Advertisement

Immunologic Research

, Volume 28, Issue 1, pp 13–24 | Cite as

The transplantation of hematopoietic stem cells after non-myeloablative conditioning

A cellular therapeutic approach to hematologic and genetic diseases
  • Michael Maris
  • Rainer Storb
Article

Abstract

Originally, allogeneic hematopoietic stem cell transplantation (HSCT) was viewed as a form of rescue from the marrow lethal effects of high doses of chemo-radiotherapy used to both eradicate malignancy and to provide sufficient immunosuppression to ensure allogeneic engraftment. Clear evience of a therapeutic graft-versus-tumor (GVT) effect mediated by allogeneic affector cells (T cells) has prompted the exploration of HSCT regimens that rely solely upon host immunosuppression (non-myeloblative) to facilitate allogenic donor engraftment. The engrafted donor effector cells are then used to accomplish the task of eradicating host malignant cells. The non-myeloblative regimen developed in Seattle uses 2 Gy total body irradiation (TBI) before transplant followed by postgrafting cyclosporine (CSP) and mycophenolate mofetil (MMF). This regimen resulted in initial mixed donor-host chimerism in all patients with hematologic malignancies and genetic disorders who received HLA-matched sibling allografts. The 17% incidence of graft rejection was reduced to 3% with the addition of fludarabine, 30 mg/m2/day on d-4,-3, and-2. The non-myeloblative combination of fludarabine/TBI has also been successful at achieving high engraftment rates in recipients of 10 of 10 HLA antigen matched unrelated donor HSCTs in patients with hematologic malignancies. By reducing acute toxicities relative to conventional HSCT, most patients have received their pre- and post-HSCT therapy almost exclusively as outpatients. Acute and chronic GVHD occur after non-myeloablative HSCT, but the incidence and severity appear less compared to conventional HSCT. As in conventional transplants, immune dysregulation from GVHD and its treatment and delayed reconstitution of immune function continue to present risks to patients who have otherwise undergone successful non-myeloablative HSCT. Cellular therapeutic effects have been nobserved after non-myeloblative HSCT such as correction of inherited genetic disorders, and eradication of hematologic malignant diseases and renal cell carcinoma via GVT responses.

