Current concepts in the pathophysiology and treatment of aplastic anemia
Aplastic anemia, an unusual hematologic disease, is the paradigm of the human bone marrow failure syndromes. Almost universally fatal just a few decades ago, aplastic anemia can now be cured or ameliorated by stem-cell transplantation or immunosuppressive drug therapy. The pathophysiology is immune mediated in most cases, with activated type 1 cytotoxic T cells implicated. The molecular basis of the aberrant immune response and deficiencies in hematopoietic cells is now being defined genetically; examples are telomere repair gene mutations in the target cells and dysregulated T-cell activation pathways. Immunosuppression with antithymocyte globulins and cyclosporine is effective at restoring blood-cell production in the majority of patients, but relapse and especially evolution of clonal hematologic diseases remain problematic. Allogeneic stem-cell transplant from histocompatible sibling donors is curative in the great majority of young patients with severe aplastic anemia; the major challenges are extending the benefits of transplantation to patients who are older or who lack family donors. Recent results with alternative sources of stem cells and a variety of conditioning regimens to achieve their engraftment have been promising, with survival in small pediatric case series rivaling conventional transplantation results.
Only studies of more than 20 enrolled patients are tabulated. Responses to immunosuppressive therapy are usually partial; blood counts may not become normal but transfusions are no longer required and the neutrophil count is adequate to prevent infection. Relapse is usually responsive to further immunosuppressive therapies. Clonal evolution is to dysplastic bone marrow changes and/or cytogenetic abnormalities. For details, see “Immunosuppression”
In contrast to Table 1, response rates are not provided because, in surviving patients who do not experience primary graft rejection or secondary graft failure, full hematologic recovery with donor hematopoiesis is anticipated. Only studies reporting at least 20 patients are tabulated
GVHD indicates graft-versus-host disease; IBMTR, International Blood and Marrow Transplant Registry; and EBMT, European Group for Bone Marrow Transplant
Only studies reporting at least 5 patients are tabulated. GVHD, graft-versus-host disease; IBMTR, International Blood and Marrow Transplant Registry; MUD, matched unrelated donor; MMUD, mismatched unrelated donor; Cy, cyclophosphamide; ATG, antithymocyte globulin; TBI, total body irradiation; CP, alemtuzumab; LFI, limited field irradiation; TCD, T-cell depletion; TLI, total lymphoid irradiation; Flu, fludarabine; UCB, umbilical cord blood; MMRD, mismatched related donor; and TT, thiotepa
We are thankful to colleagues from the Hematology Branch, Drs A. John Barrett, Cynthia Dunbar, Richard Childs, and Elaine Sloand, and in Europe, Professors Judith Marsh, Gérard Socié, and André Tichelli for their careful reading of the paper and helpful criticisms.
The authors apologize to their colleagues whose papers were not cited in the bibliography due to space constraints.
Prepublished online as Blood First Edition Paper, June 15, 2006; DOI 10.1182/blood-2006-03-010777.
Supported by NIH Intramural Research program.
N.S.Y. wrote “Introduction” and “Etiologies” as well as contributed to “Pathophysiology” and “Treatment”; R.T.C. wrote “Pathophysiology”; and P.S. wrote “Treatment.” All authors contributed to the final paper.
- 1. Young NS. Aplastic anemia. In: Young NS, ed. The Bone Marrow Failure Syndromes. Philadelphia, PA: W. B. Saunders; 2000: 1-46.
- 2. Kojima S, Nakao S, Tomonaga M, et alConsensus conference on the treatment of aplastic anemia. Int J Hematol. 2000;72: 118-123. [
- 3. Marsh JCWManagement of acquired aplastic anaemia. Blood Rev. 2005;19: 143-151. [
- 4. Nakao S, Feng X, Sugimori CImmune pathophysiology of aplastic anemia. Intl J Hematol. 2005;82: 196-200. [
- 5. Young NS. Acquired aplastic anemia. In: Young NS, Gerson SL, High K, eds. Clinical Hematology. Philadelphia, PA: Elsevier; 2006: 136-157.
