1,344
Views
25
CrossRef citations to date
0
Altmetric
Review

Updates on the pathophysiology and treatment of aplastic anemia: a comprehensive review

&
Pages 433-448 | Received 22 Dec 2016, Accepted 28 Mar 2017, Published online: 28 Apr 2017

References

  • Bacigalupo A, Bruno B, Saracco P, et al. Antilymphocyte globulin, cyclosporine, prednisolone, and granulocyte colony-stimulating factor for severe aplastic anemia: an update of the GITMO/EBMT study on 100 patients. European Group for Blood and Marrow Transplantation (EBMT) Working Party on Severe Aplastic Anemia and the Gruppo Italiano Trapianti di Midolio Osseo (GITMO). Blood. 2000;95(6):1931–1934.
  • Young NS, Maciejewski J. The pathophysiology of acquired aplastic anemia. N Engl J Med. 1997;336(19):1365–1372.
  • Sakuma T, Hayashi Y, Kanomata N, et al. Histological and cytogenetic characterization of bone marrow in relation to prognosis and diagnosis of myelodysplastic syndromes. Pathol Int. 2006;56(4):191–199.
  • Auerbach AD. Fanconi anemia and its diagnosis. Mutat Res. 2009;668(1–2):4–10.
  • Walne AJ, Dokal I. Dyskeratosis Congenita: a historical perspective. Mech Ageing Dev. 2008;129(1–2):48–59.
  • Rovó A, Tichelli A, Dufour C. Diagnosis of acquired aplastic anemia. Bone Marrow Transplant. 2013;48(2):162–167.
  • Young NS, Maciejewski JP, Sloand E, et al. The relationship of aplastic anemia and PNH. Int J Hematol. 2002;76(Suppl 2):168–172.
  • Brown KE, Tisdale J, Barrett AJ, et al. Hepatitis-associated aplastic anemia. N Engl J Med. 1997;336(15):1059–1064.
  • Stalder MP, Rovó A, Halter J, et al. Aplastic anemia and concomitant autoimmune diseases. Ann Hematol. 2009;88(7):659–665.
  • Dufour C, Pillon M, Passweg J, et al. Outcome of aplastic anemia in adolescence: a survey of the severe aplastic anemia working party of the European Group for Blood and Marrow Transplantation. Haematologica. 2014;99(10):1574–1581.
  • Ades L, Mary J-Y, Robin M, et al. Long-term outcome after bone marrow transplantation for severe aplastic anemia. Blood. 2004;103(7):2490–2497.
  • Bacigalupo A, Hows J, Gluckman E, et al. Bone marrow transplantation (BMT) versus immunosuppression for the treatment of severe aplastic anaemia (SAA): a report of the EBMT SAA working party. Br J Haematol. 1988;70(2):177–182.
  • Camitta BM, Rappeport JM, Parkman R, et al. Selection of patients for bone marrow transplantation in severe aplastic anemia. Blood. 1975;45(3):355–363.
  • Rozman C, Marín P, Nomdedeu B, et al. Criteria for severe aplastic anaemia. Lancet. 1987;2(8565):955–957.
  • Catlin SN, Busque L, Gale RE, et al. The replication rate of human hematopoietic stem cells in vivo. Blood. 2011;117(17):4460–4466.
  • Olweus J, Lund-Johansen F, Terstappen LW. Expression of cell surface markers during differentiation of CD34+, CD38-/lo fetal and adult bone marrow cells. Immunomethods. 1994;5(3):179–188.
  • Maciejewski JP, Anderson S, Katevas P, et al. Phenotypic and functional analysis of bone marrow progenitor cell compartment in bone marrow failure. Br J Haematol. 1994;87(2):227–234.
  • Sutherland HJ, Eaves CJ, Eaves AC, et al. Characterization and partial purification of human marrow cells capable of initiating long-term hematopoiesis in vitro. Blood. 1989;74(5):1563–1570.
  • Maciejewski JP, Kim S, Sloand E, et al. Sustained long-term hematologic recovery despite a marked quantitative defect in the stem cell compartment of patients with aplastic anemia after immunosuppressive therapy. Am J Hematol. 2000;65(2):123–131.
