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Allogeneic hematopoietic cell transplantation: from experimental biology to clinical care

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Abstract

Purpose

For more than half a century, researchers have explored myeloablative, high-dose chemo/radiotherapy followed by allogeneic hematopoietic stem cell transplantation (HCT) for therapy of malignant and nonmalignant hematological diseases. Continuous advances in the field have changed this approach from one that was initially thought to be fraught by insurmountable complications to one that is now considered standard therapy for many diseases.

Methods

In order to extend allogeneic HCT to include elderly patients, who represent the main population affected by hematological malignancies, and to those who are medically unfit to undergo conventional HCT, novel nonmyeloablative approaches have been developed. These approaches rely on graft-vs-tumor effects for tumor eradication rather than high-dose chemoradiotherapy, and, accordingly, have lower toxicities than conventional regimens.

Results

Results with nonmyeloablative regimens have been gratifying, and this may change the future of allogeneic HCT. Advances could not have been possible without basic research and studies in pre-clinical animal models.

Conclusion

Further work is focused on improving graft-vs-tumor effects while achieving better control of graft-vs-host disease.

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References

  • Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F, Ruggeri L, Barbabietola G, Aristei C, Latini P, Reisner Y, Martelli MF (1998) Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med 339:1186–1193

    Article  CAS  PubMed  Google Scholar 

  • Aversa F, Terenzi A, Carotti A, Felicini R, Jacucci R, Zei T, Latini P, Aristei C, Santucci A, Martelli MP, Cunningham I, Reisner Y, Martelli MF (1999) Improved outcome with T-cell-depleted bone marrow transplantation for acute leukemia. J Clin Oncol 17:1545–1550

    CAS  PubMed  Google Scholar 

  • Barnes DWH, Loutit JF (1957) Treatment of murine leukaemia with X-rays and homologous bone marrow: II. Br J Haematol 3:241–252

    CAS  PubMed  Google Scholar 

  • Barnes DWH, Corp MJ, Loutit JF, Neal FE (1956) Treatment of murine leukaemia with X-rays and homologous bone marrow. Preliminary communication. Br Med J 2:626–627

    Google Scholar 

  • Baron F, Beguin Y (2000) Adoptive immunotherapy with donor lymphocyte infusions after allogeneic HPC transplantation (Review). Transfusion 40:468–476

    Article  CAS  PubMed  Google Scholar 

  • Baron F, Storb R, Little M-T (2003) Hematopoietic cell transplantation: five decades of progress (Review). Arch Med Res 34:528–544

    Article  CAS  PubMed  Google Scholar 

  • Bensinger WI, Martin PJ, Storer B, Clift R, Forman SJ, Negrin R, Kashyap A, Flowers MED, Lilleby K, Chauncey TR, Storb R, Appelbaum FR (2001) Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med 344:175–181

    Article  CAS  PubMed  Google Scholar 

  • Bethge WA, Wilbur DS, Storb R, Hamlin DK, Santos EB, Brechbiel MW, Fisher DR, Sandmaier BM (2003) Selective T-cell ablation with bismuth-213-labeled anti-TCRαβ as nonmyeloablative conditioning for allogeneic canine marrow transplantation. Blood 101:5068–5075

    Article  CAS  PubMed  Google Scholar 

  • Blaise D, Bay JO, Faucher C, Michallet M, Boiron JM, Choufi B, Cahn JY, Gratecos N, Sotto JJ, Francois S, Fleury J, Mohty M, Chabannon C, Bilger K, Gravis G, Viret F, Braud AC, Bardou VJ, Maraninchi D, Viens P (2004) Reduced-intensity preparative regimen and allogeneic stem cell transplantation for advanced solid tumors. Blood 103:435–441

    Article  CAS  PubMed  Google Scholar 

  • Blume KG, Beutler E, Bross KJ, Chillar RK, Ellington OB, Fahey JL, Farbstein MJ, Forman SJ, Schmidt GM, Scott EP, Spruce WE, Turner MA, Wolf JL (1980) Bone-marrow ablation and allogeneic marrow transplantation in acute leukemia. N Engl J Med 302:1041–1046

    CAS  PubMed  Google Scholar 

  • Bornhauser M, Schuler U, Porksen G, Naumann R, Geissler G, Thiede C, Schwerdtfeger R, Ehninger G, Thiede HM (1999) Mycophenolate mofetil and cyclosporine as graft-versus-host disease prophylaxis after allogeneic blood stem cell transplantation. Transplantation 67:499–504

    Article  CAS  PubMed  Google Scholar 

  • Bortin MM (1970) A compendium of reported human bone marrow transplants. Transplantation 9:571–587

    CAS  PubMed  Google Scholar 

  • Burchenal JH, Oettgen HF, Holmberg EAD, Hemphill SC, Reppert JA (1960) Effect of total body irradiation on the transplantability of mouse leukemias. Cancer Res 20:425

    CAS  PubMed  Google Scholar 

  • Childs R, Clave E, Contentin N, Jayasekera D, Hensel N, Leitman S, Read EJ, Carter C, Bahceci E, Young NS, Barrett AJ (1999) Engraftment kinetics after nonmyeloablative allogeneic peripheral blood stem cell transplantation: full donor T-cell chimerism precedes alloimmune responses. Blood 94:3234–3241

