Journal of Clinical Immunology

, Volume 22, Issue 2, pp 64–69 | Cite as

Treatment of Leukemia by Alloreactive Lymphocytes and Nonmyeloablative Stem Cell Transplantation

  • Shimon Slavin
  • Arnon Nagler
  • Michael Y. Shapira
  • Mehmet Aker
  • Cividalli Gabriel
  • Reuven Or


Allogeneic bone marrow or blood stem cell transplantation (BMT) represents an important therapeutic tool for treatment of otherwise incurable malignant and nonmalignant diseases, especially acute and chronic leukemias. Until recently, myeloablative regimens were considered mandatory for effective eradication of all malignant cells of host origin. Our preclinical and ongoing clinical studies indicated that eradication of host immunohematopoietic cells, including chemoradiotherapy-resistant leukemia, could be achieved by adoptive allogeneic cell therapy with donor lymphocyte infusion following induction of host-versus-graft transplantation tolerance mediated by engraftment of donor stem cells in the course of BMT. Thus, eradication of blood cancer cells, especially in patients with chronic myeloid leukemia and less frequently in patients with other hematologic malignancies, could be frequently accomplished despite complete resistance of such tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience suggested that graft-versus-leukemia (GVL) effects might be a useful tool for both treatment and prevention of relapse. Based on the aforementioned rationale, we speculated that the therapeutic benefit of BMT may be improved by using a safer conditioning as part of the transplant procedure, with the goal in mind to induce host-versus-graft tolerance to enable subsequent induction of GVL effects rather than attempt to eliminate host cells with hazardous myeloablative chemoradiotherapy. The latter hypothesis suggested that effective BMT procedure may be accomplished without lethal conditioning of the host, using a new well-tolerated nonmyeloablative regimen, thus possibly minimizing immediate and late side effects related to myeloablative procedures considered until recently mandatory for conditioning of BMT recipients. Recent clinical observations suggest that effective treatment of leukemia may be accomplished with a well-tolerated nonmyeloablative stem cell transplantation (NST) regimen, while avoiding immediate and late toxicity and minimizing procedure-related mortality. Taken together, our cumulative data suggest that high-dose chemotherapy and radiation therapy may be successively replaced by a more effective biological tool—alloreactive donor lymphocytes—thus setting the stage for innovative immunotherapeutic procedures for more selective and effective treatment of patients in need of BMT, including those resistant to conventional chemoradiotherapy.