  • Wilson A, Laurenti E, Oser G, et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell. 2008;135(6):1118–1129.
  • Sato T, Onai N, Yoshihara H, et al. Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon-dependent exhaustion. Nat Med. 2009;15(6):696–700.
  • Passegué E, Wagers AJ, Giuriato S, et al. Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates. J Exp Med. 2005;202(11):1599–1611.
  • Maciejewski JP, Selleri C, Sato T, et al. A severe and consistent deficit in marrow and circulating primitive hematopoietic cells (long-term culture-initiating cells) in acquired aplastic anemia. Blood. 1996;88(6):1983–1991.
  • Zeng W, Chen G, Kajigaya S, et al. Gene expression profiling in CD34 cells to identify differences between aplastic anemia patients and healthy volunteers. Blood. 2004;103(1):325–332.
  • Wang J, Sun Q, Morita Y, et al. A differentiation checkpoint limits hematopoietic stem cell self-renewal in response to DNA damage. Cell. 2012;148(5):1001–1014.
  • Mauch P, Rosenblatt M, Hellman S. Permanent loss in stem cell self renewal capacity following stress to the marrow. Blood. 1988;72(4):1193–1196.
  • Shao L, Luo Y, Zhou D. Hematopoietic stem cell injury induced by ionizing radiation. Antioxid Redox Signal. 2014;20(9):1447–1462.
  • Malkin D, Koren G, Saunders EF. Drug-induced aplastic anemia: pathogenesis and clinical aspects. Am J Pediatr Hematol Oncol. 1990;12(4):402–410.
  • Morinet F, Leruez-Ville M, Pillet S, et al. Concise review: anemia caused by viruses. Stem Cells. 2011;29(11):1656–1660.
  • Xing L, Liu C, Fu R, et al. CD8+HLA-DR+ T cells are increased in patients with severe aplastic anemia. Mol Med Rep. 2014;10(3):1252–1258.
  • Risitano AM, Maciejewski JP, Green S, et al. In-vivo dominant immune responses in aplastic anaemia: molecular tracking of putatively pathogenetic T-cell clones by TCR beta-CDR3 sequencing. Lancet. 2004;364(9431):355–364.
  • Schuster FR, Hubner B, Führer M, et al. Highly skewed T-cell receptor V-beta chain repertoire in the bone marrow is associated with response to immunosuppressive drug therapy in children with very severe aplastic anemia. Blood Cancer J. 2011;1(3):e8.
  • Goto M, Kuribayashi K, Takahashi Y, et al. Identification of autoantibodies expressed in acquired aplastic anaemia. Br J Haematol. 2013;160(3):359–362.
  • Kordasti S, Marsh J, Al-Khan S, et al. Functional characterization of CD4+ T cells in aplastic anemia. Blood. 2012;119(9):2033–2043.
  • Kordasti S, Costantini B, Seidl T, et al. Deep-phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment. Blood. 2016;128:1193–1205.
  • Giannakoulas NC, Karakantza M, Theodorou GL, et al. Clinical relevance of balance between type 1 and type 2 immune responses of lymphocyte subpopulations in aplastic anaemia patients. Br J Haematol. 2004;124(1):97–105.
  • Liu C, Li Z, Sheng W, et al. Abnormalities of quantities and functions of natural killer cells in severe aplastic anemia. Immunol Invest. 2014;43(5):491–503.
  • Hanaoka N, Nakakuma H, Horikawa K, et al. NKG2D-mediated immunity underlying paroxysmal nocturnal haemoglobinuria and related bone marrow failure syndromes. Br J Haematol. 2009;146(5):538–545.
  • Philpott NJ, Scopes J, Marsh JC, et al. Increased apoptosis in aplastic anemia bone marrow progenitor cells: possible pathophysiologic significance. Exp Hematol. 1995;23(14):1642–1648.
