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84 Haematologica (ed. esp.), volumen 85, supl. 2, octubre 2000 11. Slavin S, Naparstek E, Nagler A, Ackerstein A, Samuel S, Kapelushnik J et al. Allogeneic cell therapy with donor peripheral blood cells and recombinant human interleukin-2 to treat leukemia relapse after allogeneic bone marrow transplantation. Blood 1996; 87: 2195-2204. 12. Giralt SA, Champlin RE. Leukemia Relapse After Allogeneic Bone Marrow Transplantation. Blood 1994; 84: 3603-3612. 13. Mackinnon S, Papadopoulos EB, Caralasi MH, Reich L, Collins RH, Boulad F et al. 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 1995; 86: 1261-1268. 14. Pelot MR, Pearson DA, Swenson K, Zhao G, Sachs J, Yang YG et al. Lymphohematopoietic graft-versus-host reactions can be induced without graft-versus-host disease in murine mixed chimeras stablished with a cyclophosphamide based non-myeloabplative conditioning regimen. Biology of Blood and Marrow Transplantation 1999; 5: 133-140. 15. Ildtad ST, Sachs DH. Reconstitution wtih syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts and xenografts. Nature 1984; 307: 168-170. 16. Slavin S, Fuks Z, Kaploin H, Strober S. Transplantation of allogeneic bone marrow without graft vs host disease using total lymphoid irradiation. J Exp Med 1978; 147: 963-972. 17. Tomita Y, Sachs DH, Kahn A, Sykes M. Additional m-Ab injections can replace thymic irratiation to allow indiction of mixed chimerism and tolerance in mice receiving bone marrow transplantation after conditioning with anti-T cell m-Abs and 3 Gy whole body irradiation. Transplantation 1996; 61: 469-475. 18. Sykes M, Szot GL, Swenson KA, Pearson DA. Induction of high levels of allogeneic hematopoietic reconstitution and donor specific tolerance without myelosuppressive conditioning. Nat Med 1997; 3: 783-787. 19. Sykes M, Preffer F, McAfee S, Saidman SL, Weymouth D, Andrews DM et al. Mixed lymphohaemopoietic chimaerism and graft versus lymphoma effects after non-myeloabplative therapy and HLA mismatched bone marrow transplantation. Lancet 1999; 353: 1755-1759. 20. Díez-Martín JL, Forés R, Jiménez A, Martino R, Pérez de Oteyza J, Urbano-Ispizua A et al. Utilización de los linfocitos del donante como tratamiento de la recaída tras un alotrasplante en las leucemias agudas (LA). Registro del Grupo Español de Trasplante Hemopoyético. Methods and Findings in Experimental and Clinical Pharmacology 2000; 22 (Supl. 1): 23-31. 21. Collins RH, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 1997; 15: 433-444. 22. Guinan E. Costimulatory blockade as a mechanism of inducing tolerance in the allograft setting. En: Schechter GP, Hoffman R, Schrier SL, Bajus JL, eds. Hematology 1999. American Society of Hematology Education Program Book. Washington, 1999; 383-388. 23. Storb R, Yu C, Zaucha M, Deeg J, Goeorges G, Kiem HP et al. Stable mixed hematopoietic chimerism in dogs given donor antigen, CTLA4-Ig, and 100 cGy total body irradiation before and farmacologic immunosuppresion after marow transplant. Blood 1999; 94: 2523-2529. 24. Li H, Kaufman CL, Boggs SS, Johnson PC, Patrene KD, Singer GG, ILDtad ST. Mixed Allogeneic chimerism induced by a sublethal approach prevents autoimmune diabetes and reverses insulinitis in nonobese diabetic mice (NOD). J Immunol 1996; 156: 380-387. 25. Kawai T, Cosimi AB, Calvin RB, Powelson J, Eason J, Kozlowski T et al. Mixed allogeneic chimerism and renal allograft tolerance in cynomolgus monkeys. Transplantation 1997; 59: 256-263. 