- 6. Schrezenmeier H, Bacigalupo A. Aplastic Anemia: Pathophysiology and Treatment. Cambridge, United Kingdom: Cambridge University Press; 2000.
- 7. Choudhry VP, Gupta S, Gupta M, Kashyap R, Saxena RPregnancy associated aplastic anemia: a series of 10 cases with review of literature. Hematolgy. 2002;7: 233-238. [
- 8. Lu J, Basu A, Melenhorst J, Young NS, Brown KEAnalysis of T-cell repertoire in hepatitis-associated aplastic anemia. Blood. 2004;103: 4588-4593. [
- 9. Morgan GJ, Alvares CLBenzene and the hemopoietic stem cell. Chem Biol Interact. 2005;153-154: 217-222. [
- 10. Young NS. Drugs and chemicals. In: Young NS, Alter BP, eds. Aplastic Anemia, Acquired and Inherited. Philadelphia, PA: W. B. Saunders; 1994: 100-132.
- 11. Gerson WT, Fine DG, Spielberg SP, Sensenbrenner LLAnticonvulsant-induced aplastic anemia: increased susceptibility to toxic drug metabolites in vitro. Blood. 1983;61: 889-893. [
- 12. Sutton JF, Stacey M, Kearsey SE, et alIncreased risk for aplastic anemia and myelodysplastic syndrome in individuals lacking GSTT1 gene. Pediatric Blood Cancer. 2004;42: 122-126. [
- 13. Dufour C, Syahn J, Bacigalupo A, et alGenetic polymorphisms of CYP3A4, GSTT1, GSTM1, GSTP1 and NQO1 and the risk of acquired idiopathic aplastic anemia in Caucasian patients. Haematologica. 2005;90: 1027-1031. [
- 14. Bacigalupo AAetiology of severe aplastic anaemia and outcome after allogeneic bone marrow transplantation or immunosuppression. Eur J Haematol. 1996;57(suppl 60): 16-19. [
- 15. Kaufman DW, Kelly JP, Levy M, Shapiro S. The Drug Etiology of Agranulocytosis and Aplastic Anemia. New York, NY: Oxford; 1991.
- 16. Issaragrisil S, Kaufman D, Anderson T, et alThe epidemiology of aplastic anemia in Thailand. Blood. 2006;107: 1299-1307.
- 17. Hirano N, Butler MO, von Bergwelt-Baildon MS, et alAutoantibodies frequently detected in patients with aplastic anemia. Blood. 2003;102: 4567-4575. [
- 18. Feng X, Chuhjo T, Sugimori C, et alDiazepam-binding inhibitor-related protein 1: a candidate autoantigen in acquired aplastic anemia patients harboring a minor populatoin of paroxysmal nocturnal hemoglobinuria-type cells. Blood. 2004; 104: 2425-2431. [
- 19. Hinterberger W, Rowlings PA, Hinterberger-Fischer M, et alResults of transplanting bone marrow from genetically identical twins into patients with aplastic anemia. Ann Intern Med. 1997;126: 116-122. [
- 20. Young NSHematopoietic cell destruction by immune mechanisms in aquired aplastic anemia. Semin Hematol. 2000;37: 3-14. [
- 21. Sloand EM, Kim S, Maciejewski JP, et alIntracellular interferon-γ in circulating and marrow T cells detected by flow cytometry and the response to imunosuppressive therapy in patients with aplastic anemia. Blood. 2002;100: 1185-1191. [
- 22. Risitano AM, Maciejewski JP, Green S, et alInvivo dominant immune responses in aplastic anaemia: molecular tracking of putatively pathogenetic T-cell clones by TCR beta-CDR3 sequencing. Lancet. 2004;364: 355-364. [
- 23. Maciejewski JP, Selleri C, Anderson S, Young NSFas 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: 3183-3190. [
- 24. Selleri C, Maciejewski JP, Sato T, Young NSInterferon-γ constitutively expressed in the stromal microenviroment of human marrow cultures mediates potent hematopoietic inhibition. Blood. 1996; 87: 4149-4157. [
- 25. Bloom ML, Wolk A, Simon-Stoos K, et alA mouse model of human immune mediated bone marrow failure. Exp Hematol. 2004;32: 1163-1172. [
- 26. Chen J, Lipovsky K, Ellison FM, Calado RT, Young NSBystander destruction of hematopoietic progenitor and stem cells in a mouse model of infusion-induced bone marrow failure. Blood. 2004;104: 1671-1678. [
- 27. Chen J, Young NSA murine model of bone marrow failure mediated by disparity in minor histocompatibility antigens [abstract]. Blood. 2004; 106: 12a. Abstract 132.