  • Maciejewski JP, Selleri C, Sato T, et al. Increased expression of Fas antigen on bone marrow CD34+ cells of patients with aplastic anaemia. Br J Haematol. 1995;91(1):245–252.
  • Killick SB, Cox CV, Marsh JC, et al. Mechanisms of bone marrow progenitor cell apoptosis in aplastic anaemia and the effect of anti-thymocyte globulin: examination of the role of the Fas-Fas-L interaction. Br J Haematol. 2000;111(4):1164–1169.
  • Maciejewski J, Selleri C, Anderson S, et al. Fas antigen expression on CD34+ human marrow cells is induced by interferon gamma and tumor necrosis factor alpha and potentiates cytokine-mediated hematopoietic suppression in vitro. Blood. 1995;85(11):3183–3190.
  • Sloand E, Kim S, Maciejewski JP, et al. Intracellular interferon-gamma in circulating and marrow T cells detected by flow cytometry and the response to immunosuppressive therapy in patients with aplastic anemia. Blood. 2002;100(4):1185–1191.
  • Dufour C, Svahn J, Bacigalupo A. Front-line immunosuppressive treatment of acquired aplastic anemia. Bone Marrow Transplant. 2013;48(2):174–177.
  • Kakagianni T, Giannakoulas NC, Thanopoulou E, et al. A probable role for trail-induced apoptosis in the pathogenesis of marrow failure. Implications from an in vitro model and from marrow of aplastic anemia patients. Leuk Res. 2006;30(6):713–721.
  • Zhang J-Y, Chang H, Meng W-T. [The polymorphism of interferon gamma gene CA short tandem repeat is associated with aplastic anemia]. Sichuan Da Xue Xue Bao Yi Xue Ban. 2008;39(1):23–25, 58.
  • Blackburn EH. Switching and signaling at the telomere. Cell. 2001;106(6):661–673.
  • Brümmendorf TH, Maciejewski JP, Mak J, et al. Telomere length in leukocyte subpopulations of patients with aplastic anemia. Blood. 2001;97(4):895–900.
  • Lee JJ, Kook H, Chung IJ, et al. Telomere length changes in patients with aplastic anaemia. Br J Haematol. 2001;112(4):1025–1030.
  • Scheinberg P, Cooper JN, Sloand EM, et al. Association of telomere length of peripheral blood leukocytes with hematopoietic relapse, malignant transformation, and survival in severe aplastic anemia. Jama. 2010;304(12):1358–1364.
  • Yamaguchi H, Calado RT, Ly H, et al. Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med. 2005;352(14):1413–1424.
  • Yamaguchi H, Baerlocher GM, Lansdorp PM, et al. Mutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome. Blood. 2003;102(3):916–918.
  • Houben JM, Moonen HJJ, Van Schooten FJ, et al. Telomere length assessment: biomarker of chronic oxidative stress? Free Radic Biol Med. 2008;44(3):235–246.
  • Dumitriu B, Feng X, Townsley DM, et al. Telomere attrition and candidate gene mutations preceding monosomy 7 in aplastic anemia. Blood. 2015;125(4):706–709.
  • Katagiri T, Sato-Otsubo A, Kashiwase K, et al. Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia. Blood. 2011;118(25):6601–6609.
  • Maciejewski JP, Selleri C. Evolution of clonal cytogenetic abnormalities in aplastic anemia. Leuk Lymphoma. 2004;45(3):433–440.
  • Maciejewski JP, Risitano A, Sloand EM, et al. Distinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia. Blood. 2002;99(9):3129–3135.
  • Mikhailova N, Sessarego M, Fugazza G, et al. Cytogenetic abnormalities in patients with severe aplastic anemia. Haematologica. 1996;81(5):418–422.
  • Yoshizato T, Dumitriu B, Hosokawa K, et al. Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia. N Engl J Med. 2015;373(1):35–47. .
  • Frickhofen N, Heimpel H, Kaltwasser JP, et al. Antithymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia. Blood. 2003;101(4):1236–1242.
  • Rosenfeld S, Follmann D, Nunez O, et al. Antithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. Jama. 2003;289(9):1130–1135.