    CAS  PubMed  Google Scholar 

  • Childs R, Chernoff A, Contentin N, Bahceci E, Schrump D, Leitman S, Read EJ, Tisdale J, Dunbar C, Linehan WM, Young NS, Barrett AJ (2000) Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 343:750–758

    Article  CAS  PubMed  Google Scholar 

  • Clift RA, Buckner CD, Appelbaum FR, Bearman SI, Petersen FB, Fisher LD, Anasetti C, Beatty P, Bensinger WI, Doney K, Hill R, McDonald G, Martin P, Sanders J, Singer J, Stewart P, Sullivan KM, Witherspoon R, Storb R, Hansen J, Thomas ED (1990) Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens. Blood 76:1867–1871

    CAS  PubMed  Google Scholar 

  • Clift RA, Buckner CD, Appelbaum FR, Bryant E, Bearman SI, Petersen FB, Fisher LD, Anasetti C, Beatty P, Bensinger WI, Doney K, Hill RS, McDonald GB, Martin P, Meyers J, Sanders J, Singer J, Stewart P, Sullivan KM, Witherspoon R, Storb R, Hansen JA, Thomas ED (1991) Allogeneic marrow transplantation in patients with chronic myeloid leukemia in the chronic phase: a randomized trial of two irradiation regimens. Blood 77:1660–1665

    CAS  PubMed  Google Scholar 

  • Clift RA, Buckner CD, Thomas ED, Bensinger WI, Bowden R, Bryant E, Deeg HJ, Doney KC, Fisher LD, Hansen JA, Martin P, McDonald GB, Sanders JE, Schoch G, Singer J, Storb R, Sullivan KM, Witherspoon RP, Appelbaum FR (1994) Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide. Blood 84:2036–2043

    CAS  PubMed  Google Scholar 

  • Clift RA, Radich J, Appelbaum FR, Martin P, Flowers MED, Deeg HJ, Storb R, Thomas ED (1999) Long-term follow-up of a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide for patients receiving allogeneic marrow transplants during chronic phase of chronic myeloid leukemia (Letter). Blood 94:3960–3962

    CAS  Google Scholar 

  • Collins RH Jr, Goldstein S, Giralt S, Levine J, Porter D, Drobyski W, Barrett J, Johnson M, Kirk A, Horowitz M, Parker P (2000) Donor leukocyte infusions in acute lymphocytic leukemia. Bone Marrow Transplant 26:511–516

    Article  PubMed  Google Scholar 

  • Couban S, Simpson DR, Barnett MJ, Bredeson C, Hubesch L, Howson-Jan K, Shore TB, Walker IR, Browett P, Messner HA, Panzarella T, Lipton JH, Canadian Bone Marrow Transplant Group (2002) A randomized multicenter comparison of bone marrow and peripheral blood in recipients of matched sibling allogeneic transplants for myeloid malignancies. Blood 100:1525–1531

    Article  CAS  PubMed  Google Scholar 

  • Deeg HJ, Storb R, Weiden PL, Schumacher D, Shulman H, Graham T, Thomas ED (1981) High-dose total-body irradiation and autologous marrow reconstitution in dogs: dose-rate-related acute toxicity and fractionation-dependent long-term survival. Radiat Res 88:385–391

    CAS  PubMed  Google Scholar 

  • Deeg HJ, Storb R, Weiden PL, Raff RF, Sale GE, Atkinson K, Graham TC, Thomas ED (1982) Cyclosporin A and methotrexate in canine marrow transplantation: engraftment, graft-versus-host disease, and induction of tolerance. Transplantation 34:30–35

    CAS  PubMed  Google Scholar 

  • Deeg HJ, Sullivan KM, Buckner CD, Storb R, Appelbaum FR, Clift RA, Doney K, Sanders JE, Witherspoon RP, Thomas ED (1986) Marrow transplantation for acute nonlymphoblastic leukemia in first remission: toxicity and long-term follow-up of patients conditioned with single dose or fractionated total body irradiation. Bone Marrow Transplant 1:151–157

    CAS  PubMed  Google Scholar 

  • Diaconescu R, Flowers CR, Storer B, Sorror ML, Maris MB, Maloney DG, Sandmaier BM, Storb R (2004) Morbidity and mortality with nonmyeloablative compared to myeloablative conditioning before hematopoietic cell transplantation from HLA matched related donors. Blood 104:1550–1558

    Article  CAS  PubMed  Google Scholar 

  • Feinstein LC, Sandmaier BM, Hegenbart U, McSweeney PA, Maloney DG, Gooley TA, Maris MB, Chauncey TR, Bruno B, Appelbaum FR, Niederwieser DW, Storb RF (2003) Non-myeloablative allografting from human leucocyte antigen-identical sibling donors for treatment of acute myeloid leukaemia in first complete remission. Br J Haematol 120:281–288

    Article  PubMed  Google Scholar 

  • Flowers MED, Parker PM, Johnston LJ, Matos AVB, Storer B, Bensinger WI, Storb R, Appelbaum FR, Forman SJ, Blume KG, Martin PJ (2002) Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial. Blood 100:415–419

