Autologous and allogeneic hematopoietic cell transplantations (HCT) after high-dose conditioning are curative for many patients with hematologic malignancies. The major limitation of autologous HCT is disease recurrence, while the problem with allogeneic HCT is the restriction to relatively young and otherwise medically fit patients because of complications from high-dose therapy coupled with those from graft-versus-host disease (GVHD). The well-described benefits of graft-versus-tumor (GVT) effects have stimulated the development of conditioning regimens with attenuated doses of chemoradiotherapy that may provide both a degree of cytoreduction before allografting (reduced intensity) and facilitate allogeneic cell engraftment through immuno- suppression (nonmyeloablative). Both reduced-intensity and nonmyeloablative approaches seek to exploit GVT activity of donor cells to eradicate cancer. Because of intrinsic or acquired insensitivity of some malignancies to standard dose chemotherapy and the limitations of GVT effects in eradicating large tumor burdens, high-dose autologous HCT has been used before reduced-intensity and nonmyeloablative allogeneic HCT. This approach appears to improve response rates for malignancies such as multiple myeloma and lymphoma, while avoiding morbidity and mortality of high-dose allogeneic HCT. This review details the rationale, benefits and limitations of this approach.

1.
Thomas ED, Storb R, Clift RA, Fefer A, Johnson FL, Neiman PE, Lerner KG, Glucksberg H, Buckner CD: Bone-marrow transplantation. N Engl J Med 1975;292:832–843, 895–902.
2.
Schmitz N, Pfistner B, Sextro M, Sieber M, Carella AM, Haenel M, Boissevain F, Zschaber R, Muller P, Kirchner H, Lohri A, Decker S, Koch B, Hasenclever D, Goldstone AH, Diehl V, German Hodgkin’s Lymphoma Study Group, Lymphoma Working Party of the European Group for Blood and Marrow Transplantation: Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin’s disease: A randomised trial. Lancet 2002;359:2065–2071.
3.
Slovak ML, Kopecky KJ, Cassileth PA, Harrington DH, Theil KS, Mohamed A, Paietta E, Willman CL, Head DR, Rowe JM, Forman SJ, Appelbaum FR: Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group study. Blood 2000;96:4075–4083.
4.
Weiden PL, Flournoy N, Thomas ED, Prentice R, Fefer A, Buckner CD, Storb R: Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med 1979;300:1068–1073.
5.
Weiden PL, Sullivan KM, Flournoy N, Storb R, Thomas ED, and 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;304:1529–1533.
6.
Baron F, Maris MB, Sandmaier BM, Storer BE, Sorror M, Diaconescu R, Woolfrey AE, Chauncey TR, Flowers MED, Mielcarek M, Maloney DG, Storb R: Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol, in press.
7.
Kröger N, Perez-Simon JA, Myint H, Klingemann H, Shimoni A, Nagler A, Martino R, Alegre A, Tomas JF, Schwerdtfeger R, Kiehl M, Fauser A, Sayer HG, Leon A, Beyer J, Zabelina T, Ayuk F, San Miguel JF, Brand R, Zander AR: Relapse to prior autograft and chronic graft-versus-host disease are the strongest prognostic factors for outcome of melphalan/fludarabine-based dose-reduced allogeneic stem cell transplantation in patients with multiple myeloma. Biol Blood Marrow Transplant 2004;10:698–708.
8.
Attal M, Harousseau J-L, Facon T, Guilhot F, Doyen C, Fuzibet J-G, Monconduit M, Hullen C, Caillot D, Bouabdallah R, Voillat L, Sotto J-J, Grosbois B, Bataille R: Double autologous transplantation improves survival of multiple myeloma patients: final analysis of a prospective randomized study of the ‘Intergroupe Francophone du Myélome’ (IFM 94) (abstract No 7). Blood 2002;100(pt 1):5a.
9.