26. Santos GW, Sensenbrenner LL, Burke PJ, Mullins GM, Blas WB, Tutschka PJ et al. The use of cyclophosphammide for clinical marrow transplantation. Transplantation Proceedings 1972; 4: 559-565. 27. Huss R, Deeg JH, Gooley T, Bryant E, Leisenring W, Clift R et al. Effect of mixed chimerism on graft-versus-host disease, disease recurrence and survival after HLA-identical marrow transplantation for aplastic anemia or chronic myelogenous leukemia. Bone Marrow Transplantation 1996; 18: 767-773. 28. Petz LD, Yam P, Wallace RB, Stock AD, deLange G, Knowlton RG et al. Mixed hematopoietic chimerism following bone marrow transplantation for hematologic malignancies. Blood 1987; 70: 1331-1338. 29. Marmont AM, Horowitz MM, Gale RP, Sabozinski K, Ash RC, Van Bekkum W et al. T-cell depletion of HLA identical transplants in leukemia. Blood 1991; 78: 2120-2128. 30. Roy DC, Tantravahi R, Murray C, Dear K, Gorgone B, Anderson KC. Natural history of mixed chimerism after bone marrow transplantation with CD6-depleted allogeneic marrow: a stable equilibrium. Blood 1990; 75: 296-303. 31. Andreani M, Manna M, Lucarelli G, Tonucci P, Agostinelli F, Ripalti M et al. Persistence of mixed chimerism in patients transplanted for the treatment of Thalassemia. Blood 1996; 87: 3494-3501. 32. Starzl TE, Demetris AJ, Trucco M, Zeevi A, Ramos H, Terasaki P et al. Chimerism and donor specific non-reactivity 27 to 29 years after kidney allotransplantation. Transplantation 1993; 55: 1272-1277. 33. Barrett AJ, Mavroudis D, Tisdale J, Molldrem J, Clave E, Dunbar C et al. T-cell depleted bone marrow transplantation and delayed T-cell add-back to control acute GVHD and conserve a graft-versus-eukemia effect. Bone Marrow Transplantation 1998; 21: 543-551. 34. Naparstek E, Or R, Nagler A, Cividalli G, Engelhard D, Aker M et al. 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 relapses. Br J Haematol 1995; 89: 506-515. 35. McSweeney P, Niederwieser D, Shizuru J, Molina A, Wagner J, Minor S et al. Outpatient allografting with minimally myelosuppressive, immunosuppressive conditioning of low dose TBI and post-grafting cyclosporine and mycophenolate mofetyl. Blood 1999; 94 (Supl. 1): 393a. 36. Spitzer T, MacAfee S, Sackstein R, Colby C, Toh HC, Multani P et al. Intentional induction of mixed chimerism and achievement of antitumor responses after non-myeloablative conditioning therapy and HLA-matched donor bone marrow transplantation for refractory hematologic malignancies. Biology of Blood and Marrow Transplantation 2000; 6: 309-320. 37. Carella AM, Giralt S, Slavin S. Low intensity regimens with allogeneic hematopoietic stem cell transplantation as treatment of hematologic neoplasia. Haematologica 2000; 85: 304-313. 38. 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 non ablative chemotherapy and allogeneic blood progenitor cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 1998; 16: 2817-2824. 39. Childs R, Contentin N, Clave E, Bahceci E, Hansel N, Boland C et al. Reduced toxicity and transplant related mortality following non-myeloablative allogenei peripheral blood stem cell transplantation for malignant diseases. Blood 1999; 94 (Supl. 1): 393a. 40. Slavin S. Comunicación Oral. 26 annual meeting of the EBMT. Innsbruck March 2000. 41. Michallet M, Bilger K, Garban F, Attal M, Huyn A, Blaise D et al. Allogeneic hematopoietic stem cell transplantats after immune-ablative preparative regimen. A report of 92 patients. Blood 1999; 94 (Supl. 1): 348a. 42. Molina A, McSweeney P, Malloney DG, Sandmayer B, Bensinger W, Nash R et al. Non-myeloablative peripheral blood stem cell allografts following cytoreductive autotransplants for treatment of multiple myeloma. Blood 1999; 94 (Supl. 1): 347a. 43. Hernández-Navarro F, de la Serna J, Díez-Martín JL, Hernández D, Llamas P, Lahuerta JJ et al. Trasplante alogénico de progenitores hematopoyéticos tras acondicionamiento no mieloablativo en pacientes con neoplasias hematológicas avanzadas. Resultados preliminares de un estudio cooperativo. Methods and Findings in Experimental and Clinical Pharmacology 2000; 22 (Supl. 1): 83-86. 