To review antithymocyte immunoglobulin (ATG) and its current role in the treatment of severe aplastic anemia (SAA), focusing on ATG in immunosuppressive therapy compared with bone marrow transplantation (BMT).
DATA SOURCES:
A MEDLINE search (1966 to 1996) of English-language literature and human subjects pertaining to ATG and BMT therapy in SAA was performed. Additional literature was obtained from reference lists of pertinent articles identified through the search.
STUDY SELECTION AND DATA EXTRACTION:
All articles were considered for possible inclusion in the review. Pertinent information, as judged by the authors, was selected for discussion.
DATA SYNTHESIS:
The hallmark of SAA is pancytopenia and bone marrow hypoplasia. Although the etiology in a majority of cases remains unknown, current data implicate an immune-mediated destruction of stem cells. ATG is a potent immunosuppressive agent and has emerged as an important therapy for patients with SAA. The exact mechanism of immunosuppressive action is not fully understood, although ATG appears to disrupt cell-mediated immune responses resulting in inhibition or altered T-cell function. Numerous trials have evaluated the use of ATG both as monotherapy and in combination with other immunosuppressive agents. Treatment with ATG in SAA has demonstrated a 40–70% response rate. Data suggest that intensive immunosuppressive therapy with ATG in combination with cyclosporine may provide the optimal immunosuppressive treatment. Questions still remain concerning complications and long-term survival of the patients. Although more than a 2-year follow-up shows a decline in mortality, a plateau in the survival curve was not achieved. BMT is a potential treatment for SAA. Although there is a high initial mortality due to treatment-related toxicities, successful marrow engraftment provides a cure for SAA. Many patients (75–90%) experience long-term survival after allogenic BMT. Age, donor availability, and severity of disease limit the number of eligible patients.
CONCLUSIONS:
Due to excellent results with BMT, it has become the therapy of choice for selected patients with SAA. For patients who are not eligible for BMT, intensive immunosuppressive therapy with ATG and cyclosporine is recommended. Further study to better understand the pathogenesis of SAA and prevent treatment-related complications is essential to provide the best care to all patients.
Get full access to this article
View all access options for this article.
References
1.
GaleRPChamplinREFeigSAFitchenJ.Aplastic anemia: Biology and treatment: UCLA conference. Ann Intern Med1981; 95:477–94.
2.
CamittaBMThomasEDNathanDG, A prospective study of androgens and bone marrow transplantation for treatment of severe aplastic anemia. Blood1979; 53:504–14.
3.
ZoumbosNCGasconPDjeuJYTrostSRYoungNS, Circulating activated suppressor T lymphocytes in aplastic anemia. N Engl J Med1985; 312:257–65.
4.
HottaTKatoTMaedaHYamaoHYamadaHSaitoH, Functional change in marrow stromal cells in aplastic anemia. Acta Haematol1985; 74:65–9.
5.
SelleriCSatoTAndersonSYoungNSMaciejewskiJP, Interferon-gamma and tumor necrosis factor-alpha suppress both early and late stages of hematopoiesis and induce programmed cell death. J Cell Physiol1995; 165:538–46.
6.
MaciejewskiJPSelleriCSatoTAndersonSYoungNS, Increased expression of FAS antigen on bone marrow CD34+ cells of patients with aplastic anemia. Br J Haematol1995; 91:245–52.
7.
MaciejewskiJPAndersonSKatevasPYoungNS, Phenotypic and functional analysis of bone marrow progenitor cell compartment in bone marrow failure. Br J Haematol1994; 87:227–34.
8.
YoungNSBarrettAJ, The treatment of severe acquired aplastic anemia. Blood1995; 85:3367–77.
9.
MarshJCWChangJTestaNGHowsJMDexterTM, Hematopoietic defect in aplastic anemia assessed by long term marrow culture. Blood1990; 76:1748–57.
10.
CamittaBMStorbRThomasED, Aplastic anemia: Pathogenesis, diagnosis, treatment, and prognosis. N Engl J Med1982; 306:645–52.
11.
MatheGAmielJLSchwarzenbergLChoagJTrolardPSchneiderM, Bone marrow graft in man after conditioning by antilymphocytic serum. Br Med J1970; 2:131–6.
12.
SingerJWDoneyKCThomasED, Co-culture studies of untransfused patients with aplastic anemia. Blood1979; 54:180–4.
13.