Bone marrow or blood stem cell transplantation nonmyeloablative stem cell transplantation minitransplant graft versus leukemia effect donor lymphocyte infusion hematologic malignancies leukemia 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Weiden PL, Sullivan KM, Fluornoy N, et al: Antileukemic effect of chronic graft-versus-host disease: Contribution to improved survival after allogeneic marrow transplantation. N Engl J Med 304:1529–1533, 1981Google Scholar
  2. 2.
    Weiden PL, Fluornoy N, Sanders JE, Sullivan KM, Thomas ED: Antileukemic effect of graft-versus-host disease contributes to improved survival after allogeneic marrow transplantation. Transplantation 13:248–251, 1981Google Scholar
  3. 3.
    Sullivan KM, Weiden PL, Storb R, et al: Influence of acute and chronic graft-versus-host disease on relapse and survival after bone marrow transplantation from HLA-identical siblings as treatment of acute and chronic leukemia. Blood 73:1720–1726, 1989Google Scholar
  4. 4.
    Horowitz M, Gale RP, Sondel PM, et al: Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75:555–562, 1990Google Scholar
  5. 5.
    Ringden O, Horowitz MM, for the Advisory Committee of the International BMT Registry: Graft-versus-leukemia reactions in humans. Transplant Proc 21:2989–2992, 1989Google Scholar
  6. 6.
    Slavin S, Naparstek E, Or R, Weiss L: Prevention of GVHD and induction of graft vs leukemia (GVL) effects: Will it ever be possible? BMT (Suppl 1):208, 1988 Abstract. pp. 208Google Scholar
  7. 7.
    Slavin S, Or R, Naparstek E, Ackerstein A, Weiss L: Cellularmediated immunotherapy of leukemia in conjunction with autologous and allogeneic bone marrow transplantation in experimental animals and man. Blood 72(Suppl 1):407a, 1988Google Scholar
  8. 8.
    Slavin S, Naparstek E, Nagler A, Ackerstein A, Kapelushnik Y, Or R: Allogeneic cell therapy for relapsed leukemia following bone marrow transplantation with donor peripheral blood lymphocytes. Exp Hematol 23:1553–1562, 1995Google Scholar
  9. 9.
    Slavin S, Naparstek E, Nagler A, Ackerstein A, Samuel S, Kapelushnik J, Brautbar C, Or R: Allogeneic cell therapy with donor peripheral blood cells and recombinant human interleukin-2 to treat leukemia relapse post allogeneic bone marrow transplantation. Blood 87:2195–2204, 1996Google Scholar
  10. 10.
    Sinkovics JG, Shullenberger CC: Effect of hematopoietic chimerism on the course of Rauscher's viral mouse leukemia. Proc Am Assoc Cancer Res 4:62–72, 1963Google Scholar
  11. 11.
    Boranic M, Tonkovic I: Time pattern of the antileukemia effect of graft-versus-host reaction in mice, I. Cellular events. Cancer Res 31:1140–1147, 1971Google Scholar
  12. 12.
    Bortin MM, Truitt RL, Rimm AA, Bach FH: Graft-versusleukaemia reactivity induced by alloimmunization without augmentation of graft-versus-host reactivity. Nature 281:490–491, 1979Google Scholar
  13. 13.
    Slavin S, Weiss L, Morecki S, Weigensberg M: Eradication of murine leukemia with histoincompatible marrow grafts in mice conditioned with total lymphoid irradiation (TLI). Cancer Immunol Immunother 11:155–161, 1981Google Scholar
  14. 14.
    Giralt S, Estey E, Albitar M, et al: Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: Harnessing graft-versus-leukemia without myeloablative therapy. Blood 89:4531–4536, 1997Google Scholar
  15. 15.
    Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, Varadi G, Kirschbaum M, Ackerstein A, Samuel S, Ben-Tal O, Eldor A, Or R: Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and non-malignant hematologic diseases. Blood 91(3):756–763, 1998Google Scholar
  16. 16.
    Khouri I, Keating M, Przepiorka D, et al: Engraftment and induction of GVL with fludarabine based non-ablative preparative regimens in patients with chronic lymphocytic leukemia and lymphoma. Blood 88(Suppl 1);301a, 1996Google Scholar
  17. 17.
    Carella AM, Champlin R, Slavin S, McSweeney P, Strob R: “Mini-allografts”: ongoing trials in humans. Bone Marrow Transplant 25(4):345–350, 2000Google Scholar
  18. 18.
    McSweeney PA, Wagner JL, Maloney DG, Radich J, Shizuru J, Bensinger WI, Bryant E, Chauncey TR, Flowers MED, Kauffman M, Minor CS, Nash RA, Blume K, Storb R: Outpatient PBSC allografts using immunosuppression with low-dose TBI before, and cyclosporine (CSP) and mycophenolate mofetil (MMF) after transplant. Blood 92(Suppl 1):519a, 1998Google Scholar
  19. 19.
    Naparstek E, Or R, Nagler A, Cividalli G, Engelhard D, Aker M, Gimon Z, Manny N, Sacks T, Tochner Z, Weiss L, Samuel S, Brautbar C, Hale G, Waldmann H, Steinberg S M, Slavin S: T-cell-depleted allogeneic bone marrow transplantation for acute leukaemia using Campath-1 antibodies and post-transplant administration of donor's peripheral blood lymphocytes for prevention of relapse. B J Haematol 89:506–515, 1995Google Scholar