    Article  CAS  PubMed  Google Scholar 

  • Ford CE, Hamerton JL, Barnes DWH, Loutit JF (1956) Cytological identification of radiation-chimaeras. Nature 177:452–454

    CAS  PubMed  Google Scholar 

  • Forman SJ, Spruce WE, Farbstein MJ, Wolf JL, Scott EP, Nademanee AP, Fahey JL, Hecht T, Zaia JA, Krance RA, Findley DO, Blume KG (1983) Bone marrow ablation followed by allogeneic marrow grafting during first complete remission of acute nonlymphocytic leukemia. Blood 61:439–442

    CAS  PubMed  Google Scholar 

  • Gale RP, Horowitz MM, Ash RC, Champlin RE, Goldman JM, Rimm AA, Ringden O, Stone JAV, Bortin MM (1994) Identical twin bone marrow transplants for leukemia. Ann Intern Med 120:646–652

    CAS  PubMed  Google Scholar 

  • Giralt S, Estey E, Albitar M, van Besien K, Rondón G, Anderlini P, O’Brien S, Khouri I, Gajewski J, Mehra R, Claxton D, Andersson B, Beran M, Przepiorka D, Koller C, Kornblau S, Körbling M, Keating M, Kantarjian H, Champlin R (1997) Engraftment of allogeneic hematopoietic progenitor cells with purine analog-containing chemotherapy: harnessing graft-versus-leukemia without myeloablative therapy. Blood 89:4531–4536

    CAS  PubMed  Google Scholar 

  • Goldman JM, Apperley JF, Jones L, Marcus R, Goolden AWG, Batchelor R, Hale G, Waldmann H, Reid CD, Hows J, Gordon-Smith E, Catovsky D, Galton DAG (1986) Bone marrow transplantation for patients with chronic myeloid leukemia. N Engl J Med 314:202–207

    CAS  PubMed  Google Scholar 

  • Goldman JM, Gale RP, Horowitz MM, Biggs JC, Champlin RE, Gluckman E, Hoffmann RG, Jacobsen SJ, Marmont AM, McGlave PB, Messner HA, Rimm AA, Rozman C, Speck B, Tura S, Weiner RS, Bortin MM (1988) Bone marrow transplantation for chronic myelogenous leukemia in chronic phase: increased risk of relapse associated with T-cell depletion. Ann Intern Med 108:806–814

    CAS  PubMed  Google Scholar 

  • Goulmy E (1997) Human minor histocompatibility antigens: new concepts for marrow transplantation and adoptive immunotherapy (Review). Immunol Rev 157:125–140

    CAS  PubMed  Google Scholar 

  • Hansen JA, Gooley TA, Martin PJ, Appelbaum F, Chauncey TR, Clift RA, Petersdorf EW, Radich J, Sanders JE, Storb RF, Sullivan KM, Anasetti C (1998) Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med 338:962–968

    Article  CAS  PubMed  Google Scholar 

  • Hansen JA Petersdorf EW (1999) Unrelated donor hematopoietic cell transplantation. In: Thomas ED, Blume KG, Forman SJ (eds) Hematopoietic cell transplantation. Blackwell, Boston, pp 915–928

  • Hogan WJ, Little M-T, Zellmer E, Friedetzky A, Diaconescu R, Gisburne S, Lee R, Kuhr C, Storb R (2003) Postgrafting immunosuppression with sirolimus and cyclosporine facilitates stable mixed hematopoietic chimerism in dogs given sublethal total body irradiation before marrow transplantation from DLA-identical littermates. Biol Blood Marrow Transplant 9:489–495

    Article  CAS  PubMed  Google Scholar 

  • Hurley CK, Fernandez VM, Setterholm M (2003) Maximizing optimal hematopoietic stem cell donor selection from registries of unrelated adult volunteers. Tissue Antigens 61:415–424

    CAS  PubMed  Google Scholar 

  • Jacobson LO, Marks EK, Robson MJ, Gaston EO, Zirkle RE (1949) Effect of spleen protection on mortality following X-irradiation. J Lab Clin Med 34:1538–1543

    Google Scholar 

  • Junghanss C, Boeckh M, Carter RA, Sandmaier BM, Maris MB, Maloney DG, Chauncey T, McSweeney PA, Little M-T, Corey L, Storb R (2002a) Incidence and outcome of cytomegalovirus infections following nonmyeloablative compared with myeloablative allogeneic stem cell transplantation, a matched control study. Blood 99:1978–1985

    Article  CAS  PubMed  Google Scholar 

  • Junghanss C, Marr KA, Carter RA, Sandmaier BM, Maris MB, Maloney DG, Chauncey T, McSweeney PA, Storb R (2002b) Incidence and outcome of bacterial and fungal infections following nonmyeloablative compared with myeloablative allogeneic hematopoietic stem cell transplantation: a matched control study. Biol Blood Marrow Transplant 8:512–520

    Article  PubMed  Google Scholar 

  • Khouri IF, Keating M, Körbling M, Przepiorka D, Anderlini P, O’Brien S, Giralt S, Ippoliti C, Wolff B von, Gajewski J, Donato M, Claxton D, Ueno N, Andersson B, Gee A, Champlin R (1998) 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 16:2817–2824