Key Words

Hematopoietic stem cells Graft-versus-tumor effect Non-myeloablative transplants 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Jacobson LO, Marks EK, Robson MJ, Gaston EO, Zirkle RE: Effect of spleen protection on mortality followingx-irradiation. J Lab Clin Med 1949;34:1538.Google Scholar
  2. 2.
    Thomas ED, Storb R, Clift RA, Fefer A, Johnson FL, Neiman PE, et al.: Bone-marrow transplantation. N Engl J Med 1975;292: 832–843, 895–902.PubMedCrossRefGoogle Scholar
  3. 3.
    Burchenal JH, Oettgen HF, Holmberg EAD, Hemphill SC, Reppert JA: Effect of total body irradiation on the transplantability of mouse leukemias. Cancer Res 1960; 20:425.PubMedGoogle Scholar
  4. 4.
    Barnes DWH, Loutit JF: Treatment of murine leukaemia with x-rays and homologous bone marrow: II. Br J Haematol 1957;3:241.PubMedGoogle Scholar
  5. 5.
    Mathé G, Amiel JL, Schwarzenberg L, Catton A, Schneider M: Adoptive immunotherapy of acute leukemia: Experimental and clinical results. Cancer Res 1965;25: 1525.PubMedGoogle Scholar
  6. 6.
    Weiden PL, Flournoy N, Thomas ED, Prentice R, Fefer A, Buckner CD, et al.: Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med 1979;300:1068.PubMedCrossRefGoogle Scholar
  7. 7.
    Weiden PL, Sullivan KM, Flournoy N, Storb R, Thomas ED, the Seattle Marrow Transplant Team: Antileukemic effect of chronic graft-versus-host disease. Contribution to improved survival after allogeneic marrow transplantation. N Engl J Med 1981; 304:1529.PubMedCrossRefGoogle Scholar
  8. 8.
    Storb R, Yu C, Wagner JL, Deeg HJ, Nash RA, Kiem H-P, et al.: Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood 1997;89:3048.PubMedGoogle Scholar
  9. 9.
    Woolfrey AE, Nash RA, Frangoul HA, McSweeney PA, Sanders JE, Ochs HD, et al.: Non-myeloablative transplant regimen used for induction of multi-lineage allogeneic hematopoietic mixed donor-host chimerism in patients with T-cell immunodeficiency. Blood 1998;92(Suppl 1):520a (abstract).Google Scholar
  10. 10.
    Schaap N, Schattenberg A, Mensink E, Preijers F, Hillegers M, Knops R, et al.: Long-term followup of persisting mixed chimerism after partially T cell-depletedallogeneic stem cell transplantation. Leukemia 2002;16:13.PubMedCrossRefGoogle Scholar
  11. 11.
    Mattsson J, Uzunel M, Tammik L, Aschan J, Ringden O: Leukemia lineage-specific chimerism analysisis a sensitive predictor of relapse in patients with acute myeloid leukemia and myelodysplastic syndrome after allogeneic stem cell transplantation. Leukemia 2001; 15:1976.PubMedGoogle Scholar
  12. 12.
    McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG, et al.: Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001; 97:3390.PubMedCrossRefGoogle Scholar
  13. 13.
    Weissinger F, Sandmaier BM, Maloney DG, Bensinger WI, Gooley T, Storb R: Decreased transfusion requirements for patients receiving nonmyeloblative compared with conventional peripheral blood stem cell transplants from HLA-identical siblings. Blood 2001;98:3584.PubMedCrossRefGoogle Scholar
  14. 14.
    Martin PJ, Hansen JA, Torok-Storb B, Durnam D, Przepiorka D, O'Quigley J, et al.: Graft failure in patients receiving T cell-depleted HLA-identicallogeneic, marrow transplants. Bone Marrow Transplant 1988;3:445.PubMedGoogle Scholar
  15. 15.
    Cheson BD: Infectious and immunosuppressive complications of purine analog therapy (Review). J Clin Oncol 1995;13:2431.PubMedGoogle Scholar
  16. 16.
    Frank DA, Mahajan S, Ritz J: Fludarabine-induced immunosuppression is associated with inhibition of STATI signaling. Nat Med 1999;5:444.PubMedCrossRefGoogle Scholar
  17. 17.
    Consoli U, El-Tounsi I, Sandoval A, Snell V, Kleine H-D, Brown W, et al.: Differential induction of apoptosis by fludarabine monophosphate in leukemic B and normal T cells in chronic lymphocytic leukemia. Blood 1998;91:1742.PubMedGoogle Scholar
  18. 18.
    Boldt DH, Von Hoff DD, Kuhn JG, Hersh M: Effects on human peripherallymphocytes of in vivo administration of 9-β-d-arabinofuranosyl-2-fluoroadenine-5′-monophosphate (NSC 31 2887), a new purine antimetabolite. Cancer Res 1984;44:4661.PubMedGoogle Scholar
  19. 19.
    Sandmaier BM, Maloney DG, Gooley T, Hegenbart U, Shizuru J, Sahebi F, et al.: Nonmyeloablative hematopoietic stem cell transplants (HSCT) from HLA-matched related donors for patients with hematologic malignancies: clinical results of TBI-based conditioning regimen. Blood 2001;98 (Part I) 742a (abstract).Google Scholar