- 28. Nakao S, Takamatsu H, Chuhjo T, et alIdentification of a specific HLA class II haplotype strongly associated with susceptibility to cyclosporine-dependent aplastic anemia. Blood. 1994;84: 4257-4261. [
- 29. Maciejewski JP, Follmann D, Rivera CE, et alIncreased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and PNH/aplastic anemia syndrome. Blood. 2001;98: 3513-3519. [
- 30. Peng J, Liu C, Zhu K, et alThe TNF2 allele is a risk factor to severe aplastic anemia independent of HLA-DR. Hum Immunol. 2003;64: 896-901. [
- 31. Demeter J, Messer G, Schrezenmeier HClinical relevance of the TNF-alpha promoter/enhancer polymorphism in patients with aplastic anemia. Ann Hematol. 2002;81: 566-569. [
- 32. Dufour C, Capasso M, Svahn J, et alHomozygosis for (12) CA repeats in the first intron of the human IFN-gamma gene is significantly associated with the risk of aplastic anaemia in Caucasian population. Br J Haematol. 2004;126: 682-685. [
- 33. Gidvani V, Ramkissoon S, Wong E, et alTumor necrosis factor-alpha and interleukin-6 promoter gene polymorphisms in acquired bone marrow failure syndromes [abstract]. Proceedings of the 46th ASH Annual Meeting. 2004;104: 12b. Abstract 3707.
- 34. Solomou EE, Keyvanfar K, Young NST-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia. Blood. 2006; 107: 3983-3991.
- 35. Xu JL, Nagasaka T, Nakashima NInvolvement of cytotoxic granules in the apoptosis of aplastic anaemia. Br J Haematol. 2003;120: 850-852. [
- 36. Zeng W, Kajigaya S, Chen G, et alTranscript profile of CD4+ and CD8+ cells from the bone marrow of acquired aplastic anemia patients. Exp Hematol. 2004;32: 806-814. [
- 37. Poggi A, Negrini S, Zocchi MR, et alPatients with paroxysmal nocturnal hemoglobinuria have a high frequency of peripheral-blood T cells expressing activating isoforms of inhibiting superfamily receptors. Blood. 2005;106: 2399-2408. [
- 38. Howe EC, Wlodarski M, Ball EJ, Rybicki L, Maciejewski JPKiller immunoglobulin-like receptor genotype in immune-mediated bone marrow failure syndromes. Exp Hematol. 2005;33: 1357-1362. [
- 39. Maciejewski JP, Selleri C, Tadatsugu S, Anderson S, Young NSA severe and consistent deficit in marrow and circulating primitive hematopoietic cells (long-term culture-initiating cells) in acquired aplastic anemia. Blood. 1996;88: 1983-1991. [
- 40. Schrezenmeier H, Jenal M, Herrmann F, Heimpel H, Raghavachar AQuantitative analysis of cobblestone area-forming cells in bone marrow of patients with aplastic anemia by limiting dilution assay. Blood. 1996;88: 4474-4480. [
- 41. Philpott NJ, Scopes J, Marsh JCW, Gordon-Smith EC, Gibson FMIncreased apoptosis in aplastic anemia bone marrow progenitor cells: possible pathophysiologic significance. Exp Hematol. 1995;23: 1642-1648. [
- 42. Kakagianni T, Giannakoulas NC, Thanopoulou E, et alA 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: 713-721. [
- 43. Zeng W, Chen G, Kajigaya S, et alGene expression profiling in CD34 cells to identify differences between aplastic anemia patients and healthy volunteers. Blood. 2004;103: 325-332. [
- 44. Zeng W, Miyazato A, Chen G, Kajigaya S, Young NSInterferon-γ-induced gene expression in CD34 cells: identification of pathologic cytokine-specific signature profiles. Blood. 2006;107: 167-175.