    CAS  PubMed  Google Scholar 

  • Kolb HJ, Mittermüller J, Clemm C, Holler G, Ledderose G, Brehm G, Heim M, Wilmanns W (1990) Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76:2462–2465

    CAS  PubMed  Google Scholar 

  • Kolb HJ, Schattenberg A, Goldman JM, Hertenstein B, Jacobsen N, Arcese W, Ljungman P, Ferrant A, Verdonck L, Niederwieser D, van Rhee F, Mittermueller J, de Witte T, Holler E, Ansari H (1995) Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. European Group for Blood and Marrow Transplantation Working Party Chronic Leukemia. Blood 86:2041–2050

    CAS  PubMed  Google Scholar 

  • Kolb HJ, Schmidt C, Barrett AJ, Schendel DJ (2004) Graft-versus-leukemia reactions in allogeneic chimeras. Blood 103:767–776

    Article  CAS  PubMed  Google Scholar 

  • Kurtzberg J, Laughlin M, Graham ML, Smith C, Olson JF, Halperin EC, Ciocci G, Carrier C, Stevens CE, Rubinstein P (1996) Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients. N Engl J Med 335:157–166

    Article  CAS  PubMed  Google Scholar 

  • Lochte HL Jr, Levy AS, Guenther DM, Thomas ED, Ferrebee JW (1962) Prevention of delayed foreign marrow reaction in lethally irradiated mice by early administration of methotrexate. Nature 196:1110–1111

    CAS  PubMed  Google Scholar 

  • Lorenz E, Uphoff D, Reid TR, Shelton E (1951) Modification of irradiation injury in mice and guinea pigs by bone marrow injections. J Natl Cancer Inst 12:197–201

    CAS  PubMed  Google Scholar 

  • Mackinnon S, Papadopoulos EB, Carabasi MH, Reich L, Collins NH, Boulad F, Castro-Malaspina H, Childs BH, Gillio AP, Kernan NA (1995) Adoptive immunotherapy evaluating escalating doses of donor leukocytes for relapse of chronic myeloid leukemia after bone marrow transplantation: separation of graft-versus-leukemia responses from graft-versus-host disease. Blood 86:1261–1268

    CAS  PubMed  Google Scholar 

  • Main JM, Prehn RT (1955) Successful skin homografts after the administration of high dosage X radiation and homologous bone marrow. J Natl Cancer Inst 15:1023–1029

    CAS  PubMed  Google Scholar 

  • Makinodan T (1956) Circulating rat cells in lethally irradiated mice protected with rat bone marrow. Proc Soc Exp Biol Med 92:174–179

    CAS  PubMed  Google Scholar 

  • Maloney DG, Sahebi F, Stockerl-Goldstein KE, Sandmaier BM, Molina AJ, Bensinger W, McSweeney PA, Storer BE, Niederwieser D, Chauncey T, Appelbaum FR, Blume KG, Forman SJ, Storb R (2001) Combining an allogeneic graft-vs-myeloma effect with high-dose autologous stem cell rescue in the treatment of multiple myeloma. Blood 98 (part 1):434a–435a, #1822 (abstract)

    Google Scholar 

  • Maloney DG, Molina AJ, Sahebi F, Stockerl-Goldstein KE, Sandmaier BM, Bensinger W, Storer B, Hegenbart U, Somlo G, Chauncey T, Bruno B, Appelbaum FR, Blume KG, Forman SJ, McSweeney P, Storb R (2003) Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 102:3447–3454

    Article  CAS  PubMed  Google Scholar 

  • Maraninchi D, Gluckman E, Blaise D, Guyotat D, Rio B, Pico JL, Leblond V, Michallet M, Dreyfus F, Ifrah N, Bordigoni A (1987) Impact of T-cell depletion on outcome of allogeneic bone-marrow transplantation for standard-risk leukaemias. Lancet 2:175–178

    Article  CAS  PubMed  Google Scholar 

  • Marijt WA, Heemskerk MH, Kloosterboer FM, Goulmy E, Kester MG, van der Hoorn MA, van Luxemburg-Heys SA, Hoogeboom M, Mutis T, Drijfhout JW, van Rood JJ, Willemze R, Falkenburg JH (2003) Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia. Proc Natl Acad Sci 100:2742–2747

    Article  CAS  PubMed  Google Scholar 

  • Maris M, Niederwieser D, Sandmaier B, Maloney D, Shizuru J, Petersdorf E, Blume K, Chauncey T, Pulsipher M, McSweeney P, Storer B, Anasetti C, Woolfrey A, Slattery J, Agura E, Little M-T, Hegenbarth U, Storb R (2001) 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 98 (part 1):858a, #3563 (abstract)

    Google Scholar 

  • Maris M, Storb R (2003) The transplantation of hematopoietic stem cells after non-myeloablative conditioning: a cellular therapeutic approach to hematologic and genetic diseases. Immunol Res 28:13–24

    Article  PubMed  Google Scholar 

  • Maris MB, Niederwieser D, Sandmaier BM, Storer B, Stuart M, Maloney D, Petersdorf E, McSweeney P, Pulsipher M, Woolfrey A, Chauncey T, Agura E, Heimfeld S, Slattery J, Hegenbart U, Anasetti C, Blume K, Storb R (2003) HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood 102:2021–2030