  • Tichelli A, Schrezenmeier H, Socié G, et al. A randomized controlled study in patients with newly diagnosed severe aplastic anemia receiving antithymocyte globulin (ATG), cyclosporine, with or without G-CSF: a study of the SAA Working Party of the European Group for Blood and Marrow Transplantation. Blood. 2011;117(17):4434–4441.
  • Kojima S, Hibi S, Kosaka Y, et al. Immunosuppressive therapy using antithymocyte globulin, cyclosporine, and danazol with or without human granulocyte colony-stimulating factor in children with acquired aplastic anemia. Blood. 2000;96(6):2049–2054.
  • Kadia TM, Borthakur G, Garcia-Manero G, et al. Final results of the phase II study of rabbit anti-thymocyte globulin, ciclosporin, methylprednisone, and granulocyte colony-stimulating factor in patients with aplastic anaemia and myelodysplastic syndrome. Br J Haematol. 2012;157(3):312–320.
  • Scheinberg P, Nunez O, Weinstein B, et al. Horse versus rabbit antithymocyte globulin in acquired aplastic anemia. N Engl J Med. 2011;365(5):430–438. .
  • Marsh JC, Bacigalupo A, Schrezenmeier H, et al. Prospective study of rabbit antithymocyte globulin and cyclosporine for aplastic anemia from the EBMT Severe Aplastic Anaemia Working Party. Blood. 2012;119(23):5391–5396.
  • Passweg JR, Socié G, Hinterberger W, et al. Bone marrow transplantation for severe aplastic anemia: has outcome improved? Blood. 1997;90(2):858–864.
  • Locasciulli A, Oneto R, Bacigalupo A, et al. Outcome of patients with acquired aplastic anemia given first line bone marrow transplantation or immunosuppressive treatment in the last decade: a report from the European Group for Blood and Marrow Transplantation (EBMT). Haematologica. 2007;92(1):11–18.
  • Ahn M-J, Choi J-H, Lee -Y-Y, et al. Outcome of adult severe or very severe aplastic anemia treated with immunosuppressive therapy compared with bone marrow transplantation: multicenter trial. Int J Hematol. 2003;78(2):133–138.
  • Dulley FL, Vigorito AC, Aranha FJP, et al. Addition of low-dose busulfan to cyclophosphamide in aplastic anemia patients prior to allogeneic bone marrow transplantation to reduce rejection. Bone Marrow Transplant. 2004;33(1):9–13.
  • Bai LY, Chiou TJ, Liu JH, et al. Hematopoietic stem cell transplantation for severe aplastic anemia–experience of an institute in Taiwan. Ann Hematol. 2004;83(1):38–43.
  • Kim HJ, Park CY, Park YH, et al. Successful allogeneic hematopoietic stem cell transplantation using triple agent immunosuppression in severe aplastic anemia patients. Bone Marrow Transplant. 2003;31(2):79–86.
  • Kahl C, Leisenring W, Deeg HJ, et al. Cyclophosphamide and antithymocyte globulin as a conditioning regimen for allogeneic marrow transplantation in patients with aplastic anaemia: a long-term follow-up. Br J Haematol. 2005;130(5):747–751.
  • Passweg JR, Pérez WS, Eapen M, et al. Bone marrow transplants from mismatched related and unrelated donors for severe aplastic anemia. Bone Marrow Transplant. 2006;37(7):641–649.
  • Kojima S, Matsuyama T, Kato S, et al. Outcome of 154 patients with severe aplastic anemia who received transplants from unrelated donors: the Japan Marrow Donor Program. Blood. 2002;100(3):799–803.
  • Deeg HJ, O’Donnell M, Tolar J, et al. Optimization of conditioning for marrow transplantation from unrelated donors for patients with aplastic anemia after failure of immunosuppressive therapy. Blood. 2006;108(5):1485–1491.
  • Camitta BM, Thomas ED, Nathan DG, et al. A prospective study of androgens and bone marrow transplantation for treatment of severe aplastic anemia. Blood. 1979;53(3):504–514.
