The role of immunotherapy in the treatment of acute myeloblastic leukemia: from allogeneic bone marrow transplantation to the application of interleukin 2

  • H. Grant Prentice
  • Ian D. Macdonald
  • Michael D. Hamon
Part of the Cancer Treatment and Research book series (CTAR, volume 64)


Three decades ago, few patients with acute myeloblastic leukemia (AML) achieved remission, and almost none were cured [1]. Now, with the application of modern intensive combination chemotherapy, more than 80% of children and young adults reach this first hurdle [2,3]. Although the majority are destined to relapse, if treated with this modality alone [4], this risk can be reduced to less than 20% by the use of allogeneic bone marrow transplantation (BMT) following myeloablative/immunosuppressive chemoradiotherapy [5]. Preclinical studies predicted an immunotherapeutic benefit of BMT [6,7] (vide infra), but prior to our understanding of the HLA system and the use of BMT, the first clinical attempts to apply immunological measures in the treatment of leukemia involved studies with Bacille Calmette Guerin vaccination done by Mathe [8]. Subsequent randomized studies demonstrated no effect on length of remission but did show prolongation of postrelapse survival-the first evidence of benefit from planned immunotherapy (as opposed to spontaneous cures seen in the occasional patient). These studies indicated limited benefit, but they did herald the modern era of immunotherapy in which recombinant technology has made relevant cytokines available in therapeutic quantities. We reason that the antileukemic immunological benefits of allogeneic BMT identified in man as the graft versus leukemia (GvL) phenomenon [5] can be induced by Interleukin 2 [9] without the requirement for a donor and that its use in the setting of minimal residual disease (MRD) in AML deserves further investigation.


Chronic Myeloid Leukemia Minimal Residual Disease Total Body Irradiation Acute Myeloblastic Leukemia Relapse Risk 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Mangalik A, Boggs DR, Wintrobe MM, Cartwright GE (1966). The influence of chemotherapy on survival in acute leukaemia III A comparison of patients treated during 1958-1964 with those treated in two sequentially preceding periods. Blood 27: 490–498.PubMedGoogle Scholar
  2. 2.
    Nesbit ME, Woods WG (1992). Therapy of acute myeloid leukemia in children. Leukemia 6(Suppl 2):31–35.PubMedGoogle Scholar
  3. 3.
    Zittoun R (1992). Chemotherapy of acute myelogenous leukemia. A review. Leukemia 6(Suppl 2):36–38.Google Scholar
  4. 4.
    Preisler HD, Raza A (1992). Current problems in the treatment of acute myelocytic leukemia (AML) and some possible solutions. Leukemia 6(Suppl 2): 81–84.PubMedGoogle Scholar
  5. 5.
    Horowitz MM, Gale RP, Sondel PM, et al. (1990). Graft versus leukemia reactions after bone marrow transplantation. Blood 75: 555–562.PubMedGoogle Scholar
  6. 6.
    Barnes DWH, Loutit JF (1957). Treatment of murine leukaemia with X-rays and homologous bone marrow: II. Br J Haematol 3: 241–252.PubMedCrossRefGoogle Scholar
  7. 7.
    Weiss L, Morecki S, Vitetta ES, Slavin S (1983). Suppression and elimination of BCL1 leukemia by allogeneic bone marrow transplantation. J Immunol 130: 2452–2455.PubMedGoogle Scholar
  8. 8.
    Mathe G, Schwarzenberg L, Amiel JL, Schneider M, Cattan A, Schlumberger JR (1967). The immunological approach to the treatment of human cancer. Eur J Cancer 3: 423–433.PubMedCrossRefGoogle Scholar
  9. 9.
    Verdonck LF, van Heughten HG, Giltray J, Franks CR (1991). Amplification of the graft versus leukemia effect in man by interleukin 2. Transplantation 51: 1120–1124.PubMedCrossRefGoogle Scholar
  10. 10.