- 45. Ball SE, Gibson FM, Rizzo S, et alProgressive telomere shortening in aplastic anemia. Blood. 1998;91: 3582-3592. [
- 46. Brummendorf TH, Maciejewski JP, Young NS, Lansdorp PLTelomere length in leukocyte subpopulations of patients with aplastic anemia. Blood. 2001;97: 895-900. [
- 47. Fogarty PF, Yamaguchi H, Wiestner A, et alLate presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA. Lancet. 2003;362: 1628-1630. [
- 48. Yamaguchi H, Baerlocher GM, Lansdorp PL, et alMutations of the human telomerase RNA gene (TERC) in aplastic anemia and myelodysplastic syndrome. Blood. 2003;102: 916-918. [
- 49. Yamaguchi H, Calado RT, Ly H, et alMutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. N Engl J Med. 2005;352: 1413-1424. [
- 50. Savage SA, Calado RT, Lansdorp PM, Chanock SJ, Young NSGenetic variation in telomeric repeat binding factor 1 but not telomeric repeat binding factor 2 are associated with aplastic anemia. Exp Hematol. 2006;34: 664-671. [
- 51. Thornley I, Dror Y, Sung L, Wynn RF, Freedman MHAbnormal telomere shortening in leucocytes of children with Shwachman-Diamond syndrome. Br J Haematol. 2002;117: 189-192. [
- 52. Calado RT, Bruno T, Wilkerson KL, Young NSEvidence for T-cell oligoclonal expansion in aplastic anemia associated with telomerase complex mutations: pathophysiological and clinical implications [abstract]. Blood. 2005;106: 307a. Abstract 1052.
- 53. Young NSParoxysmal nocturnal hemoglobinuria: current issues in pathophysiology and treatment. Curr Hematol Rep. 2005;4: 103-109. [
- 54. Sugimori C, Chuhjo T, Feng X, et alMinor population of CD55-CD59 blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia. Blood. 2006;107: 1308-1314. [
- 55. Takami A, Zeng W, Wang H, Matsuda T, Nakao SCytotoxicity against lymphoblastoid cells mediated by a T-cell clone from an aplastic anaemia patient: role of CD59 on target cells. Br J Haematol. 1999;107: 791-796. [
- 56. Karadimitris A, Notaro R, Koehne G, Roberts IAG, Luzzatto LPNH cells are as sensitive to T-cell-mediated lysis as their normal counterparts: implications for the pathogenesis of paroxysmal nocturnal haemoglobinuria. Brit J Haematol. 2000;111: 1158-1163. [
- 57. Chen G, Kirby M, Zeng W, Young NS, Maciejewski JPSuperior growth of glycophosphatidy linositol-anchored protein-deficient progenitor cells in vitro is due to the higher apoptotic rate of progenitors with normal phenotype in vivo. Exp Hematol. 2002;30: 774-782. [
- 58. Chen G, Zeng W, Maciejewski JP, et alDifferential gene expression profile in hematopoietic progenitors form paroxysmal nocturnal hemoglobinuria patients reveals an apoptosis/immune response in `normal' phenotype cells. Leukemia. 2005;19: 862-868. [
- 59. Hanaoka N, Kawaguchi T, Horikawa K, et alImmunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP. Blood. 2006;107: 1184-1191. [
- 60. Maciejewski JP, Selleri CEvolution of clonal cytogenetic abnormalities in aplastic anemia. Leuk Lymphoma. 2004;45: 433-440. [
- 61. Sloand EM, Fuhrer M, Risitano A, et alPreferential suppression of trisomy 8 versus normal hematopoietic cell growth by autologous lymphocytes in patients with trisomy 8 myelodysplastic syndrome. Blood. 2005;106: 841-851.