    Article  CAS  PubMed  Google Scholar 

  • Marmont AM, Horowitz MM, Gale RP, Sobocinski K, Ash RC, van Bekkum DW, Champlin RE, Dicke KA, Goldman JM, Good RA, Herzig RH, Hong R, Masaoka T, Rimm AA, Ringden O, Speck B, Weiner RS, Bortin MM (1991) T-cell depletion of HLA-identical transplants in leukemia. Blood 78:2120–2130

    CAS  PubMed  Google Scholar 

  • Martin PJ, Hansen JA, Buckner CD, Sanders JE, Deeg HJ, Stewart P, Appelbaum FR, Clift R, Fefer A, Witherspoon RP, Kennedy MS, Sullivan KM, Flournoy N, Storb R, Thomas ED (1985) Effects of in vitro depletion of T cells in HLA-identical allogeneic marrow grafts. Blood 66:664–672

    CAS  PubMed  Google Scholar 

  • Mathé G, Amiel JL, Schwarzenberg L, Catton A, Schneider M (1965) Adoptive immunotherapy of acute leukemia: experimental and clinical results. Cancer Res 25:1525–1531

    PubMed  Google Scholar 

  • McSweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG, Chauncey TR, Gooley TA, Hegenbart U, Nash RA, Radich J, Wagner JL, Minor S, Appelbaum FR, Bensinger WI, Bryant E, Flowers MED, Georges GE, Grumet FC, Kiem H-P, Torok-Storb B, Yu C, Blume KG, Storb RF (2001) Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 97:3390–3400

    Article  CAS  PubMed  Google Scholar 

  • Mielcarek M, Martin PJ, Leisenring W, Flowers MED, Maloney DG, Sandmaier BM, Maris MB, Storb R (2003) Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 102:756–762

    Article  CAS  PubMed  Google Scholar 

  • Mohty M, Kuentz M, Michallet M, Bourhis JH, Milpied N, Sutton L, Jouet JP, Attal M, Bordigoni P, Cahn JY, Boiron JM, Blaise D, Societe Francaise de Greffe de Moelle et de Therapie Cellulaire (2002) Chronic graft-versus-host disease after allogeneic blood stem cell transplantation: long-term results of a randomized study. Blood 100:3128–3134

    Article  CAS  PubMed  Google Scholar 

  • Molina AJ Storb RF (2000) Hematopoietic stem cell transplantation in older adults. In: Rowe JM, Lazarus HM, Carella AM (eds) Handbook of bone marrow transplantation. Martin Dunitz, London, pp 111–137

  • Morris EC, Rebello P, Thomson KJ, Peggs KS, Kyriakou C, Goldstone AH, Mackinnon S, Hale G (2003) Pharmacokinetics of alemtuzumab used for in vivo and in vitro T-cell depletion in allogeneic transplantations: relevance for early adoptive immunotherapy and infectious complications. Blood 102:404–406

    Article  CAS  PubMed  Google Scholar 

  • Nash RA, Antin JH, Karanes C, Fay JW, Avalos BR, Yeager AM, Przepiorka D, Davies S, Petersen FB, Bartels P, Buell D, Fitzsimmons W, Anasetti C, Storb R, Ratanatharathorn V (2000) Phase 3 study comparing methotrexate and tacrolimus with methotrexate and cyclosporine for prophylaxis of acute graft-versus-host disease after marrow transplantation from unrelated donors. Blood 96:2062–2068

    CAS  PubMed  Google Scholar 

  • Niederwieser D, Maris M, Shizuru JA, Petersdorf E, Hegenbart U, Sandmaier BM, Maloney DG, Storer B, Lange T, Chauncey T, Deininger M, Pönisch W, Anasetti C, Woolfrey A, Little M-T, Blume KG, McSweeney PA, Storb RF (2003) Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases. Blood 101:1620–1629

    Article  CAS  PubMed  Google Scholar 

  • Nowell PC, Cole LJ, Habermeyer JG, Roan PL (1956) Growth and continued function of rat marrow cells in X-radiated mice. Cancer Res 16:258–261

    CAS  PubMed  Google Scholar 

  • Papadopoulos EB, Carabasi MH, Castro-Malaspina H, Childs BH, Mackinnon S, Boulad F, Gillio AP, Kernan NA, Small TN, Szabolcs P, Taylor J, Yahalom J, Collins NH, Bleau SA, Black PM, Heller G, O’Reilly RJ, Young JW (1998) T-cell-depleted allogeneic bone marrow transplantation as postremission therapy for acute myelogenous leukemia: freedom from relapse in the absence of graft-versus-host disease. Blood 91:1083–1090

    CAS  PubMed  Google Scholar 

  • Ratanatharathorn V, Nash RA, Przepiorka D, Devine SM, Klein JL, Weisdorf D, Fay JW, Nademanee A, Antin JH, Christiansen NP, Van Der Jagt R, Herzig RH, Litzow MR, Wolff SN, Longo WL, Petersen FB, Karanes C, Avalos B, Storb R, Buell DN, Maher RM, Fitzsimmons WE, Wingard JR (1998) Phase III study comparing methotrexate and tacrolimus (Prograf, FK506) with methotrexate and cyclosporine for graft-versus-host-disease prophylaxis after HLA-identical sibling bone marrow transplantation. Blood 92:2303–2314