44. Garban F, Attal M, Rossi JF, Sotto J. High efficiency of non-myeloablative allogeneic stem cell transplantation in poor prognosis myeloma patients. Blood 1999; 94 (Supl. 1): 347a 45. Mitchell E, Horwiz A, Barrett J, Childs R, Miller JA, Leitman SF et al. Non-myeloablative T-cell depleted allogeneic peripheral blood stem cell transplantation for patients with chronic granulomatous disease. Blood 1999; 94 (Supl. 1): 710a. 46. Craddock C, Hughes T, Johnston R, Kreiter S, Bardy P, Apperley J et al. Engraftment of T-depleted allogeneic peripheral blood stem cells using a non-myeloablative conditioning regimen. Blood 1999; 94 (Supl. 1): 394a. 47. Russell NH, Cull G, Byrne JL, Stainer C, Rebello P, Hale G et al. Evaluation of non-myeloablative conditioning combining BEAM with in vivo pretransplant Campath-1G for allogeneic transplantation in patients with lymphoma. Blood 1999; 94 (Supl. 1): 394a. 48. Giralt S, Cohen A, Claxton D, Ueno N, Gajewski J, Khouri I et al. Fludarabine/Melphalan as a less intense preparative regimen for unrelated donor transplants in patients with hematologic malignancies. Blood 1998; 92 (Supl. 1): 289a. 49. Shimoni A, Anderlini P, Andersson B, Andreeff M, Brownschweig I, Claxton D et al. Allogeneic transplantation for leukemia in patients bolder than 60 years. Age should not exclude treatment with non-myeloablative regimens. Blood 1999; 94 (Supl. 1): 710a. 50. Giralt S, Weber D, Aleman A, Anagnastopoulos A, Anderlini P, Brownschweig I et al. Non-myeloablative conditioning with Fludarabine/Melphalan for patients with multiple myeloma. Blood 1999; 94 (Supl. 1): 347a. 51. Molina A, McSweeney P, Maloney DG, Sandmayer B, Wagner JL, Nash R et al. Degree of early donor T-cell chimerism predicts GVHD and graft rejection in patients with non-myeloablative hematopoietic stem cell allografts. Blood 1999; 94 (Supl. 1): 394a. 52. Childs R, Contentin N, Clave E, Bahceci E, Chernoff A, Linehan M et al. Sustained regrassion of metastatic renal cell carcinoma following non-myeloablative allogeneic peripheral blood stem cell transplantation: a new application of allogeneic immunotherapy. Blood 1999; 94 (Supl. 1): 710a. 53. Barnes D, Loutit J. Treatment of murine leukaemia with X-rays and homologous bone marrow. British J Haematol 1957; 3: 241-252. 54. Weiss L, Lubin I, Factorowich Y et al. Effective graft versus leukemnia effects independently of graft versus host disease following T-cell depleted allogeneic bone marrow transplantation in a murine model of B-cell leukemia/lymphoma (BCL1). Role of cell therapy and rIL-2. J Immunol 1994; 153: 2562-2567. 55. Kolb HJ, Gunther W, Schumm M, Holler E, Wilmanns W, Thierfelder S. Adoptive immunotherapy in canine chimeras. Transplantation 1997; 63: 430-436. 56. Johnson B, Truitt R. Delayed infusion of immunocompetent donor cells after bone marrow transplantation breaks graft-host tolerance and allows for persistent antileukemic reactivity without severe graft-versus-host disease. Blood 1995; 85: 3302-3308. 57. Giralt S, Hester J, Huh Y, Hisch-Ginsberg CH, Rondon G, Seong D et al. CD8-depleted donor lymphocyte infussion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation. Blood 1995; 86: 4337-4343.