  20. 20.
    Naparstek E, Nagler A, Or R, Slavin S: Allogeneic cell mediated immunotherapy using donor lymphocytes for prevention of relapse in patients treated with allogeneic BMT for hematological malignancies. Clin Transplants J.M. Cecka & P.I. Terasaki 12(24): 281–290, 1996Google Scholar
  21. 21.
    Kapelushnik J, Or R, Aker M, Cividalli G, Nagler A, Naparstek E, Varadi G, Ackerstein A, Amar A, Slavin S: Allogeneic cell therapy of severe beta thalassemia major by displacement of host stem cells in mixed chimera by donor blood lymphocytes. Bone Marrow Transplant 19:96–98, 1996Google Scholar
  22. 22.
    Kapelushnik J, Or R, Slavin S, Nagler A: Fludarabine based protocol for BMT in Fanconi anemia. Bone Marrow Transplant 29(12):1109–1110, 1997Google Scholar
  23. 23.
    Slavin S, Nagler A, Naparstek E, Varadi G, Ben-Yosef R, Panighari S, Samuel S, Ackerstein A, Or R: A new nonmyeloablative protocol using fludarabine and low-dose TBI in preparation for allogeneic blood stem cell transplantation for high risk patients with malignant and non-malignant disorders. Blood 10(Suppl 1);388b 1994Google Scholar
  24. 24.
    Nagler A, Slavin S, Varadi G, Naparstek E, Samuel S, Or R: Allogeneic peripheral blood stem cell transplantation using a fludarabine-based low intensity conditioning regimen for a malignant lymphoma. Bone Marrow Transplant 25(10):1021–1028, 2000Google Scholar
  25. 25.
    Nagler A, Or R, Naparstek E, Varadi G, Brautbar C, Slavin S: Matched unrelated bone marrow transplantation (BMT) using a non-myeloablative conditioning regimen. Blood 10(1);289a, 1992Google Scholar
  26. 26.
    Nagler A, Or R, Naparstek E, Varadi G, Ben-Yosef R, Slavin S: Secondary allogeneic stem cell transplantation (alloSCT) using a non-myeloablative conditioning regimen for patients with hematological malignancies. Blood 10(1);137a, 1992Google Scholar
  27. 27.
    Slavin S: Treatment of myeloid leukemias with non-myeloablative stem cell transplantation: accomplishments and future goals. Hematology 81–89, 2000 (Educational Symposium, ASH, December 2000). G.P. Schechter, N. Berliner, TM.J. Telen eds. pp. 81‐90Google Scholar
  28. 28.
    Slavin S, Strober S, Fuks Z, Kaplan HS: Long-term survival of skin allografts in mice treated with fractionated total lymphoid irradiation. Science 193:1252–54, 1976Google Scholar
  29. 29.
    Slavin S: Total lymphoid irradiation. Immunol Today 3:88–92, 1987Google Scholar
  30. 30.
    Slavin S, Fuks Z, Kaplan HS, Strober S: Transplantation of allogeneic bone marrow without graft vs host disease using total lymphoid irradiation. J Exp Med 147:963–972, 1978Google Scholar
  31. 31.
    Slavin S, Weiss L, Morecki S, Weigensberg M: Eradication of murine leukemia with histoincompatible marrow grafts in mice conditioned with total lymphoid irradiation (TLI). Cancer Immunol Immunother 11:155–158, 1981Google Scholar
  32. 32.
    Moscovitch M, Slavin S: Anti-tumor effects of allogeneic bone marrow transplantation in (NZB _ NZW)F1 hybrids with spontaneous lymphosarcoma. J Immunol 132:997–1000, 1984Google Scholar
  33. 33.
    Morecki S, Yacovlev E, Diab A, Slavin S: Allogeneic cell therapy for a murine mammary carcinoma. Cancer Res 58:3891–3895, 1998Google Scholar
  34. 34.
    Childs R, Chernoff A, Contentin N, Bahceci E, Schrump D, Leitman S, Read EJ, Tisdale J, Dunbar C, Linehan WM, Young NS, Barrett AJ: Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 14;343(11):750–758, 2000Google Scholar
  35. 35.
    Slavin S. Cancer Immunotherapy with alloreactive lymphocytes. New Engl J Med 343(11);802–803, 2000Google Scholar
  36. 36.
    Gratwohl A, Hermans J, Goldman JM, Arcese A, Carreras E, Devergie A, Frassoni F, Gahrton G, Kolb HJ, Niederwieser D, Ruutu T, Vernant JP, de Witte T, Apperley J for the chronic leukemia Working Party of the EBMT: Lancet 352:1087, 1998Google Scholar
  37. 37.
    Slavin S: Immunotherapy of cancer with alloreactive lymphocytes (review). Lancet Oncol 2:491–498, 2001Google Scholar

Copyright information

© Plenum Publishing Corporation 2002

Authors and Affiliations

  • Shimon Slavin
    • 1
  • Arnon Nagler
    • 1
  • Michael Y. Shapira
    • 1
  • Mehmet Aker
  • Cividalli Gabriel
    • 2
  • Reuven Or
    • 1
  1. 1.Department of Bone Marrow Transplantation and Department ofCancer Immunotherapy, Danny Cunniff Leukemia Research LaboratoryHadassah University HospitalJerusalemIsrael
  2. 2.Department of PediatricsHadassah University HospitalJerusalemIsrael

Personalised recommendations