  • Kwon JH, Kim I, Lee YG, et al. Clinical course of non-severe aplastic anemia in adults. Int J Hematol. 2010;91(5):770–775.
  • Thomas ED, Storb R, Fefer A, et al. Aplastic anaemia treated by marrow transplantation. Lancet. 1972;1(7745):284–289.
  • Bacigalupo A, Brand R, Oneto R, et al. Treatment of acquired severe aplastic anemia: bone marrow transplantation compared with immunosuppressive therapy–The European Group for Blood and Marrow Transplantation experience. Semin Hematol. 2000;37(1):69–80.
  • Gluckman E, Horowitz MM, Champlin RE, et al. Bone marrow transplantation for severe aplastic anemia: influence of conditioning and graft-versus-host disease prophylaxis regimens on outcome. Blood. 1992;79(1):269–275.
  • Bacigalupo A, Oneto R, Bruno B, et al. Current results of bone marrow transplantation in patients with acquired severe aplastic anemia. Report of the European Group for Blood and Marrow transplantation. On behalf of the Working Party on Severe Aplastic Anemia of the European Group for Blood and Marrow Transplantation. Acta Haematol. 2000;103(1):19–25.
  • Schrezenmeier H, Passweg JR, Marsh JCW, et al. Worse outcome and more chronic GVHD with peripheral blood progenitor cells than bone marrow in HLA-matched sibling donor transplants for young patients with severe acquired aplastic anemia. Blood. 2007;110(4):1397–1400.
  • Bacigalupo A, Socié G, Schrezenmeier H, et al. Bone marrow versus peripheral blood as the stem cell source for sibling transplants in acquired aplastic anemia: survival advantage for bone marrow in all age groups. Haematologica. 2012;97(8):1142–1148.
  • Champlin RE, Perez WS, Passweg JR, et al. Bone marrow transplantation for severe aplastic anemia: a randomized controlled study of conditioning regimens. Blood. 2007;109(10):4582–4585.
  • Champlin RE, Horowitz MM, Van Bekkum DW, et al. Graft failure following bone marrow transplantation for severe aplastic anemia: risk factors and treatment results. Blood. 1989;73(2):606–613.
  • Deeg HJ, Self S, Storb R, et al. Decreased incidence of marrow graft rejection in patients with severe aplastic anemia: changing impact of risk factors. Blood. 1986;68(6):1363–1368.
  • Storb R, Champlin RE. Bone marrow transplantation for severe aplastic anemia. Bone Marrow Transplant. 1991;8(2):69–72.
  • May WS, Sensenbrenner LL, Burns WH, et al. BMT for severe aplastic anemia using cyclosporine. Bone Marrow Transplant. 1993;11(6):459–464.
  • Marsh JC, Gupta V, Lim Z, et al. Alemtuzumab with fludarabine and cyclophosphamide reduces chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia. Blood. 2011;118(8):2351–2357.
  • Samarasinghe S, Steward C, Hiwarkar P, et al. Excellent outcome of matched unrelated donor transplantation in paediatric aplastic anaemia following failure with immunosuppressive therapy: a United Kingdom multicentre retrospective experience. Br J Haematol. 2012;157(3):339–346.
  • Killick SB, Bown N, Cavenagh J, et al. Guidelines for the diagnosis and management of adult aplastic anaemia. Br J Haematol. 2016;172(2):187–207.
  • Aljurf M, Al-Zahrani H, Van Lint MT, et al. Standard treatment of acquired SAA in adult patients 18-40 years old with an HLA-identical sibling donor. Bone Marrow Transplant. 2013;48(2):178–179.
  • Eapen M, Ramsay NK, Mertens AC, et al. Late outcomes after bone marrow transplant for aplastic anaemia. Br J Haematol. 2000;111(3):754–760.
  • Kim H, Lee K-H, Yoon -S-S, et al. Allogeneic hematopoietic stem cell transplant for adults over 40 years old with acquired aplastic anemia. Biol Blood Marrow Transplant. 2012;18(10):1500–1508.