XLII Reunión Nacional de la AEHH y XVI Congreso de la SETH. Simposios 85 58. Papadopoulos EB, Ladanyi M, Emanuel D, Mackinnon S, Boulad F, Carabasi MH et al. Infussion of donor leukocytes as treatment of Epstein Barr Virus associated lymphoproliferative disorders complicating allogeneic marrow transplantation. N Eng J Med 1994; 330: 1185-1191. 59. Porter DL, Connors JM, Van Deerlin VMD, Duffy KM, McGarigle C, Saidman SL, Leonard D, Antin JH. Graft versus Host induction with donor leukocyte infusions as primary therapy for patients with malignancies. J Clin Oncol 1999; 17: 1234-1243. 60. Higano CS, Brixey M, Bryant EM, Durnam D, Doney K, Sullivan K et al. Durable complete remission of acute nonlymphocytic leukemia associated with discontinuation of immunosupression following relapse after allogeneic bone marrow transplantation. Transplantation 1990; 50: 175-177. 61. Sullivan KM, Storb R, Buckner CD, Fefer A, Fisher LL, Weiden P. Graft-versus-host disease as adoptive immunotherapy in patients with advanced hematologic neoplasms. N Eng J Med 1989; 320: 828-834. 62. Mutis T, Verdijk R, Schrama E, Esendam B, Brand A, Goulmy E. Feasibility of immunotherapy of relapsed leukemia with ex vivo generated cytotoxyc T lymphocytes specefic for hematopoietic system restricted minor histocompatibility antigens. Blood 1999; 93: 2336-2341. 63. Bonini CH, Ferrari G, Verzeletti S, Servida P, Zappone E, Ruggieri L et al. HSV-tK gene transfer into donor lymphocytes for control of allogeneic graft-versus leukemia. Science 1997; 276: 1719-1724. NONMYELOABLATIVE ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION R. STORB 1,2 , P.A. MCSWEENEY 1,2 , B.M. SANDMAIER 1,2 , R.A. NASH 1,2 , G. GEORGES 1,2 , D.G. MALONEY 1,2 , A. MOLINA 1 , M. MARIS 1,2 , A. WOOLFREY 1,2 , TH.CHAUNCEY 1,2,3 , M. ZAUCHA 1 , K.G. BLUME 4 , J. SHIZURU 4 , AND D. NIEDERWIESER 1 Fred Hutchinson Cancer Research Center, 2 University of Washington School of Medicine, 3 Veterans Administration Medical Center, Seattle, WA; 4 Stanford University School of Medicine, Stanford, CA; University of Leipzig, Leipzig, Germany. The finding of Jacobson et al 1 . that mice could be protected from the marrow lethal effects of ionizing total body irradiation (TBI) by shielding their spleens with lead marked the beginning of the modern era of hematopoietic stem cell transplantation (HSCT). The finding led to further animal experiments which demonstrated that the radioprotection was effected by transplantable HSC 2-4 . These experiments resulted in the development of a treatment schema for human patients with marrow-based diseases, such as leukemias 5 . According to this schema, patients would be given high-doses of systemic chemoradiation therapy to destroy their underlying diseases. The therapy’s intensity would be limited only by serious Supported in part by grants HL36444, HL03701, CA18221, CA15704, CA78902, CA49605 and DK42716 from the National Institutes of Health, DHHS, Bethesda, MD, USA. Support was also provided by the Gabriella Rich Leukemia Foundation. R.S. also received support from the Laura Landro Salomon Endowment Fund, and through a prize awarded by the Josef Steiner Krebsstiftung, Bern, Switzerland. toxicities to non-marrow organs, for example, gut, lung, heart, and liver. The role assigned to the HSCT was to afford radio-(chemotherapy)-protection. The treatment schema forms the basis for most current HSCT. Even so, at least two observations have raised questions whether the conventional transplant schema is universally valid. One is that many hematological malignancies cannot be wiped out by high-dose therapy, even though treatment has been intensified to a point where serious organ toxicities are common 5,6 . The other is that many of the observed cures can be ascribed to immunological anti-tumor reactions brought about by the allografts 7-10 . In fact, donor lymphocyte infusions have been used to reinduce remissions in some patients with relapse after conventional HSCT 11,12 . The two observations, the fact that associated toxicities have limited conventional HSCT to younger patients with good organ function, and a better understanding of how to manipulate both host and donor immune functions, have led to a radical rethinking of how allogeneic HSCT might be done in the future. Specifically, instead of trying to eradicate malignant cells through high-dose therapy, the HSCT donor’s immune cells are used for that purpose, invoking an allogeneic graft-versus-tumor effect. This approach allows extending HSCT to also include patients who are too old or medically infirm to qualify for conventional allotransplants. The development of the new nonmyeloablative HSCT approach used in Seattle, Stanford, and Leipzig made use of two experimental facts. These are that both host-versus-graft (HVG) and graft-versus-host (GVH) reactions are mediated by T lymphocytes in the setting of major histocompatibility complex (MHC) identical HSCT. This has opened up the possibility of identifying posttransplant immunosuppression which reduces the risks of both GVHD and HVG reactions, and, thus, eliminates the need for intensive and potentially organ-toxic pretransplant therapy. We investigated this possibility in a preclinical canine model in which nonmyelotoxic posttransplant immunosuppression was substituted for the cytotoxic pretransplant conditioning therapy in a stepwise fashion 13,14 . In the new transplant schema that evolved from these studies, some immunosuppression is delivered before HSCT to reduce host immune reactivity, while a more extended course of immunosuppression is administered after transplant with the dual purpose of altering both donor and host immune responses. After posttransplant immunosuppression has been discontinued, mutual graft-host tolerance develops which may become manifest as stable mixed donor/host hematopoietic chimerism. A well-tolerated and effective transplant regimen which was established in dogs uses a low and nonmyeloablative dose of 200 cGy (given at the low dose rate of 7 cGy/min) TBI before and a combination of the de novo purine synthesis inhibitor mycophenolate