    CAS  PubMed  Google Scholar 

  • Riddell SR Greenberg PD (1999) Adoptive immunotherapy with antigen-specific T cells. In: Thomas ED, Blume KG, Forman SJ (eds) Hematopoietic cell transplantation, 2nd edn. Blackwell, Boston, pp 327–341

  • Rubinstein P, Carrier C, Scaradavou A, Kurtzberg J, Adamson J, Migliaccio AR, Berkowitz RL, Cabbad M, Dobrila NL, Taylor PE, Rosenfield RE, Stevens CE (1998) Outcomes among 562 recipients of placental-blood transplants from unrelated donors. N Engl J Med 339:1565–1577

    Article  CAS  PubMed  Google Scholar 

  • Sandmaier BM, Maloney DG, Gooley T, Hegenbart U, Shizuru J, Sahebi F, Chauncey T, Agura E, Bruno B, McSweeney P, Forman S, Blume K, Niederwieser D, Storb R (2001) Nonmyeloablative hematopoietic stem cell transplants (HSCT) from HLA-matched related donors for patients with hematologic malignancies: clinical results of a TBI-based conditioning regimen. Blood 98 (part 1):742a–743a, #3093 (abstract)

    Google Scholar 

  • Santos GW, Tutschka PJ, Brookmeyer R, Saral R, Beschorner WE, Bias WB, Braine HG, Burns WH, Elfenbein GJ, Kaizer H, Mellits D, Sensenbrenner LL, Stuart RK, Yeager AM (1983) Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med 309:1347–1353

    CAS  PubMed  Google Scholar 

  • Schmitz N, Bacigalupo A, Hasenclever D, Nagler A, Gluckman E, Clark P, Bourquelot P, Greinix H, Frickhofen N, Ringden O, Zander A, Apperley JF, Gorin C, Borkett K, Schwab G, Goebel M, Russell NH, Gratwohl A (1998) Allogeneic bone marrow transplantation vs filgrastim-mobilised peripheral blood progenitor cell transplantation in patients with early leukaemia: first results of a randomised multicentre trial of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant 21:995–1003

    Article  CAS  PubMed  Google Scholar 

  • Slavin S, Naparstek E, Nagler A, Ackerstein A, Kapelushnik J, Or R (1995) Allogeneic cell therapy for relapsed leukemia after bone marrow transplantation with donor peripheral blood lymphocytes. Exp Hematol 23:1553–1562

    CAS  PubMed  Google Scholar 

  • Slavin S, Nagler A, Naparstek E, Kapelushnik Y, Aker M, Cividalli G, Varadi G, Kirschbaum M, Ackerstein A, Samuel S, Amar A, Brautbar C, Ben-Tal O, Eldor A, Or R (1998) 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 91:756–763

    CAS  PubMed  Google Scholar 

  • Socié G, Clift RA, Blaise D, Devergie A, Ringden O, Martin PJ, Remberger M, Deeg HJ, Ruutu T, Michallet M, Sullivan KM, Chevret S (2001) Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: long-term follow-up of the 4 randomized studies. Blood 98:3569–3574

    Article  PubMed  Google Scholar 

  • Sorror ML, Maris MB, Storer B, Sandmaier BM, Diaconescu R, Flowers C, Maloney DG, Storb R (2004) Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of pretransplant comorbidities. Blood 104:961–968

    Article  CAS  PubMed  Google Scholar 

  • Spitzer TR, McAfee S, Sackstein R, Colby C, Toh HC, Multani P, Saidman S, Weymouth DW, Preffer F, Poliquin C, Foley A, Cox B, Andrews D, Sachs DH, Sykes M (2000) Intentional induction of mixed chimerism and achievement of antitumor responses after nonmyeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies. Biol Blood Marrow Transplant 6:309–320

    CAS  PubMed  Google Scholar 

  • Storb R (2002) Hematopoietic cell transplantation as immunotherapy for hematologic malignancy. In: Perry MC (ed) American Society of Clinical Oncology 2002 Educational Book. American Society of Clinical Oncology, Alexandria, Virginia, pp 77–83

  • Storb R (2003) Allogeneic hematopoietic stem cell transplantation: yesterday, today, and tomorrow. Exp Hematol 31:1–10

    Article  PubMed  Google Scholar 

  • Storb R, Epstein RB, Graham TC, Thomas ED (1970) Methotrexate regimens for control of graft-versus-host disease in dogs with allogeneic marrow grafts. Transplantation 9:240–246

    CAS  PubMed  Google Scholar 

  • Storb R, Thomas ED, Buckner CD, Clift RA, Johnson FL, Fefer A, Glucksberg H, Giblett ER, Lerner KG, Neiman P (1974) Allogeneic marrow grafting for treatment of aplastic anemia. Blood 43:157–180

    CAS  PubMed  Google Scholar 

  • Storb R, Prentice RL, Thomas ED (1977) Treatment of aplastic anemia by marrow transplantation from HLA identical siblings. Prognostic factors associated with graft versus host disease and survival. J Clin Invest 59:625–632