  • Gupta V, Eapen M, Brazauskas R, et al. Impact of age on outcomes after bone marrow transplantation for acquired aplastic anemia using HLA-matched sibling donors. Haematologica. 2010;95(12):2119–2125.
  • Dufour C, Veys P, Carraro E, et al. Similar outcome of upfront-unrelated and matched sibling stem cell transplantation in idiopathic paediatric aplastic anaemia. A study on behalf of the UK Paediatric BMT Working Party, Paediatric Diseases Working Party and Severe Aplastic Anaemia Working Party of EBMT. Br J Haematol. 2015;171(4):585–594.
  • Miao M, Zhang X, Xu T, et al. Haploidentical hematopoietic stem cell transplantation for acquired severe aplastic anemia. Blood. 2015;126(23):3227–3227.
  • Xu L-P, Jin S, Wang S-Q, et al. Upfront haploidentical transplant for acquired severe aplastic anemia: registry-based comparison with matched related transplant. J Hematol Oncol. 2017;10(1):25.
  • Luznik L, O’Donnell PV, Symons HJ, et al. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008;14(6):641–650.
  • Im HJ, Koh KN, Choi ES, et al. Excellent outcome of haploidentical hematopoietic stem cell transplantation in children and adolescents with acquired severe aplastic anemia. Biol Blood Marrow Transplant. 2013;19(5):754–759.
  • Yagasaki H, Kojima S, Yabe H, et al. Tacrolimus/Methotrexate versus cyclosporine/methotrexate as graft-versus-host disease prophylaxis in patients with severe aplastic anemia who received bone marrow transplantation from unrelated donors: results of matched pair analysis. Biol Blood Marrow Transplant. 2009;15(12):1603–1608.
  • Kuwatsuka Y, Kanda J, Yamazaki H, et al. A Comparison of Outcomes for Cord Blood Transplantation and Unrelated Bone Marrow Transplantation in Adult Aplastic Anemia. Biol Blood Marrow Transplant. 2016;22(10):1836–1843.
  • Socié G, Rosenfeld S, Frickhofen N, et al. Late clonal diseases of treated aplastic anemia. Semin Hematol. 2000;37(1):91–101.
  • Speck B, Gluckman E, Haak HL, et al. Treatment of aplastic anaemia by antilymphocyte globulin with and without allogeneic bone-marrow infusions. Lancet. 1977;2(8049):1145–1148.
  • Champlin R, Ho W, Gale RP. Antithymocyte globulin treatment in patients with aplastic anemia: a prospective randomized trial. N Engl J Med. 1983;308(3):113–118.
  • Marsh J, Hows JM, Bryett KA, et al. Survival after antilymphocyte globulin therapy for aplastic anemia depends on disease severity. Blood. 1987;70(4):1046–1052.
  • Frickhofen N, Kaltwasser JP, Schrezenmeier H, et al. Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. The German Aplastic Anemia Study Group. N Engl J Med. 1991;324(19):1297–1304.
  • Rosenfeld S, Kimball J, Vining D, et al. Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia. Blood. 1995;85(11):3058–3065.
  • Bacigalupo A, Chaple M, Hows J, et al. Treatment of aplastic anaemia (AA) with antilymphocyte globulin (ALG) and methylprednisolone (MPred) with or without androgens: a randomized trial from the EBMT SAA working party. Br J Haematol. 1993;83(1):145–151.
  • Gluckman E, Rokicka-Milewska R, Hann I, et al. Results and follow-up of a phase III randomized study of recombinant human-granulocyte stimulating factor as support for immunosuppressive therapy in patients with severe aplastic anaemia. Br J Haematol. 2002;119(4):1075–1082.
  • Olnes MJ, Scheinberg P, Calvo KR, et al. Eltrombopag and improved hematopoiesis in refractory aplastic anemia. N Engl J Med. 2012;367(1):11–19.
  • Desmond R, Townsley DM, Dumitriu B, et al. Eltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug. Blood. 2014;123(12):1818–1825.
  • Kadia T, Ravandi F, Daver N, et al. Single-center experience of immunosuppressive therapy with or without eltrombopag in patients with aplastic anemia. Blood. 2015;126(23):4779–4779.