    Truitt RL, Shih C, LeFever AV (1986). Manipulation of graft versus host disease for a graft versus leukemia effect after allogeneic bone marrow transplantation in AKR mice with spontaneous leukemia/lymphoma. Transplantation 41: 301–310.PubMedCrossRefGoogle Scholar
  11. 11.
    Truitt RL, Atasoylu AA (1991). Contribution of CD4+ and CD8+ T cells to graft versus host disease and graft versus leukemia reactivity after transplantation of MHC compatible bone marrow. Bone Marrow Transplant 8: 51–58.PubMedGoogle Scholar
  12. 12.
    Truitt RL, LeFever AV, Shih CY, Jeske J, Martin T (1990). Graft versus leukemia effect. In Graft vs. Host Disease: Immunology, Pathophysiology and Treatment, Burakoff SJ, Deeg HJ, Ferrara J, Atkinson K (eds). Marcel Dekker: New York, pp. 177–204.Google Scholar
  13. 13.
    Sykes M, Romick ML, Sachs DH (1990). Interleukin 2 prevents graft-versus-host disease while preserving the graft-versus-leukemia effect of allogeneic T cells. Proc Natl Acad Sci USA 87: 5633–5637.PubMedCrossRefGoogle Scholar
  14. 14.
    Sykes M, Eisenthal A, Sachs DH (1988). Mechanism of protection from graft-vs.-host disease in murine mixed allogeneic chimeras. I. Development of a null cell population suppressive of cell-mediated lympholysis responses and derived from the syngeneic bone marrow component. J Immunol 140: 2903–2911.PubMedGoogle Scholar
  15. 15.
    Sykes M, Romick ML, Hoyles KA, Sachs DH (1990). In vivo administration of interleukin 2 plus T cell-depleted syngeneic marrow prevents graft-versus-host disease mortality and permits alloengraftment. J Exp Med 171: 645–658.PubMedCrossRefGoogle Scholar
  16. 16.
    Uberti J, Martilotti F, Chou T, Kaplan J (1992). Human lymphokine activated killer (LAK) cells suppress generation of allospecific cytotoxic T cells: implications for use of LAK cells to prevent graft versus host disease in allogeneic bone marrow transplantation. Blood 79: 261–268.PubMedGoogle Scholar
  17. 17.
    Rees J. Personal communication; Medical Research Council AML 9 data on file.Google Scholar
  18. 18.
    Hamon MD, Cunningham JM, Gilmore M, et al. (1991). Allogeneic T cell depleted (TCD) bone marrow transplantation (BMT) for patients with acute leukaemia in first remission. Haematologica 76: 68.Google Scholar
  19. 19.
    Weiden PI, Sullivan KM, Flournoy N, Storb R, Thomas ED (1979). Antileukemic effect of graft-versus-host disease in human recipients of allogeneic bone marrow grafts. N Engl J Med 300: 1068–1073.PubMedCrossRefGoogle Scholar
  20. 20.
    Ferrara JLM, Deeg HJ (1991). Graft-versus host-disease. N Engl J Med 324: 667–674.PubMedCrossRefGoogle Scholar
  21. 21.
    Pollard CM, Powles RL, Miller JL, et al. (1986). Leukaemic relapse following Campath-1 treated bone marrow transplantation for leukaemia. Lancet ii: 1343–1344.CrossRefGoogle Scholar
  22. 22.
    Atkinson K, Biggs J, Dodds A et al. (1988). High incidence of early leukaemic relapse in patients given cyclosporin and T cell depleted HLA identical sibling marrow transplants for acute leukaemia in first remission. Aust NZ J Med 18: 587–593.CrossRefGoogle Scholar
  23. 23.
    Burnett AK, Hann IM, Robertson AG, et al. (1988). Prevention of graft versus host disease by ex vivo T cell depletion: reduction in graft failure with augmented total body irradiation. Leukemia 2: 300–303.PubMedGoogle Scholar
  24. 24.