- 62. Sloand EM, Rezvani K, Mainwaring L, et alMyelodysplasia with trisomy 8 is associated with a cytotoxic CD8 T cell immune response to Wilms tumor-1 protein (WT1) [abstract]. Blood. 2004; 104: 138a. Abstract 474.
- 63. Sloand EM, Mainwaring L, Tarnowka MK, Barrett AJ, Young NSCD34 cells from patients with trisomy 8 express early apoptotic markers but do not undergo programmed cell death because of upregulation of anti-apoptotic proteins [abstract]. Blood. 2003;102: 145a. Abstract 497.
- 64. Maciejewski JP, Risitano AM, Nunez O, Young NSDistinct clinical outcomes for cytogenetic abnormalities evolving from aplastic anemia. Blood. 2002;99: 3129-3135. [
- 65. Kojima S, Ohara A, Tsuchida M, et alRisk factors for evolution of acquired aplastic anemia into myelodysplastic syndrome and acute myeloid leukemia after immunosuppressive therapy in children. Blood. 2002;100: 786-790. [
- 66. Sloand EM, Yong A, Solomou EE, et alGranulocyte colony-stimulating factor preferentially stimulates proliferation of monosomy 7 cells bearing the isoform IV receptor. Proc Natl Acad Sci U S A. In press.
- 67. Frickhofen N, Rosenfeld SJImmunosuppressive treatment of aplastic anemia with antithymocyte globuilin and cyclosporine. Semin Hematol. 2000; 37: 56-68. [
- 68. Frickhofen N, Heimpel H, Kaltwasser JP, Schrezenmaier HAntithymocyte globulin with or without cyclosporin A: 11-year follow-up of a randomized trial comparing treatments of aplastic anemia. Blood. 2003;101: 1236-1242. [
- 69. Bacigalupo A, Bruno B, Saracco P, et alAntilymphocyte globuilin, 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: 1931-1934. [
- 70. Rosenfeld S, Follman D, Nunez O, Young NSAntithymocyte globulin and cyclosporine for severe aplastic anemia: association between hematologic response and long-term outcome. JAMA. 2003;289: 1130-1135. [
- 71. Kojima S, Hibi S, Kosaka Y, et alImmunosuppressive therapy using antithymocyte globulin, cyclosporine, and danazol with or without human granulocyte colony-stimulating factor in children with acquired aplastic anemia. Blood. 2000;96: 2049-2054. [
- 72. Scheinberg P, Nunez O, Wu C, Young NSTreatment of severe aplastic anaemia with combined immunosuppression: antithymocyte globulin, ciclosporin, and mycophenolate mofetil. Br J Haematol. 2006;133: 606-611. [
- 73. Marsh J, Schrezenmeier H, Marin P, et alProspective 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 Anemia Working Party. Blood. 1999;93: 2191-2195. [
- 74. Raghavachar A, Kolbe K, Höffken K, et alA randomized trial of standard immunosuppression versus cyclosporine and filgastrim in severe aplastic anemia [abstract]. Blood. 1997;90: 439a. Abstract 1951.