MaciejewskiJPHibbsJRAndersonSKatevasPYoungNS, Bone marrow and peripheral blood lymphocyte phenotype in patients with bone marrow failure. Exp Hematol1994; 22:1102–10.
14.
PlantaniasLGasconPBieloryLGriffithPNienhuisAYoungN.Lymphocyte phenotype and lymphokines following anti-thymocyte globulin therapy in patients with aplastic anemia. Br J Haematol1987; 66:437–43.
15.
ZoumbosNCGasconPDjeuJYYoungNS, Interferon is a mediator of hematopoietic suppression in aplastic anemia in vitro and possibly in vivo. Proc Nat Acad Sci U S A1985; 82:188–92.
16.
NisticoAYoungNS, Gamma-interferon gene expression in the bone marrow of patients with aplastic anemia. Ann Intern Med1994; 120:463–9.
17.
LaverJCastro-MalaspinaMKemanNLevickJEvansRLO'ReillyRJ, In vitro interferon-gamma production by cultured T-cells in severe aplastic anemia: Correlation with granulomonopoietic inhibition in patients who respond to anti-thymocyte globulin. Br J Haematol1988; 69:545–50.
18.
RameshwarPGasconP.Release of interleukin-1 and interleukin-6 from human monocytes by antithymocyte globulin: Requirement for de-novo synthesis. Blood1993; 80:2531–8.
19.
NimerSDGoldeDWKwanKLeeKClarkSChamplinR.In vitro production of granulocyte-macrophage colony-stimulating factor in aplastic anemia: Possible mechanisms of action of antithymocyte globulin. Blood1991; 78:163–8.
20.
NissenCMoserYSpeckBGratwohlAWeisJ.Stimulatory serum factors in aplastic anemia. II. Prognostic significance for patients treated with high dose immunosuppression. Br J Haematol1985; 61:499–512.
21.
NissenCMoserYWeisJSpeckB.Stimulatory serum factors in aplastic anemia. I. Serum releaser activity for hematopoietic growth factors, a regulator. Br J Haematol1985; 61:491–8.
22.
GrabensteinJD, Isoantibodies: II. Comparison of antilymphocyte antibodies. Hosp Pharm1993; 28:42–9.
23.
HunterRFHuangAT, Antithymocyte globulin: A realistic approach to therapy for severe aplastic anemia. South Med J1986; 79:1121–5.
24.
RaefskyELGasconPGratwohlASpeckBYoungNS, Biological and immunological characterization of ATG and ALG. Blood1986; 68:712–9.
25.
PescovitzMDBookBKMilgromMLLeapmanSBPetersenBFiloRS, Comparison of Minnesota antilymphoblast globulin and Upjohn antithymocyte globulin for induction immunosuppression of human renal allografts. Surgery1994; 116:811–8.
26.
LumCTUmenAJKasiskeBGoerdtPHeim-DuthoyKLAndersenRC, Clinical impact of replacing Minnesota antilymphocyte globulin with Atgam. Transplantation1995; 59:371–6.
27.
CrumpMLarrattLMMakiECurtisJEMindenMDMeharchandJM, Treatment of adults with severe aplastic anemia: Primary therapy with antithymocyte globulin (ATG) and rescue of ATG failures with bone marrow transplantation. Am J Med1992; 92:596–602.
28.
ArranzROteroMJRamosRSteegmannJLLamanaMLTomasJF, Clinical results in 50 multiply transfused patients with severe aplastic anemia treated with bone marrow transplantation to immunosuppressive therapy. Bone Marrow Transplant1994; 13:383–7.
29.
SoderstromTOlaussonMBlohmeIEnskogAMjomstedtLWramnerB, Development of a Tolerogenic immune balance and elimination of auto-reactive B cells — Two important effects of antithymocyte globulin treatment. Transplant Proc1990; 22:1795–7.
30.
De SouzaMHDiamondHRSilvaMLCamposMMBouzasLFTabakD, Immunological recovery after bone marrow transplantation for severe aplastic anemia: A Brazilian experience. Eur J Haematol1994; 53:150–5.
31.
MooreKWO'GerraAde Waal MalefytRVieiraPMosmannTR, Interleukin-10. Annu Rev Immunol1993; 11:165–90.
32.
TagaKTosatoG.IL-10 inhibits human T-cell proliferation and IL-2 production. J Immunol1992; 148:1143–6.
33.