    Gale RP, personal communication.Google Scholar
  25. 25.
    Kim TH, McGlave PB, Ramsay N, et al. (1990). Comparison of two total body irradiation regimens in allogeneic bone marrow transplantation for acute non-lymphoblastic leukemia in first remission. Int J Radiat Oncol Biol Phys 19: 889–897.PubMedCrossRefGoogle Scholar
  26. 26.
    Salomon O, Lapidot T, Terenzi A, Lubin I, Rabi I, Reisner Y (1990). Induction of donor type chimerism in murine recipients of bone marrow allografts by different radiation regimens currently used in treatment of leukemia patients. Blood 76: 1872–1878.PubMedGoogle Scholar
  27. 27.
    Maraninchi D, Gluckman E, Blaise D, et al. (1987). Impact of T cell depletion on outcome of allogeneic bone marrow transplantation for standard risk leukaemias. Lancet ii: 175–178.CrossRefGoogle Scholar
  28. 28.
    Mitsuyasu RT, Champlin RE, Gale RP, et al. (1986). Treatment of donor bone marrow with monoclonal anti-T cell antibody and complement for the prevention of graft versus host disease. Ann Intern Med 105: 20–26.PubMedGoogle Scholar
  29. 29.
    Clift RA, Buckner CD, Appelbaum FR, et al. (1990). Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: A randomized trial of two irradiation regimens. Blood 76: 1867–1871.PubMedGoogle Scholar
  30. 30.
    Storb R, Deeg HJ, Pepe M, et al. (1989). Methotrexate and cyclosporine versus cyclosporin alone for prophylaxis of graft versus host disease in patients given HLA idetical marrow grafts for leukemia: long term follow up of a controlled trial. Blood 73: 1729–1734.PubMedGoogle Scholar
  31. 31.
    Antin JH, Bierer BE, Smith BR, et al. (1991). Selective depletion of bone marrow T lymphocytes with anti CD5 monoclonal antibodies—effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies. Blood 78: 2139–2149.PubMedGoogle Scholar
  32. 32.
    Bacigalupo A, van Lint MT, Occhini D, et al. (1991). Increased risk of leukemic relapse with high dose cyclosporin A after allogeneic marrow transplant for acute leukemia. Blood 77: 1423–1428.PubMedGoogle Scholar
  33. 33.
    Jones RJ, Vogelsang GB, Hess AD, et al. (1989). Induction of graft-versus-host disease after autologous bone marrow transplantation. Lancet i:754–757.CrossRefGoogle Scholar
  34. 34.
    Talbot DC, Powles RL, Sloane JP, et al. (1990). Induced graft versus host disease following autologous bone marrow transplantation in acute myeloid leukemia. Bone Marrow Transplantation 6: 17–20.PubMedGoogle Scholar
  35. 35.
    Sullivan KM, Storb R, Buckner CD, et al. (1989). Graft versus host disease as adoptive immunotherapy in patients with advanced hematologic neoplasms. N Engl J Med 320: 828–838.PubMedCrossRefGoogle Scholar
  36. 36.
    Kolb HJ, Mittermuller J, Clemm CH, et al. (1990). Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76: 2462–2465.PubMedGoogle Scholar
  37. 37.
    Brenner MK, Heslop HE (1992). Immunotherapy of Leukemia. Leukemia 6(Suppl 1):76–79.PubMedGoogle Scholar
  38. 38.
    Fisch P, Malkovsky M, Kovats S, et al. (1990). Recognition by human Vγ9/Vδ2 T cells of a GroEL homolog on Daudi Burkitt’s lymphoma cells. Science 250: 1269–1273.PubMedCrossRefGoogle Scholar
  39. 39.
    Reittie JE, Gottlieb D, Heslop HE, et al. (1989). Endogenously generated activated killer cells circulate after autologous and allogeneic marrow transplantation but not after chemotherapy. Blood 73: 1351–1355.PubMedGoogle Scholar
  40. 40.