- 75. Fuhrer M, Rampf U, Baumann I, et alImmunosuppressive therapy for aplastic anemia in children: a more severe disease predicts better survival. Blood. 2005;106: 2102-2104. [
- 76. Fang JP, Xu HG, Huang SL, Chen C, Huang KImmunosuppressive treatment of aplastic anemia in Chinese children with antithymocyte globulin and cyclosporine. Pediatr Hematol Oncol. 2006; 23: 45-50. [
- 77. Tichelli A, Socié G, Henry-Amar M, et alEffectiveness of immunosuppressive therapy in older patients with aplastic anemia: The European Group for Blood and Marrow Transplantation Several Aplastic Anaemia Working Party. Ann Intern Med. 1999;130: 193-201. [
- 78. Tichelli A, Passweg J, Nissen C, et alRepeated treatment with horse antilymphocyte globulin for severe aplastic anaemia. Br J Haematol. 1998; 100: 393-400. [
- 79. Scheinberg P, Nunez O, Young NSRetreatment with rabbit anti-thymocyte globulin and cyclosporine for patients with relapsed or refractory severe aplastic anemia. Br J Haematol. 2006;133: 622-627. [
- 80. Socié G, Rosenfeld S, Frickhofen N, Gluckman E, Tichelli ALate clonal diseases of treated aplastic anemia. Semin Hematol. 2000;37: 91-101. [
- 81. Jeng MR, Naidu PE, Rieman MD, et alGranulocyte-macrophage colony stimulating factor and immunosuppression in the treatment of pediatric acquired severe aplastic anemia. Pediatr Blood Cancer. 2005;45: 170-175. [
- 82. Gluckman E, Rokicka-Milewska R, Hann I, et alResults 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: 1075-1082. [
- 83. Brodsky RA, Sensenbrenner LL, Smith BD, et alDurable treatment-free remission after high dose cyclophosphamide therapy for previously severe aplastic anemia. Ann Intern Med. 2001;135: 477-483. [
- 84. Brodsky RA, Chen A, Dorr DM, Brodsky I, Jones RJHigh dose cyclophosphamide (CY) for severe aplastic anemia (SAA): safety and long term follow-up [abstract]. Blood. 2005;106: 41a-42a. Abstract 129.
- 85. Tisdale JF, Dunn DE, Geller NL, et alHigh-dose cyclophosphamide in severe aplastic anemia: a randomized trial. Lancet. 2000;356: 1554-1559. [
- 86. Tisdale JF, Maciejewski JP, Nunez O, Rosenfeld SJ, Young NSLate complications following treatment for severe aplastic anemia (SAA) with high-dose cyclophosphamide (Cy): follow-up of a randomized trial. Blood. 2002;100: 4668-4670. [
- 87. 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: 330-334. (Erratum in: Br J Haematol. 2000; 108:461.) [
- 88. Gupta V, Gordon-Smith EC, Cook G, et alA third course of anti-thymocyte globulin in aplastic anaemia is only beneficial in previous responders. Br J Haematol. 2005;129: 110-117. [
- 89. Howard SC, Naidu PE, Hu XJ, et alNatural history of moderate aplastic anemia in children. Pediatr Blood Cancer. 2004;43: 545-551. [
- 90. Maciejewski JP, Sloand EM, Nunez O, Boss C, Young NSRecombinant humanized anti-IL-2 receptor antibody (Daclizumab) produces responses in patients with moderate aplastic anemia. Blood. 2003;102: 3584-3586. [
- 91. Calado RT, Yewdell WT, Wilkerson KL, Kajigaya S, Young NSSex hormones up-regulate telomerase activity of normal human hematopoietic cells and restore telomerase activity in carriers of telomerase complex mutations [abstract]. Blood. 2005;106: 641a. Abstract 2276.