AbounaGMAl-AbdullaIHKelly-SullivanDKumurALooseJPhillipsK, Randomized clinical trial of antithymocyte globulin induction in renal transplantation comparing a fixed daily dose with dose adjustment according to T cell monitoring. Transplantation1995; 59:1564–8.
34.
HaradaMGaleRP, Evaluation of antithymocyte globulin for human bone marrow transplantation. Transplantation1982; 33:625–30.
35.
GasconPZoumbosNCScalaGDjeuJYMooreJGYoungNS, Lymphokine abnormalities in aplastic anemia: Implications for the mechanism of action of antithymocyte globulin. Blood1985; 65:407–11.
36.
BjorkholmM.Aplastic anaemia: Pathogenic mechanisms and treatment with special reference to immunomodulation. J Intern Med1992; 231:575–82.
37.
YoungNLeonardEPlantaniasL.Lymphocytes and lymphokines in aplastic anemia: Pathogenic role and implication for pathogenesis. Blood Cells1987; 13:87–92.
38.
KawanoYNissenCGratwohlASpeckB.Immunostimulatory effect of different antilymphocyte globulin preparations: A possible clue to clinical effect. Br J Haematol1988; 68:115–9.
39.
PanellaTJHuangAT, Effects of thimerosal in leukemia cell lines and on normal hematopoiesis. Cancer Res1990; 50:4429–35.
40.
GasconPScalaG.Decreased interleukin-1 production in aplastic anemia. Am J Med1988; 85:668–71.
41.
BieloryLGasconPLawleyTJNienhuisAFrankMMYoungNS, Serum sickness and hematopoietic recovery with antithymocyte globulin in bone marrow patients. Br J Haematol1986; 63:729–36.
42.
RosenfeldSJKimballJViningDYoungNS, Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia. Blood1995; 85:3058–65.
43.
BieloryLWrightRNienhuisAWYoungNSKalinerMA, Antithymocyte globulin hypersensitivity in bone marrow failure patients. JAMA1988; 260:3164–7.
44.
BrooksCDKarlKJFrancomSF, Atgam skin test standardization. Transplantation1994; 58:1135–7.
45.
PepperRPultavitumaAPalutkeMRosenbergJ.A reversible acute reaction following intravenous administration of antithymocyte globulin. Int Arch Allergy1971; 41:920–31.
46.
BieloryLGasconPLawleyTJYoungNSFrankMM, Human serum sickness: A prospective analysis of 35 patients treated with equine antithymocyte globulin for bone marrow failure. Medicine1988; 67:40–57.
47.
ZoumbosNCDjeuJYYoungNS, Interferon is the suppressor of hematopoiesis generated by stimulated lymphocytes in vitro. J Immunol1984; 133:769–74.
48.
MatheGSchwarzenbergL.Treatment of bone marrow aplasia by bone marrow graft after conditioning with antilymphocyte globulin: Long term results. Exp Hematol1976; 4:256–64.
49.
ChamplinRHoWGaleP.Antithymocyte globulin treatment in patients with aplastic anemia: A prospective randomized trial. N Engl J Med1983; 308:113–8.
50.
SpeckBGratwohlANissenCOsterwalderBWurschATichelliA, Treatment of severe aplastic anemia. Exp Hematol1986; 14:126–30.
DoneyKPepeMStorbRBryantEAnasettiCApplebaumFR, Immunosuppressive therapy of aplastic anemia: Results of a prospective randomized trial of antithymocyte globulin (ATG), methylprednisolone, and oxymetholone to ATG, very high dose methylprednisolone, and oxymetholone. Blood1992; 79:2566–71.
53.
StryckmanPADumontJPVeluTHDebusscherL.Cyclosporine in refractory severe aplastic anemia (letter). N Engl J Med1984; 310:655–6.
54.
Hinterberger-FischerMHockerPLechnerKSeewannHHinterbergerW.Oral cyclosporin-A is effective treatment for untreated and also for previously immunosuppressed patients with severe bone marrow failure. Eur J Haematol1989; 43:136–42.
55.
EsperouHDevergieAHehnPLallemandAGluckmanE.A randomized study comparing cyclosporin A and antithymocyte globulin for treatment of severe aplastic anemia. Nouv Rev Fr Hematol1989; 31:65–8.
56.