    CAS  PubMed  Google Scholar 

  • Storb R, Prentice RL, Buckner CD, Clift RA, Appelbaum F, Deeg J, Doney K, Hansen JA, Mason M, Sanders JE, Singer J, Sullivan KM, Witherspoon RP, Thomas ED (1983) Graft-versus-host disease and survival in patients with aplastic anemia treated by marrow grafts from HLA-identical siblings. Beneficial effect of a protective environment. N Engl J Med 308:302–307

    CAS  PubMed  Google Scholar 

  • Storb R, Deeg HJ, Farewell V, Doney K, Appelbaum F, Beatty P, Bensinger W, Buckner CD, Clift R, Hansen J, Hill R, Longton G, Lum L, Martin P, McGuffin R, Sanders J, Singer J, Stewart P, Sullivan K, Witherspoon R, Thomas ED (1986a) Marrow transplantation for severe aplastic anemia: methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention of acute graft-versus-host disease. Blood 68:119–125

    CAS  PubMed  Google Scholar 

  • Storb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P, Bensinger W, Buckner CD, Clift R, Doney K, Farewell V, Hansen J, Hill R, Lum L, Martin P, McGuffin R, Sanders J, Stewart P, Sullivan K, Witherspoon R, Yee G, Thomas ED (1986b) Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 314:729–735

    CAS  PubMed  Google Scholar 

  • Storb R, Raff RF, Appelbaum FR, Deeg HJ, Fitzsimmons W, Graham TC, Pepe M, Pettinger M, Sale G, Van Der Jagt R, Schuening FG (1993) FK506 and methotrexate prevent graft-versus-host disease in dogs given 9.2 Gy total body irradiation and marrow grafts from unrelated DLA-nonidentical donors. Transplantation 56:800–807

    CAS  PubMed  Google Scholar 

  • Storb R, Etzioni R, Anasetti C, Appelbaum FR, Buckner CD, Bensinger W, Bryant E, Clift R, Deeg HJ, Doney K, Flowers M, Hansen J, Martin P, Pepe M, Sale G, Sanders J, Singer J, Sullivan KM, Thomas ED, Witherspoon RP (1994) Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia. Blood 84:941–949

    CAS  PubMed  Google Scholar 

  • Storb R, Yu C, Wagner JL, Deeg HJ, Nash RA, Kiem H-P, Leisenring W, Shulman H (1997) Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood 89:3048–3054

    CAS  PubMed  Google Scholar 

  • Storb R, Yu C, Barnett T, Wagner JL, Deeg HJ, Nash RA, Kiem H-P, McSweeney P, Seidel K, Georges G, Zaucha JM (1999a) Stable mixed hematopoietic chimerism in dog leukocyte antigen-identical littermate dogs given lymph node irradiation before and pharmacologic immunosuppression after marrow transplantation. Blood 94:1131–1136

    CAS  PubMed  Google Scholar 

  • Storb R, Yu C, Zaucha JM, Deeg HJ, Georges G, Kiem H-P, Nash RA, McSweeney PA, Wagner JL (1999b) Stable mixed hematopoietic chimerism in dogs given donor antigen, CTLA4Ig, and 100 cGy total body irradiation before and pharmacologic immunosuppression after marrow transplant. Blood 94:2523–2529

    CAS  PubMed  Google Scholar 

  • Storb R, Blume KG, O’Donnell MR, Chauncey T, Forman SJ, Deeg HJ, Hu WW, Appelbaum FR, Doney K, Flowers MED, Sanders J, Leisenring W (2001) Cyclophosphamide and antithymocyte globulin to condition patients with aplastic anemia for allogeneic marrow transplantations: the experience in four centers. Biol Blood Marrow Transplant 7:39–44

    Article  CAS  PubMed  Google Scholar 

  • Sykes M, Preffer F, McAfee S, Saidman SL, Weymouth D, Andrews DM, Colby C, Sackstein R, Sachs DH, Spitzer TR (1999) Mixed lymphohaemopoietic chimerism and graft-versus-lymphoma effects after non-myeloablative therapy and HLA-mismatched bone-marrow transplantation. Lancet 353:1755–1759

    Article  CAS  PubMed  Google Scholar 

  • Thomas ED, Storb R, Clift RA, Fefer A, Johnson FL, Neiman PE, Lerner KG, Glucksberg H, Buckner CD (1975) Bone-marrow transplantation. N Engl J Med 292:832–843, 895–902

    CAS  PubMed  Google Scholar 

  • Thomas ED, Buckner CD, Banaji M, Clift RA, Fefer A, Flournoy N, Goodell BW, Hickman RO, Lerner KG, Neiman PE, Sale GE, Sanders JE, Singer J, Stevens M, Storb R, Weiden PL (1977) One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 49:511–533

    CAS  PubMed  Google Scholar 

  • Thomas ED, Buckner CD, Clift RA, Fefer A, Johnson FL, Neiman PE, Sale GE, Sanders JE, Singer JW, Shulman H, Storb R, Weiden PL (1979a) Marrow transplantation for acute nonlymphoblastic leukemia in first remission. N Engl J Med 301:597–599

    CAS  PubMed  Google Scholar 

  • Thomas ED, Sanders JE, Flournoy N, Johnson FL, Buckner CD, Clift RA, Fefer A, Goodell BW, Storb R, Weiden PL (1979b) Marrow transplantation for patients with acute lymphoblastic leukemia in remission. Blood 54:468–476

