yang F, Jiang M, Hu L, Feng K, Zhang J, Yu Z, Li B, Xu C, Li Y, Wang J, Hu J, Lou X, Chen H: The correlation between cotransplantation of mesenchymal stem cells and higher recurrence rate in hematologic malignancy patients: outcome of a pilot clinical study. Leukemia 2008;22:593-599.
Karlsson H, Samarasinghe S, Ball LM, Sundberg B, Lankester AC, Dazzi F, Uzunel M, Rao K, Veys P, Le Blanc K, Ringdén O, Amrolia PJ: Mesenchymal stem cells exert differential effects on alloantigen and virus-specific T-cell responses. Blood 2008;112:532-541.
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