84 <strong>Haematologica</strong> (ed. esp.), volumen 85, supl. 2, octubre 2000<br />

11. Slavin S, Naparstek E, Nagler A, Ackerstein A, Samuel S, Kapelushnik J<br />

et al. Allogeneic cell therapy with donor peripheral blood cells and recombinant<br />

human interleukin-2 to treat leukemia relapse after allogeneic<br />

bone marrow transplantation. Blood 1996; 87: 2195-2204.<br />

12. Giralt SA, Champlin RE. Leukemia Relapse After Allogeneic Bone Marrow<br />

Transplantation. Blood 1994; 84: 3603-3612.<br />

13. Mackinnon S, Papadopoulos EB, Caralasi MH, Reich L, Collins RH,<br />

Boulad F et al. Adoptive immunotherapy evaluating escalating doses<br />

of donor leukocytes for relapse of chronic myeloid leukemia after bone<br />

marrow transplantation: separation of graft-versus-leukemia responses<br />

from graft-versus-host disease. Blood 1995; 86: 1261-1268.<br />

14. Pelot MR, Pearson DA, Swenson K, Zhao G, Sachs J, Yang YG et al.<br />

Lymphohematopoietic graft-versus-host reactions can be induced without<br />

graft-versus-host disease in murine mixed chimeras stablished<br />

with a cyclophosphamide based non-myeloabplative conditioning regimen.<br />

Biology of Blood and Marrow Transplantation 1999; 5: 133-140.<br />

15. Ildtad ST, Sachs DH. Reconstitution wtih syngeneic plus allogeneic or<br />

xenogeneic bone marrow leads to specific acceptance of allografts and<br />

xenografts. Nature 1984; 307: 168-170.<br />

16. Slavin S, Fuks Z, Kaploin H, Strober S. Transplantation of allogeneic<br />

bone marrow without graft vs host disease using total lymphoid irradiation.<br />

J Exp Med 1978; 147: 963-972.<br />

17. Tomita Y, Sachs DH, Kahn A, Sykes M. Additional m-Ab injections can<br />

replace thymic irratiation to allow indiction of mixed chimerism and tolerance<br />