    CAS  PubMed  Google Scholar 

  • Thomas ED, Clift RA, Hersman J, Sanders JE, Stewart P, Buckner CD, Fefer A, McGuffin R, Smith JW, Storb R (1982) Marrow transplantation for acute nonlymphoblastic leukemia in first remission using fractionated or single-dose irradiation. Int J Radiat Oncol Biol Phys 8:817–821

    CAS  PubMed  Google Scholar 

  • Thomas ED, Clift RA, Fefer A, Appelbaum FR, Beatty P, Bensinger WI, Buckner CD, Cheever MA, Deeg HJ, Doney K, Flournoy N, Greenberg P, Hansen JA, Martin P, McGuffin R, Ramberg R, Sanders JE, Singer J, Stewart P, Storb R, Sullivan K, Weiden PL, Witherspoon R (1986) Marrow transplantation for the treatment of chronic myelogenous leukemia. Ann Intern Med 104:155–163

    CAS  PubMed  Google Scholar 

  • Uphoff DE (1958) Alteration of homograft reaction by A-methopterin in lethally irradiated mice treated with homologous marrow. Proc Soc Exp Biol Med 99:651–653

    CAS  PubMed  Google Scholar 

  • van Bekkum DW, de Vries MJ (1967) Radiation chimaeras. Logos Press, London

  • Vigorito AC, Azevedo WM, Marques JF, Azevedo AM, Eid, KA, Aranha FJ, Lorand-Metze I, Oliveira GB, Correa ME, Reis AR, Miranda EC, de Souza CA (1998) A randomised, prospective comparison of allogeneic bone marrow and peripheral blood progenitor cell transplantation in the treatment of haematological malignancies. Bone Marrow Transplant 22:1145–1151

    Article  CAS  PubMed  Google Scholar 

  • Vos O, Davids JAG, Weyzen WWH, van Bekkum DW (1956) Evidence for cellular hypothesis in radiation protection by bone marrow cells. Acta Physiol Pharmacol Neerland 4:482–486

    CAS  Google Scholar 

  • Wagner JE, Barker JN, Defor TE, Baker KS, Blazar BR, Eide C, Goldman A, Kersey J, Krivit W, MacMillan ML, Orchard PJ, Peters C, Weisdorf DJ, Ramsay NK, Davies SM (2002) Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood 100:1611–1618

    CAS  PubMed  Google Scholar 

  • Warren EH, Greenberg PD, Riddell SR (1998) Cytotoxic T-lymphocyte-defined human minor histocompatibility antigens with a restricted tissue distribution. Blood 91:2197–2207

    CAS  PubMed  Google Scholar 

  • Weiden PL, Flournoy N, Thomas ED, Prentice R, Fefer A, Buckner CD, Storb R (1979) Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med 300:1068–1073

    CAS  PubMed  Google Scholar 

  • Weiden PL, Sullivan KM, Flournoy N, Storb R, Thomas ED, and the Seattle Marrow Transplant Team (1981) Antileukemic effect of chronic graft-versus-host disease. Contribution to improved survival after allogeneic marrow transplantation. N Engl J Med 304:1529–1533

    CAS  PubMed  Google Scholar 

  • Weissinger F, Sandmaier BM, Maloney DG, Bensinger WI, Gooley T, Storb R (2001) Decreased transfusion requirements for patients receiving nonmyeloablative compared with conventional peripheral blood stem cell transplants from HLA-identical siblings. Blood 98:3584–3588

    Article  CAS  PubMed  Google Scholar 

  • Woolfrey AE, Nash RA, Sanders JE, Ochs HD, Thomson B, Storb R (2000) A nonmyeloablative regimen for induction of multi-lineage hematopoietic mixed donor-host chimerism in nonmalignant disorders. Blood 98 (part 1):784a, #3390 (abstract)

    Google Scholar 

  • Woolfrey A, Pulsipher MA, Storb R (2001) Nonmyeloablative hematopoietic cell transplant for treatment of immune deficiency. Curr Opin Pediatr 13:539–545

    Article  CAS  PubMed  Google Scholar 

  • Yu C, Seidel K, Nash RA, Deeg HJ, Sandmaier BM, Barsoukov A, Santos E, Storb R (1998) Synergism between mycophenolate mofetil and cyclosporine in preventing graft-versus-host disease among lethally irradiated dogs given DLA-nonidentical unrelated marrow grafts. Blood 91:2581–2587

    CAS  PubMed  Google Scholar 

  • Zaucha JM, Yu C, Zellmer E, Takatu A, Junghanss C, Little M-T, Storb R (2001) Effects of extending the duration of postgrafting immunosuppression and substituting granulocyte-colony-stimulating factor-mobilized peripheral blood mononuclear cells for marrow in allogeneic engraftment in a nonmyeloablative canine transplantation model. Biol Blood Marrow Transplant 7:513–516

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements. This work was supported in part by grants CA78902, CA18029, CA15704, and HL36444 from the NIH, Bethesda, Maryland.

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Diaconescu, R., Storb, R. Allogeneic hematopoietic cell transplantation: from experimental biology to clinical care. J Cancer Res Clin Oncol 131, 1–13 (2005). https://doi.org/10.1007/s00432-004-0611-6

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