    Price G, Brenner MK, Prentice HG, Hoffbrand AV, Newland AC (1986). Cytotoxic effects of tumour necrosis factor and gamma interferon on acute myeloid leukaemia blasts. Br J Cancer 55: 287–290.CrossRefGoogle Scholar
  41. 41.
    Ikinciogullari A, Oblakowski P, Hamon MD, et al. (submitted). Activation marker expression on the peripheral blood lymphocytes of normal volunteers, recipients of interleukin 2 and patients undergoing bone marrow transplantation.Google Scholar
  42. 42.
    Heslop HE, Gottlieb DJ, Bianchi AC, et al. (1989). In vivo induction of gamma interferon and tumour necrosis factor by interleukin 2 infusion following intensive chemotherapy or autologous marrow transplantation. Blood 74: 1374–1380.PubMedGoogle Scholar
  43. 43.
    Prentice HG, Hamon MD, Cunningham JM, et al. (1991). Autologous bone marrow transplantation (ABMT) with or without interleukin 2 (IL2) immunotherapy for patients with acute myeloblastic leukaemia (AML) in first remission. Haematologica 76: 55.Google Scholar
  44. 44.
    Weisdorf DJ, Anderson PM, Kersey JH, Ramsay NKC (1991). Interleukin 2 therapy immediately after autologous marrow transplantation: toxicity, T cell activation and engraftment. Blood 78(Suppl 1):226a.Google Scholar
  45. 45.
    Gottlieb DJ, Brenner MK, Heslop HE, et al. (1989). A phase I clinical trial of recombinant interleukin 2 following high dose chemotherapy for haematological malignancy: application to the elimination of minimal residual disease. Br J Cancer 60: 610–615.PubMedCrossRefGoogle Scholar
  46. 46.
    Blaise D, Olive D, Stoppa AM, et al. (1990). Hematologic and immunologic effects of the systemic administration of recombinant interleukin 2 after bone marrow transplantation. Blood 76: 1092–1097.PubMedGoogle Scholar
  47. 47.
    Blaise D, Stoppa AM, Viens, et al. (in press). Intensive immunotherapy with recombinant IL2 (rIL2) after autologous bone marrow transplantation (BMT) is associated with a high incidence of bacterial infections. Bone Marrow Transplant.Google Scholar
  48. 48.
    Macdonald D, Jiang YZ, Gordon AA, et al. (1990). Recombinant interleukin 2 for acute myeloid leukaemia in first complete remission: a pilot study Leuk Res 14: 967–973.PubMedCrossRefGoogle Scholar
  49. 49.
    Macdonald D, Jiang YZ, Swirsky D, et al. (1991). Acute myeloid leukaemia relapsing following interleukin 2 treatment expresses the alpha chain of the interleukin 2 receptor. Br J Haematol 77: 43–49.PubMedCrossRefGoogle Scholar
  50. 50.
    Foa R, Caretto P, Fierro MT, et al. (1990). Interleukin 2 does not promote the in vitro and in vivo proliferation and growth of human acute leukaemia cells of myeloid and lymphoid origin. Br J Haematol 75: 34–40.PubMedCrossRefGoogle Scholar
  51. 51.
    Foa R, Meloni G, Tosti S, et al. (1990). Treatment of residual disease in acute leukaemia patients with recombinant interleukin 2 (IL2): clinical and biological functions. Bone Marrow Transplant 6(Suppl 1):98–102.PubMedGoogle Scholar
  52. 52.
    Higuchi CM, Thompson JA, Petersen FB, et al. (1991). Toxicity and immunomodulatory effects of interleukin 2 after autologous bone marrow transplantation for hematologic malignancies. Blood 77: 2561–2568.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • H. Grant Prentice
  • Ian D. Macdonald
  • Michael D. Hamon

There are no affiliations available

Personalised recommendations