- 92. Passweg JR, Perez WS, Eapen M, et alBone marrow transplants from mismatched related and unrelated donors for severe aplastic anemia. Bone Marrow Transplant. 2006;37: 641-649. [
- 93. Reiter E, Keil F, Brugger S, et alExcellent long-term survival after allogeneic marrow transplantation in patients with severe aplastic anemia. Bone Marrow Transplant. 1997;19: 1191-1196. [
- 94. Locatelli F, Bruno B, Zecca M, et alCyclosporin A and short-term methotrexate versus cyclosporin A as graft versus host disease prophylaxis in patients with severe aplastic anemia given allogeneic bone marrow transplantation from an HLA-identical sibling: results of a GITMO/EBMT randomized trial. Blood. 2000;96: 1690-1697. [
- 95. Kim I, Yoon SS, Park S, Kim BK, Kim NKThe treatment of severe aplastic anemia: outcomes of bone marrow transplantation and immunosuppressive therapy in a single institution of Korea. J Korean Med Sci. 2003;18: 365-371.
- 96. Ahn MJ, Choi JH, Lee YY, et alOutcome of adult severe or very severe aplastic anemia treated with immunosuppressive therapy compared with bone marrow transplantation: multicenter trial. Intl J Hematol. 2003;78: 133-138. [
- 97. Kröger N, Zabelina T, Renges H, et alLong-term follow-up of allogeneic stem cell transplantation in patients with severe aplastic anemia after conditioning with cyclophosphamide plus antithymocyte globulin. Ann Hematol. 2002;81: 627-631. [
- 98. Ades L, Mary JY, Robin M, et alLong-term outcome after bone marrow transplantation for severe aplastic anemia. Blood. 2004;103: 2490-2497. [
- 99. Dulley FL, Vigorito AC, Aranha FJP, et alAddition of low-dose busulfan to cyclophosphamide in aplastic anemia patients prior to allogeneic bone marrow transplantation to reduce rejection. Bone Marrow Transplant. 2004;33: 9-13. [
- 100. Bai LY, Chiou TJ, Liu JH, et alHematopoietic stem cell transplantation for severe aplastic anemia: experience of an institute in Taiwan. Ann Hematol. 2004;83: 38-43. [
- 101. Abdelkefi A, Ben Othman T, Ladeb S, et alBone marrow transplantation for patients with acquired severe aplastic anemia using cyclophosphamide and antithymocyte globulin: the experience from a single center. Hematol J. 2003;4: 208-213. [
- 102. Kim HJ, Park CY, Park YH, et alSuccessful allogeneic hematopoietic stem cell transplantation using triple agent immunosuppression in severe aplastic anemia patients. Bone Marrow Transplant. 2003;31: 79-86. [
- 103. Gupta V, Ball SE, Yi Q, et alFavorable effect on acute and chronic graft-versus-host disease with cyclophosphamide and in vivo anti-CD52 monoclonal antibodies for marrow transplantation from HLA-identical sibling donors for acquired aplastic anemia. Biol Blood Bone Marrow Transplant. 2004;10: 867-876. [
- 104. Kahl C, Leisenring W, Deeg HJ, et alCyclophosphamide 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: 747-751. [
- 105. Storb R, Blume KG, O'Donnell MR, et alCyclophosphamide and antithymocyte globulin to condition patients with aplastic anemia for allogeneic marrow transplantations: the experience in four centers. Biol Blood Marrow Transplant. 2001;7: 39-44. [
- 106. Gomez-Almaguer D, Vela-Ojeda J, Jaime-Perez JC, et alAllografting in patients with severe, refractory aplastic anemia using peripheral blood stem cells and a fludarabine-based conditioning regimen: the Mexican experience. Am J Hematol. 2006;81: 157-161. [
- 107. Horowitz MMCurrent status of allogeneic bone marrow transplantation in acquired aplastic anemia. Semin Hematol. 2000;37: 30-42. [
- 108. Srinivasan R, Takahashi Y, McCoy JP, et alOvercoming graft rejection in heavily transfused and allo-immunised patients with bone marrow failure syndromes using fludarabine-based haematopoietic cell transplantation. Br J Haematol. 2006; 133: 305-314. [