  20. 20.
    Maloney DG, Sabebi F, Stockerl-Goldstein KE, Sandmaier BM, Molina AJ, Bensinger W, et al.: Combininganallogeneic graft-vs-myeloma effect with high-dose autologous stem cell rescue in the treatment of multiple myeloma. Blood 2001;98 (Part 1):434a (abstract).Google Scholar
  21. 21.
    Sandmaier BM, Niederwieser D, McSweeney PA, Shizuru J, Maloney DG, Radich J, et al.: Induction of molecular remissions in chronic myelogenous leukemia (CML) with nonmyeloablative HLA-identical sibling allografts. Blood 2000;96 (Part 1):201a (abstract).Google Scholar
  22. 22.
    McSweeney P, Niederwieser D, Shizuru J, Radich J, Molina A, Hegenbart U, et al.: Molecular remissions after non-myeloablative allografting for chronic myelocytic leukemia (CML). Blood 1999; 94(Suppl 1):170a (abstract).Google Scholar
  23. 23.
    Sandmaier BM, Maloney DG, Hegenbart U, McSweeney PA, Shizuru J, Sahebi F, et al.: Nonmyeloblative conditing for HLA-identical related allografts for hematologic malignancies. Blood 2000;96 (Part 1):479a (abstract).Google Scholar
  24. 24.
    Sandmaier BM, Wilbur DS, Hamlin D, Santos EB, Storb R: Nonmyeloablative marrow transplant conditioning: use of antibody-targeted BI-213. Blood 2000;96 (Part 1):517a (abstract).Google Scholar
  25. 25.
    Molina A, Sahebi F, Maloney DG, Sandmaier BM, McSweeney P, Kashyap A, et al.: Non-myeloablative peripheral blood stem cell (PBSC) allografts following cytoreductive autotransplants for treatment of multiple myeloma (MM). Blood 2000; 96 (Part 1):480a (abstract).Google Scholar
  26. 26.
    Maris MB, Sandmaier BM, Niederwieser D, Maloney DG, McSweeney PA, Chauncey T, et al.: The effect of donor lymphocyte infussions (DLI) on chimerism and persistent disease after non-myeloablative hematopoietic stem cell transplant (HSCT). Blood 2000;96 (Part 1):477a (abstract).Google Scholar
  27. 27.
    Maris M, Niederwieser D, Sandmaier B, Maloney D, Shizuru J, Petersdorf E, et al.: Nonmyeloablative hematopoietic stem cell transplants (HSCT) using 10/10 HLA antigen matched unrelated donors (URDs) for patients with advanced hematologic malignancies ineligible for conventional HSCT. Blood 2001;98 (Part 1): 858a (abstract).Google Scholar
  28. 28.
    Kottaridis PD, Milligan DW, Chopra R, Chakraverty RK, Chakrabarti S, Robinson S, et al.: In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation. Blood 2000;96: 2419.PubMedGoogle Scholar
  29. 29.
    Peggs KS, Mahendra P, Milligan DW, Chopra R, Chakraverty RK, Kottaridis PD, et al.: Non-myeloablative transplantation using matched unrelated donorsin vivo Campath-1H limits graft versus hostdisease. Blood 2000;96 (Part 1):841a (abstract).Google Scholar
  30. 30.
    Spitzer TR, McAfee S, Sackstein R, Dey B, Colby C, Grossberg H, et al.: Haploidentical donor bone marrow transplantation (BMT) for advanced hematologic malignancy (HM) following non-myeloablative preparative therapy: role of in vivo T-cell depletion with anti-thymocyte globulin or anti-CD2 monoclonal antibody therapy (medi-507). Blood 2000;96 (Part 1): 841a (abstract).Google Scholar
  31. 31.
    Giralt S, Estey E, Albitar M, van Besien K, Rondón G, Anderlini P, et al.: Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 1997;89: 4531.PubMedGoogle Scholar
  32. 32.
    Khouri I, Keating MJ, Przepiorka D, O'Brien S, Giralt S, Korbling M, et al.: Engraftment and induction of GVL with fludarabine (FAMP)-based non-ablative preparative regimen in patients with chronic lymphocytic leukemia (CLL) and lymphoma. Blood 1996;88:301a (abstract).Google Scholar
  33. 33.
    Khouri IF, Keating M, Körbling M, Przepiorka D, Anderlini P, O'Brien S, et al.: Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 1998;16:2817.PubMedGoogle Scholar
  34. 34.
    Khouri IF, Saliba RM, Giralt SA, Lee M-S, Okoroji G-J, Hagemeister FB, et al.: Nonablative allogeneic hematopoeitic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood 2001;98:3595.PubMedCrossRefGoogle Scholar
  35. 35.
    Giralt S, Thall PF, Khouri I, Wang X, Braumschweig I, Ippolitti C, et al.: Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood 2001;97:631.PubMedCrossRefGoogle Scholar
  36. 36.
    Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, et al.: Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the treatment of malignant and nonmalignant hematologic diseases. Blood 1998;91:756.PubMedGoogle Scholar
  37. 37.