Attal M, Payen C, Facon T, Michaux JL, Guilhot F, Moconduit M, Fuzibet JG, Caillot D, Dorvaux V, Harousseau JL, Cahn JY, Grobois B, Stoppa AM, Ifrah N, Sotto JJ, Pignon B, Bataille R: Single versus double transplant in myeloma: a randomized trial of the ‘Intergroupe Français du Myélome’ (IFM) (abstract No 1859). Blood 1997;90 (suppl 1):418a.
10.
Hansen JA, Gooley TA, Martin PJ, Appelbaum F, Chauncey TR, Clift RA, Petersdorf EW, Radich J, Sanders JE, Storb RF, Sullivan KM, Anasetti C: Bone marrow transplants from unrelated donors for patients with chronic myeloid leukemia. N Engl J Med 1998;338:962–968.
11.
Sorror ML, Maris MB, Storer B, Sandmaier BM, Diaconescu R, Flowers C, Maloney DG, Storb R: Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of pretransplant comorbidities. Blood 2004;104:961–968.
12.
Diaconescu R, Flowers CR, Storer B, Sorror ML, Maris MB, Maloney DG, Sandmaier BM, Storb R: Morbidity and mortality with nonmyeloablative compared to myeloablative conditioning before hematopoietic cell transplantation from HLA matched related donors. Blood 2004;104:1550–1558.
13.
Ferrara JL: Pathogenesis of acute graft-versus-host disease: Cytokines and cellular effectors (review). J Hematother Stem Cell Res 2000;9:299–306.
14.
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: 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 2000;6:309–320.
15.
de Lima M, Couriel D, Shahjahan M, Madden T, Gajewski J, Giralt S, Russell J, Champlin RE, Andersson BS: Allogeneic transplantation for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) using a low-toxicity combination of intravenous (IV) busulfan (Bu) and fludarabine (Flu) ± ATG (abstract No 3366). Blood 2002;100 (pt 1):853a.
16.
Giralt S, Aleman A, Anagnostopoulos A, Weber D, Khouri I, Anderlini P, Molldrem J, Ueno NT, Donato M, Korbling M, Gajewski J, Alexanian R, Champlin R: Fludarabine/melphalan conditioning for allogeneic transplantation in patients with multiple myeloma. Bone Marrow Transplant 2002;30:367–373.
17.
Giralt S, Thall PF, Khouri I, Wang X, Braunschweig I, Ippolitti C, Claxton D, Donato M, Bruton J, Cohen A, Davis M, Andersson BS, Anderlini P, Gajewski J, Kornblau S, Andreeff M, Przpiorka D, Ueno NT, Molldrem J, Champlin R: Melphalan and purine analog-containing preparative regimens: reduced-intensity conditioning for patients with hematologic malignancies undergoing allogeneic progenitor cell transplantation. Blood 2001;97:631–637.
18.
Peggs KS, Mahendra P, Milligan DW, Chopra R, Chakraverty RK, Kottaridis PD, Chakrabarti S, Mills AK, Parker A, Hunter AE, Hale G, Waldmann H, Pettengell R, Marsh JCW, Schey S, Williams CD, Yong K, Linch DC, Goldstone AH, Mackinnon S: Non-myeloablative transplantation using matched unrelated donors – in vivo Campath-1H limits graft versus host disease (abstract No 3634). Blood 2000;96(pt 1):841a.
19.
Kottaridis PD, Milligan DW, Chopra R, Chakraverty RK, Chakrabarti S, Robinson S, Peggs K, Verfueth S, Pettengell R, Marsh JCW, Schey S, Mahendra P, Morgan GJ, Hale G, Waldmann H, Ruiz de Elvira MC, Williams CD, Devereux S, Linch DC, Goldstone AH, Mackinnon S: In vivo CAMPATH-1H prevents graft-versus-host disease following nonmyeloablative stem cell transplantation. Blood 2000;96:2419–2425.
20.
Girgis M, Hallemeier C, Blum W, Brown R, Lin H-S, Khoury H, Goodenough LT, Vij R, Devine S, Wehde M, Postma S, Oza A, DiPersio J, Adkins D: Chimerism and clinical outcomes of 110 unrelated donor bone marrow transplants who underwent conditioning with low-dose, single-exposure total body irradiation and cyclophosphamide. Blood 2005;105:3035–3041.