in mice receiving bone marrow transplantation after conditioning<br />

with anti-T cell m-Abs and 3 Gy whole body irradiation. Transplantation<br />

1996; 61: 469-475.<br />

18. Sykes M, Szot GL, Swenson KA, Pearson DA. Induction of high levels<br />

of allogeneic hematopoietic reconstitution and donor specific tolerance<br />

without myelosuppressive conditioning. Nat Med 1997; 3: 783-787.<br />

19. Sykes M, Preffer F, McAfee S, Saidman SL, Weymouth D, Andrews DM<br />

et al. Mixed lymphohaemopoietic chimaerism and graft versus lymphoma<br />

effects after non-myeloabplative therapy and HLA mismatched<br />

bone marrow transplantation. Lancet 1999; 353: 1755-1759.<br />

20. Díez-Martín JL, Forés R, Jiménez A, Martino R, Pérez de Oteyza J, Urbano-Ispizua<br />

A et al. Utilización de los linfocitos del donante como tratamiento<br />

de la recaída tras un alotrasplante en las leucemias agudas<br />

(LA). Registro del Grupo Español de Trasplante Hemopoyético. Methods<br />

and Findings in Experimental and Clinical Pharmacology 2000;<br />

22 (Supl. 1): 23-31.<br />

21. Collins RH, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R<br />

et al. Donor leukocyte infusions in 140 patients with relapsed malignancy<br />

after allogeneic bone marrow transplantation. J Clin Oncol<br />

1997; 15: 433-444.<br />

22. Guinan E. Costimulatory blockade as a mechanism of inducing tolerance<br />

in the allograft setting. En: Schechter GP, Hoffman R, Schrier SL,<br />

Bajus JL, eds. Hematology 1999. American Society of Hematology Education<br />

Program Book. Washington, 1999; 383-388.<br />

23. Storb R, Yu C, Zaucha M, Deeg J, Goeorges G, Kiem HP et al. Stable mixed<br />

hematopoietic chimerism in dogs given donor antigen, CTLA4-Ig,<br />

and 100 cGy total body irradiation before and farmacologic immunosuppresion<br />

after marow transplant. Blood 1999; 94: 2523-2529.<br />

24. Li H, Kaufman CL, Boggs SS, Johnson PC, Patrene KD, Singer GG, ILDtad<br />

ST. Mixed Allogeneic chimerism induced by a sublethal approach<br />

prevents autoimmune diabetes and reverses insulinitis in nonobese diabetic<br />

mice (NOD). J Immunol 1996; 156: 380-387.<br />

25. Kawai T, Cosimi AB, Calvin RB, Powelson J, Eason J, Kozlowski T et al.<br />

Mixed allogeneic chimerism and renal allograft tolerance in cynomolgus<br />

monkeys. Transplantation 1997; 59: 256-263.<br />

26. Santos GW, Sensenbrenner LL, Burke PJ, Mullins GM, Blas WB, Tutschka<br />

PJ et al. The use of cyclophosphammide for clinical marrow transplantation.<br />

Transplantation Proceedings 1972; 4: 559-565.<br />

27. Huss R, Deeg JH, Gooley T, Bryant E, Leisenring W, Clift R et al. Effect<br />

of mixed chimerism on graft-versus-host disease, disease recurrence<br />

and survival after HLA-identical marrow transplantation for aplastic<br />

anemia or chronic myelogenous leukemia. Bone Marrow Transplantation<br />

1996; 18: 767-773.<br />

28. Petz LD, Yam P, Wallace RB, Stock AD, deLange G, Knowlton RG et al.<br />

Mixed hematopoietic chimerism following bone marrow transplantation<br />

for hematologic malignancies. Blood 1987; 70: 1331-1338.<br />

29. Marmont AM, Horowitz MM, Gale RP, Sabozinski K, Ash RC, Van Bekkum<br />

W et al. T-cell depletion of HLA identical transplants in leukemia.<br />

Blood 1991; 78: 2120-2128.<br />

30. Roy DC, Tantravahi R, Murray C, Dear K, Gorgone B, Anderson KC.<br />

Natural history of mixed chimerism after bone marrow transplantation<br />

with CD6-depleted allogeneic marrow: a stable equilibrium. Blood<br />

1990; 75: 296-303.<br />

31. Andreani M, Manna M, Lucarelli G, Tonucci P, Agostinelli F, Ripalti M<br />

et al. Persistence of mixed chimerism in patients transplanted for the<br />

treatment of Thalassemia. Blood 1996; 87: 3494-3501.<br />

32. Starzl TE, Demetris AJ, Trucco M, Zeevi A, Ramos H, Terasaki P et al.<br />

Chimerism and donor specific non-reactivity 27 to 29 years after kidney<br />

allotransplantation. Transplantation 1993; 55: 1272-1277.<br />

33. Barrett AJ, Mavroudis D, Tisdale J, Molldrem J, Clave E, Dunbar C et<br />

al. T-cell depleted bone marrow transplantation and delayed T-cell<br />

add-back to control acute GVHD and conserve a graft-versus-eukemia<br />

effect. Bone Marrow Transplantation 1998; 21: 543-551.<br />

34. Naparstek E, Or R, Nagler A, Cividalli G, Engelhard D, Aker M et al.<br />

T-cell depleted allogeneic bone marrow transplantation for acute leukaemia<br />

using campath-1 antibodies and post-transplant administration<br />

of donor’s peripheral blood lymphocytes for prevention of relapses.<br />

Br J Haematol 1995; 89: 506-515.<br />

35. McSweeney P, Niederwieser D, Shizuru J, Molina A, Wagner J, Minor S<br />

et al. Outpatient allografting with minimally myelosuppressive, immunosuppressive<br />