GluckmanEEsperou-BourdeauABaruchelMBoogartsJBtiereDDonadioG, Multicenter randomized study comparing cyclosporine-A alone and antithymocyte globulin with prednisone for treatment of severe aplastic anemia. Blood1992; 79:2540–6.
57.
FrickhofenNKaltwasserJPSchrezenmeierH.Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. N Engl J Med1991; 324:1297–304.
58.
MatloubYHBostromBGolembeBPriestJRamsayNK, Antithymocyte globulin, cyclosporine, and prednisone for the treatment of severe aplastic anemia in children. A pilot study. Am J Pediatr Hematol Oncol1994; 16:104–6.
59.
BacigalupoABrocciaGCordaGArceseWCarotenutoMGallaminiA, Antilymphocyte globulin, cyclosporine, and granulocyte colony-stimulating factor in patients with acquired severe aplastic anemia: Pilot study of the EBMT SAA Working Party. Blood1995; 85:1348–53.
60.
SchrezenmeierHMartinPRaghavacharAMcCannSHowsJMGluckmanE, Relapse of aplastic anemia after immunosuppressive treatment: A report for the European Bone Marrow Transplant Group Severe Anaemia Working Party. Br J Haematol1993; 85:371–7.
61.
MarshJCSocieGSchrezenmeierHTichelliAGluckmanELjungmanP, Haemopoietic growth factors in aplastic anemia: A cautionary note. European Bone Marrow Transplant Working Party for Severe Aplastic Anemia. Lancet1994; 344:172–3.
62.
PaquetteRLTebyaniNFraneMIrelandPHoWGChamplinRE, Long term outcome of aplastic anemia in adults treated with antithymocyte globulin: Comparison with bone marrow transplantation. Blood1995; 85:283–90.
63.
TichelliAGratwohlAWurschANissenCSpeckB.Late hematologic complications in severe aplastic anemia. Br J Haematol1988; 69:413–8.
64.
NajeanYHaguenauerO.Long term (5–20 years) evolution of nongrafted aplastic anemia. Blood1990; 76:222–8.
65.
DePlanqueMMBacigalupoAWurschJMHowsMDevergieAFrickhofenN, Long term follow-up of severe aplastic anaemia patients treated with antithymocyte globulin. Br J Haematol1989; 73:121–6.
66.
RosseWFWareRE, The molecular basis of paroxysmal nocturnal hemoglobinuria. Blood1995; 86:3277–86.
67.
SocieGHenery-AmarMBacigalupoAHowsJTichelliALjungmanP.Malignant tumors occurring after treatment of aplastic anemia. N Engl J Med1993; 329:1152–6.
68.
StorbR.Bone marrow transplantation for aplastic anemia. Cell Transplant1993; 2:365–79.
69.
StorbREtzioniRAnasettiCApplebaumFRBucknerCDBensingerW, Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia. Blood1994; 84:941–9.
70.
HowsJM, Severe aplastic anemia: The patient without an HLA-identical sibling. Br J Haematol1991; 77:1–4.
71.
BacigalupoJHowsJGluckmanC.Bone marrow transplantation versus immunosuppression for the treatment of severe aplastic anemia: A report of the EBMT SAA Working Party. Br J Haematol1988; 70:177–82.
72.
GluckmanEHorowitzMMChaplinREHowsJMBacigalupoABriggsJC, Bone marrow transplantation for severe aplastic anemia: Influence of conditioning and graft-versus-host disease prophylaxis regimens on outcome. Blood1992; 79:269–75.
73.
KaminskiERHowsJMGoldmanJMBatchelorJR, Lymphocytes from multi-transfused patients exhibit cytotoxicity against autologous cells. Br J Haematol1992; 81:23–6.
74.
Kohi-KumarMMorrisCDelaatCSambramoJMastersonMMuellerR, Bone marrow transplantation in Franconi anemia using matched sibling donors. Blood1994; 84:2050–4.
75.
HorstmannMStockschladerMKrugerWHoffknechtMBetkerRKabischH, Cyclophosphamide/antithymocyte globulin conditioning of patients with severe aplastic anemia for marrow transplantation from HLA-matched siblings: Preliminary results. Ann Hematol1995; 71:77–81.
76.
StorbRWeidenPLSullivanKMAppelbaumFRBeattyPBucknerCD, Second marrow transplants in patients with aplastic anemia rejecting the first graft: Use of a conditioning regimen including cyclophosphamide and antithymocyte globulin. Blood1987; 70:116–23.