21.
Storb R, Yu C, Wagner JL, Deeg HJ, Nash RA, Kiem H-P, Leisenring W, Shulman H: Stable mixed hematopoietic chimerism in DLA-identical littermate dogs given sublethal total body irradiation before and pharmacological immunosuppression after marrow transplantation. Blood 1997;89:3048–3054.
22.
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: Hematopoietic cell transplantation in older patients with hematologic malignancies: Replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood 2001;97:3390–3400.
23.
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: HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood 2003;102:2021–2030.
24.
Childs RW, Bradstock KF, Gottlieb D, Kefford R, Barrett J: Non-myeloablative allogeneic stem cell transplantation as immunotherapy for metastatic melanoma: results of a pilot study (abstract No 5277). Blood 2000;96(pt 2):353b.
25.
Khouri IF, Lee MS, Saliba RM, Andersson B, Anderlini P, Couriel D, Hosing C, Giralt S, Korbling M, McMannis J, Keating MJ, Champlin RE: Nonablative allogeneic stem cell transplantation for chronic lymphocytic leukemia: impact of rituximab on immunomodulation and survival. Exp Hematol 2004;32:28–35.
26.
Carella AM, Cavaliere M, Corsetti MT, Lerma E: Allografting with immunosuppressive conditioning of low-dose fludarabine-cyclophosphamide after autografting (abstract No 2376). Blood 2000;96(pt 1):553a.
27.
Khouri IF, Saliba RM, Giralt SA, Lee M-S, Okoroji G-J, Hagemeister FB, Korbling M, Younes A, Ippoliti C, Gajewski JL, McLaughlin P, Anderlini P, Donato ML, Cabanillas FF, Champlin RE: Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: Low incidence of toxicity, acute graft-versus-host disease, and treatment-related mortality. Blood 2001;98:3595–3599.
28.
Sandmaier BM, Hegenbart U, Shizuru J, Radich J, Maloney DG, Agura E, Bruno B, Chauncey T, Blume K, Niederwieser D, Storb R: Nonmyeloablative hematopoietic stem cell transplantation (HSCT) from HLA-identical siblings for treatment of chronic myelogenous leukemia (CML): induction of molecular remissions (abstract No 5259). Blood 2001;98(pt 2):371b.
29.
Or R, Shapira MY, Resnick I, Amar A, Ackerstein A, Samuel S, Aker M, Naparstek E, Nagler A, Slavin S: Nonmyeloablative allogeneic stem cell transplantation for the treatment of chronic myeloid leukemia in first chronic phase (comment in: Blood 2003;101:5084; author reply 5084–5085; PMID: 12788790). Blood 2003;101:441–445.
30.
Robinson SP, Goldstone AH, Mackinnon S, Carella A, Russell N, de Elvira CR, Taghipour G, Schmitz N: Chemoresistant or aggressive lymphoma predicts for a poor outcome following reduced-intensity allogeneic progenitor cell transplantation: an analysis from the Lymphoma Working Party of the European Group for Blood and Bone Marrow Transplantation. Blood 2002;100:4310–4316.
31.
Faulkner RD, Craddock C, Byrne JL, Mahendra P, Haynes AP, Prentice HG, Potter M, Pagliuca A, Ho A, Devereux S, McQuaker G, Mufti G, Yin JL, Russell NH: BEAM-alemtuzumab reduced-intensity allogeneic stem cell transplantation for lymphoproliferative diseases: GVHD, toxicity, and survival in 65 patients. Blood 2004;103:428–434.
32.
Dreger P, Brand R, Hansz J, Milligan D, Corradini P, Finke J, Deliliers GL, Martino R, Russell N, van Biezen A, Michallet M, Niederwieser D, Chronic Leukemia Working Party of the EBMT: Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning (review). Leukemia 2003;17:841–848.