- 109. Deeg HJ, Leisenring W, Storb R, et alLong-term outcome after marrow transplantation for severe aplastic anemia. Blood. 1998;91: 3637-3645. [
- 110. Gupta V, Ball SE, Sage D, et alMarrow transplants from matched unrelated donors for aplastic anaemia using alemtuzumab, fludarabine and cyclophosphamide based conditioning. Bone Marrow Transplant. 2005;35: 467-471. [
- 111. Kojima S, Inaba J, Yoshimi A, et alUnrelated donor marrow transplantation in children with severe aplastic anaemia using cyclophosphamide, anti-thymocyte globulin and total body irradiation. Br J Haematol. 2001;114: 706-711. [
- 112. Vassiliou GS, Webb DKH, Pamphilon D, Knapper S, Veys PAImproved outcome of alternative donor bone marrow transplantation in children with severe aplastic anaemia using a conditioning regimen containing low-dose total body irradiation, cyclophosphamide and Campath. Br J Haematol. 2001;114: 701-705. [
- 113. Kojima S, Matsuyama T, Kato S, et alOutcome of 154 patients with severe aplastic anemia who received transplants from unrelated donors: the Japan Marrow Donor Program. Blood. 2002;100: 799-805. [
- 114. Benesch M, Urban C, Sykora KW, et alTransplantation of highly purified CD34+ progenitor cells from alternative donors in children with refractory severe aplastic anaemia. Br J Haematol. 2004;125: 58-63. [
- 115. Kang HJ, Shin HY, Choi HS, Ahn HSFludarabine, cyclophosphamide plus thymoglobulin conditioning regimen for unrelated bone marrow transplantation in severe aplastic anemia. Bone Marrow Transplant. 2004;34: 939-943. [
- 116. Mao P, Wang S, Wang S, et alUmbilical cord blood transplant for adult patients with severe aplastic anemia using anti-lymphocyte globulin and cyclophosphamide as conditioning therapy. Bone Marrow Transplant. 2004;33: 33-38. [
- 117. Bacigalupo A, Locatelli F, Lanino E, et alFludarabine, cyclophosphamide and anti-thymocyte globulin for alternative donor transplants in acquired severe aplastic anemia: a report from the EBMT-SAA Working Party. Bone Marrow Transplant. 2005;36: 947-950. [
- 118. Bunin N, Aplenc R, Iannone R, et alUnrelated donor bone marrow transplantation for children with severe aplastic anemia: minimal GVHD and durable engraftment with partial T-cell depletion. Bone Marrow Transplant. 2006;37: 143-149. [
- 119. Lee J-H, Choi S-J, Lee J-H, et alNon-total body irradiation containing preparative regimen in alternative donor bone marrow transplantation for severe aplastic anemia. Bone Marrow Transplant. 2005;35: 755-761. [
- 120. Deeg HJ, O'Donnell M, Tolar J, et alOptimization of conditioning for marrow transplantation from unrelated donors for patients with aplastic anemia after failure of immunosuppressive therapy. Blood. 2006;108: 1485-1491.
- 121. Deeg HJ, Seidel K, Casper J, et alMarrow transplantation from unrelated donors for patients with severe aplastic anemia who have failed immunosuppressive therapy. Biol Blood Marrow Transplant. 1999;5: 243-252. [
- 122. Margolis DA, Casper JTAlternative-donor hematopoietic stem-cell transplantation for severe aplastic anemia. Semin Hematol. 2000;37: 43-55. [
- 123. Rubinstein P, Carrier C, Scaradavou A, et alOutcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med. 1997;339: 1565-1576. [
- 124. Woodard P, Cunningham JM, Benaim E, et alEffective donor lymphohematopoietic reconstitution after haploidentical CD34+-selected hematopoietic stem cell transplantation in children with refractory severe aplastic anemia. Bone Marrow Transplant. 2004;33: 411-418. [
- 125. Bacigalupo A, Brand R, Oneto R, et alTreatment 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: 69-80. [
- 126. Ehrlich PUeber einem Fall von Anämie mit Bemerkungen über regenerative Veränderungen des Knochenmarks. Charité-Annalen. 1888;13: 300-309.