    Nagler A, Aker M, Or R, Naparstek E, Varadi G, Brauthar C, et al.: Low-intensity conditioning issufficient to ensure engraftment in matched unrelated bone marrow transplantation. Exp Hematol 2001;29:362.PubMedCrossRefGoogle Scholar
  38. 38.
    Bornhauser M, Thiede C, Platzbecker U, Jenke A, Helwig A, Plettig R, et al.: Dose-reduced conditioningan dallogeneic hematopoietic stem cell transplantation from unrelated donors in 42 patients. Clin Cancer Res 2001; 7:2254.PubMedGoogle Scholar
  39. 39.
    Sykes M, Preffer F, McAfee, S, Saidman SL, Weymouth D, Andrews DM, et al.: Mixed lymphohaemopoietic chimerism and graft-versus-lymphoma effects afternon-myeloblative therapy and HLA-mismatched bone-marrow transplantation. Lancet 1999;353: 1755.PubMedCrossRefGoogle Scholar
  40. 40.
    Spitzer TR, McAfee S, Sackstein R, Colby C, Toh HC, Multani P, et al.: Intentional induction of mixed chimerism and achievement of antitumor responses after nonmye loablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies. Biol Blood Marrow Transplant 2000;6:309.PubMedCrossRefGoogle Scholar
  41. 41.
    Childs R, Clave E, Contentin N, Jayasekera D, Hensel N, Leitman S, et al.: Engraftment kinetics afternon-myeloablative allogeneic peripheral blood stem cell transplantation: full do nor T-cell chimerism precedes alloimmune responses. Blood 1999;94:3234.PubMedGoogle Scholar
  42. 42.
    Childs R, Chernoff A, Contentin N, Bahceci E, Schrump D, Leitman S, et al.: Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 2000; 343:750.PubMedCrossRefGoogle Scholar
  43. 43.
    Chakraverty R, Peggs K, Chopra R, Milligan DW, Kottaridis PD, Verfuerth S, et al.: Limiting transplantation-related mortality following unre lated donor stem cell transplantation by usinga nonmye loablative conditioning regimen. Blood 2002;99:1071.PubMedCrossRefGoogle Scholar
  44. 44.
    Michallet M, Bilger K, Garban F, Attal M, Huyn A, Blaise D, et al.: Allogeneic hematopoietic stem-cell transplantation afternon-myeloablative preparative regimens: impact of pretransplantation and posttransplantation factors on outcome. J Clin Oncol 2001;19: 3340.PubMedGoogle Scholar
  45. 45.
    Carella AM, Cavaliere M, Lerma E, Ferrara R, Tedeschi L, Romanelli A, et al.: Autografting followed by nonmyeloablative immunosuppressive chemotherapy and allogeneic peripheral-blood hematopoietic stem-cell transplantation as treatment of resistant Hodgkin's disease and non-Hodgkin's lymphoma. J Clin Oncol 2000;18:3918.PubMedGoogle Scholar
  46. 46.
    Warren EH, Gavin M, Greenberg PD, Riddell SR: Minor histocompatibility antigens as targets for T-cell therapy after bone marrow transplantation. Curr Opin Hematol 1998;5:429.PubMedCrossRefGoogle Scholar
  47. 47.
    Greenberg PD, Riddell SR, In Therapeutic Immunology. Austen KF, Burakoff SJ, Rosen FS, Strom TB, editors. Therapeutic Immunology: Blackwell Science, Malden, MA 2001;550.Google Scholar
  48. 48.
    Junghanss C, Marr KA, Carter RA, Sandmaier BM, Maris MB, Maloney DG, et al.: Incidence of bacterial and fungal infections after non-myeloablative compared to myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) Blood 2001;98 (Part 1): 479a (abstract).Google Scholar
  49. 49.
    Junghanss C, Boeckh M, Carter RA, Sandmaier BM, Maris MB, Maloney DG, et al.: Incidence and outcome of cytomegalovirus infections following non-myeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study. Blood 2002;99:1978.PubMedCrossRefGoogle Scholar
  50. 50.
    Morecki S, Gelfand Y, Nagler A, Or R, Naparstek E, Varadi G, et al.: Immune reconstitution following allogeneic stem cell transplantation in recipients conditioned by low intensity vs myeloa blative regimen. J Clin Endocrinol Metab 2001;28:243.Google Scholar
  51. 51.
    Mohty M, Faucher C, Vey N, Stoppa AM, Viret F, Chabbert I, et al.: High rate of secondary viral and bacterial infections in patients undergoing allogeneic bone marrow mini-transplantation. Bone Marrow Tranplant 2000; 26:251.CrossRefGoogle Scholar
  52. 52.
    Savage WJ, Bleesing JJH, Douek D, Brown MR, Linton GM, Malech HL, et al.: Lymphocyte reconstitution following non-myeloablative hematopoietic stem cell transplantation follows two patterns depending on age and donor/recipient chimerism. Bone Marrow Transplant 2001;28:463.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2003

Authors and Affiliations

  • Michael Maris
    • 1
  • Rainer Storb
    • 1
  1. 1.Fred Hutchinson Cancer Research Center, Seattle, WAUniversity of WashingtonSeattle

Personalised recommendations