33.
Burroughs LM, Maris MB, Sandmaier BM, Leisenring W, Jain Stuart M, Niederwieser D, McSweeney PA, Chauncey T, Maziarz R, Agura E, Little M-T, Blume KG, Storb R, Maloney DG: HLA-matched related (MRD) or unrelated donor (URD) non-myeloablative conditioning and hematopoietic cell transplant (HCT) for patients with advanced Hodgkin disease (HD) (abstract No 197). Biol Blood Marrow Transplant 2004;10(suppl 1):73–74.
34.
Maris MB, Sandmaier BM, Storer BE, Chauncey T, Stuart MJ, Maziarz RT, Agura E, Langston AA, Pulsipher M, Storb R, Maloney DG: Allogeneic hematopoietic cell transplantation after fludarabine and 2 Gy total body irradiation for relapsed and refractory mantle cell lymphoma. Blood 2004;104:3535–3542.
35.
Sorror ML, Maris MB, Sandmaier BM, Jain-Stuart M, Storer B, Hegenbart U, McSweeney P, Chauncey T, Bruno B, Wade J, Agura E, Pulsipher M, Leis J, Little M-T, Niederwieser D, Blume K, Storb R, Maloney DG: Treatment of patients (PTS) with chemotherapy-refractory chronic lymphocytic leukemia (CLL) with nonmyeloablative (NM) conditioning and hematopoietic cell transplantation (HCT) from HLA-matched related (MRD) or unrelated donors (URD) (abstract). Biol Blood Marrow Transplant 2004;10(suppl 1):26–27.
36.
Baron F, Maris MB, Sandmaier BM, Storer BE, Sorror M, Diaconescu R, Woolfrey AE, Chauncey T, Flowers MED, Mielcarek M, Maloney DG, Storb R: Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning (abstract No 184). Blood 2004;104(pt 1):56a–57a.
37.
Scott BL, Maris M, Sandmaier B, Storer B, Chauncey T, Maloney DG, Sorror M, Storb R, Deeg HJ: Myeloablative versus nonmyeloablative hemopoietic cell transplantation (HCT) for patients with myelodysplasia (MDS) or AML with multilineage dysplasia following MDS (tAML) (abstract). Blood (in press).
38.
Diaconescu R, Flowers C, Storer B, Sorror ML, Maris M, Maloney DG, Chauncey T, Sandmaier BM, Storb RF: Morbidity and mortality with nonmyeloablative compared to myeloablative conditioning before hematopoietic cell transplantation from HLA matched related donors (abstract No 261). Blood 2003;102(pt 1): 77a–78a.
39.
Kroger N, Schwerdtfeger R, Kiehl M, Sayer HG, Renges H, Zabelina T, Fehse B, Togel F, Wittkowsky G, Kuse R, Zander AR: Autologous stem cell transplantation followed by a dose-reduced allograft induces high complete remission rate in multiple myeloma. Blood 2002;100:755–760.
40.
Bearman SI, Appelbaum FR, Buckner CD, Petersen FB, Fisher LD, Clift RA, Thomas ED: Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 1988;6:1562–1568.
41.
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: Allografting with nonmyeloablative conditioning following cytoreductive autografts for the treatment of patients with multiple myeloma. Blood 2003;102:3447–3454.
42.
Georges GE, Maris MB, Sandmaier BM, Shizuru J, Niederwieser DW, Agura E, Bruno B, McSweeney PA, Storb RF, Maloney DG: Nonmyeloablative unrelated donor hematopoietic cell transplantation (HCT) for patients (pts) with poor risk, relapsed or refractory multiple myeloma (abstract No 2756). Blood 2004;104(pt 1):754a.
43.
Carella AM, Cavaliere M, Lerma E, Ferrara R, Tedeschi L, Romanelli A, Vinci M, Pinotti G, Lambelet P, Loni C, Verdiani S, De Stefano F, Valbonesi M, Corsetti MT: 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;18:3918–3924.
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