  • Townsley DM, Dumitriu B, Young NS. Bone marrow failure and the telomeropathies. Blood. 2014;124(18):2775–2783.
  • Scheinberg P, Nunez O, Wu C, et al. Treatment of severe aplastic anaemia with combined immunosuppression: anti-thymocyte globulin, ciclosporin and mycophenolate mofetil. Br J Haematol. 2006;133(6):606–611.
  • Tisdale JF, Dunn DE, Geller N, et al. High-dose cyclophosphamide in severe aplastic anaemia: a randomised trial. Lancet (London, England). 2000;356(9241):1554–1559.
  • Zhang F, Zhang L, Jing L, et al. High-dose cyclophosphamide compared with antithymocyte globulin for treatment of acquired severe aplastic anemia. Exp Hematol. 2013;41(4):328–334.
  • Scheinberg P, Townsley D, Dumitriu B, et al. Moderate-dose cyclophosphamide for severe aplastic anemia has significant toxicity and does not prevent relapse and clonal evolution. Blood. 2014;124(18):2820–2823.
  • Passweg JR, Tichelli A. Immunosuppressive treatment for aplastic anemia: are we hitting the ceiling?. Haematologica. 2009;94(3):310–312.
  • Schrezenmeier H, Marin P, Raghavachar A, et al. Relapse of aplastic anaemia after immunosuppressive treatment: a report from the European Bone Marrow Transplantation Group SAA Working Party. Br J Haematol. 1993;85(2):371–377.
  • Means RT Jr., Krantz SB, Dessypris EN, et al. Re-treatment of aplastic anemia with antithymocyte globulin or antilymphocyte serum. Am J Med. 1988;84(4):678–682.
  • Di Bona E, Rodeghiero F, Bruno B, et al. Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. Gruppo Italiano Trapianto di Midollo Osseo (GITMO). Br J Haematol. 1999;107(2):330–334.
  • Scheinberg P, Nunez O, Young NS. Retreatment with rabbit anti-thymocyte globulin and ciclosporin for patients with relapsed or refractory severe aplastic anaemia. Br J Haematol. 2006;133(6):622–627.
  • Wei J, Huang Z, Guo J, et al. Porcine antilymphocyte globulin (p-ALG) plus cyclosporine A (CsA) treatment in acquired severe aplastic anemia: a retrospective multicenter analysis. Ann Hematol. 2015;94(6):955–962.
  • Stein RS, Means RT, Krantz SB, et al. Treatment of aplastic anemia with an investigational antilymphocyte serum prepared in rabbits. Am J Med Sci. 1994;308(6):338–343.
  • Marsh J, Schrezenmeier H, Marin P, et al. Prospective Randomized Multicenter Study Comparing Cyclosporin Alone Versus the Combination of Antithymocyte Globulin and Cyclosporin for Treatment of Patients With Nonsevere Aplastic Anemia: A Report From the European Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia Working Party. Blood. 1999;93(7):2191–2195.
  • Sloand EM, Olnes MJ, Weinstein B, et al. Long-term follow-up of patients with moderate aplastic anemia and pure red cell aplasia treated with daclizumab. Haematologica. 2010;95(3):382–387.
  • Gómez-Almaguer D, Jaime-Pérez JC, Garza-Rodríguez V, et al. Subcutaneous alemtuzumab plus cyclosporine for the treatment of aplastic anemia. Ann Hematol. 2010;89(3):299–303.
  • Scheinberg P, Nunez O, Weinstein B, et al. Activity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia. Blood. 2012;119(2):345–354.
  • Kim H, Min YJ, Baek JH, et al. A pilot dose-escalating study of alemtuzumab plus cyclosporine for patients with bone marrow failure syndrome. Leuk Res. 2009;33(2):222–231.
  • Podesta M, Piaggio G, Frassoni F, et al. The assessment of the hematopoietic reservoir after immunosuppressive therapy or bone marrow transplantation in severe aplastic anemia. Blood. 1998;91(6):1959–1965.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.