conditioning of low dose TBI and post-grafting cyclosporine<br />

and mycophenolate mofetyl. Blood 1999; 94 (Supl. 1): 393a.<br />

36. Spitzer T, MacAfee S, Sackstein R, Colby C, Toh HC, Multani P et al. Intentional<br />

induction of mixed chimerism and achievement of antitumor<br />

responses after non-myeloablative conditioning therapy and HLA-matched<br />

donor bone marrow transplantation for refractory hematologic<br />

malignancies. Biology of Blood and Marrow Transplantation 2000; 6:<br />

309-320.<br />

37. Carella AM, Giralt S, Slavin S. Low intensity regimens with allogeneic<br />

hematopoietic stem cell transplantation as treatment of hematologic<br />

neoplasia. <strong>Haematologica</strong> 2000; 85: 304-313.<br />

38. Khouri IF, Keating M, Körbling M, Przepiorka D, Anderlini P, O’Brien S<br />

et al. Transplant-Lite induction of graft versus malignancy using fludarabine<br />

based non ablative chemotherapy and allogeneic blood progenitor<br />

cell transplantation as treatment for lymphoid malignancies.<br />

J Clin Oncol 1998; 16: 2817-2824.<br />

39. Childs R, Contentin N, Clave E, Bahceci E, Hansel N, Boland C et al.<br />

Reduced toxicity and transplant related mortality following non-myeloablative<br />

allogenei peripheral blood stem cell transplantation for malignant<br />

diseases. Blood 1999; 94 (Supl. 1): 393a.<br />

40. Slavin S. Comunicación Oral. 26 annual meeting of the EBMT. Innsbruck<br />

March 2000.<br />

41. Michallet M, Bilger K, Garban F, Attal M, Huyn A, Blaise D et al. Allogeneic<br />

hematopoietic stem cell transplantats after immune-ablative<br />

preparative regimen. A report of 92 patients. Blood 1999; 94 (Supl. 1):<br />

348a.<br />

42. Molina A, McSweeney P, Malloney DG, Sandmayer B, Bensinger W,<br />

Nash R et al. Non-myeloablative peripheral blood stem cell allografts<br />

following cytoreductive autotransplants for treatment of multiple myeloma.<br />

Blood 1999; 94 (Supl. 1): 347a.<br />

43. Hernández-Navarro F, de la Serna J, Díez-Martín JL, Hernández D, Llamas<br />

P, Lahuerta JJ et al. Trasplante alogénico de progenitores hematopoyéticos<br />

tras acondicionamiento no mieloablativo en pacientes con<br />

neoplasias hematológicas avanzadas. Resultados preliminares de un estudio<br />

cooperativo. Methods and Findings in Experimental and Clinical<br />

Pharmacology 2000; 22 (Supl. 1): 83-86.<br />

44. Garban F, Attal M, Rossi JF, Sotto J. High efficiency of non-myeloablative<br />

allogeneic stem cell transplantation in poor prognosis myeloma patients.<br />

Blood 1999; 94 (Supl. 1): 347a<br />

45. Mitchell E, Horwiz A, Barrett J, Childs R, Miller JA, Leitman SF et al.<br />

Non-myeloablative T-cell depleted allogeneic peripheral blood stem cell<br />

transplantation for patients with chronic granulomatous disease. Blood<br />

1999; 94 (Supl. 1): 710a.<br />

46. Craddock C, Hughes T, Johnston R, Kreiter S, Bardy P, Apperley J et al.<br />

Engraftment of T-depleted allogeneic peripheral blood stem cells using<br />

a non-myeloablative conditioning regimen. Blood 1999; 94 (Supl. 1):<br />

394a.<br />

47. Russell NH, Cull G, Byrne JL, Stainer C, Rebello P, Hale G et al. Evaluation<br />

of non-myeloablative conditioning combining BEAM with in vivo<br />

pretransplant Campath-1G for allogeneic transplantation in patients<br />

with lymphoma. Blood 1999; 94 (Supl. 1): 394a.<br />

48. Giralt S, Cohen A, Claxton D, Ueno N, Gajewski J, Khouri I et al. Fludarabine/Melphalan<br />

as a less intense preparative regimen for unrelated<br />

donor transplants in patients with hematologic malignancies. Blood<br />

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