During the last three decades, several myeloablative conditioning regimens have been used for AML allografts. In this review, we systematically examine the data from studies reporting on myeloablative conditioning regimens for AML allografts. High-dose busulfan combined with cyclophosphamide (BuCy) and cyclophosphamide in combination with total body irradiation (CyTBI) are the two most commonly used conditioning regimens for AML allografts. From the available data, there are no significant differences in survival with these two regimens. A small benefit of decreased relapse rate with CyTBI is counterbalanced by a nonsignificant increase in treatment-related mortality. The incidence of veno-occlusive disease is significantly higher in patients treated with BuCy. Therapeutic monitoring of busulfan was not reported in any of the studies comparing the regimens. Either of the regimens can be used for AML allografts, and the choice may ultimately depend on local availability and expertise. Further improvements may be possible from modifications of the standard regimens. Data from these latter studies seem to be encouraging, but are not based on comparative randomized trials.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Improving hematopoietic recovery through modeling and modulation of the mesenchymal stromal cell secretome
Stem Cell Research & Therapy Open Access 24 October 2018
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Thomas ED, Buckner CD, Banaji M et al. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 1977; 49: 511–533.
Thomas ED, Buckner CD, Clift RA et al. Marrow transplantation for acute nonlymphoblastic leukemia in first remission. N Engl J Med 1979; 301: 597–599.
Zittoun RA, Mandelli F, Willemze R et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J Med 1995; 332: 217–223.
Cassileth PA, Harrington DP, Appelbaum FR et al. Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med 1998; 339: 1649–1656.
Burnett AK, Wheatley K, Goldstone AH et al. The value of allogeneic bone marrow transplant in patients with acute myeloid leukaemia at differing risk of relapse: results of the UK MRC AML 10 trial. Br J Haematol 2002; 118: 385–400.
Ferrera J, Antin J . Pathophysiology of Graft-vs-Host Disease. Hematopoietic Stem Cell Transplantation. Blackwell Scientific Publications: Boston, MA, 1999, pp 305–315.
Gluckman E . Influence of conditioning on the outcome of allogeneic bone marrow transplantation. Int J Radiat Oncol Biol Phys 1990; 19: 1325–1327.
Clift RA, Buckner CD, Appelbaum FR et al. Allogeneic marrow transplantation in patients with acute myeloid leukemia in first remission: a randomized trial of two irradiation regimens. Blood 1990; 76: 1867–1871.
Appelbaum FR . Is there a best transplant conditioning regimen for acute myeloid leukemia? Leukemia 2000; 14: 497–501.
Grimwade D, Walker H, Oliver F et al. The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. Blood 1998; 92: 2322–2333.
Slovak ML, Kopecky KJ, Cassileth PA et al. 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.
Byrd JC, Mrozek K, Dodge RK et al. Pretreatment cytogenetic abnormalities are predictive of induction success, cumulative incidence of relapse, and overall survival in adult patients with de novo acute myeloid leukemia: results from Cancer and Leukemia Group B (CALGB 8461). Blood 2002; 100: 4325–4336.
Clift RA, Buckner CD, Thomas ED et al. Marrow transplantation for chronic myeloid leukemia: a randomized study comparing cyclophosphamide and total body irradiation with busulfan and cyclophosphamide. Blood 1994; 84: 2036–2043.
Devergie A, Blaise D, Attal M et al. Allogeneic bone marrow transplantation for chronic myeloid leukemia in first chronic phase: a randomized trial of busulfan-cytoxan vs cytoxan-total body irradiation as preparative regimen: a report from the French Society of Bone Marrow Graft (SFGM). Blood 1995; 85: 2263–2268.
Beutler E, Blume KG, Bross KJ et al. Bone marrow transplantation as the treatment of choice for ‘good risk’ adult patients with acute leukemia. Trans Assoc Am Phys 1979; 92: 189–195.
Santos GW, Tutschka PJ . Effect of busulfan on antibody production and skin allograft survival in the rat. J Natl Cancer Inst 1974; 53: 1775–1780.
Tutschka PJ, Santos GW . Bone marrow transplantation in the busulfan-treated rat. I. Effect of cyclophosphamide and rabbit antirat thymocyte serum as immunosuppression. Transplantation 1975; 20: 101–106.
Tutschka PJ, Santos GW . Bone marrow transplantation in the busulfan-treated rat. II. Effect of cyclophosphamide and antithymic serum on the presensitized state. Transplantation 1975; 20: 116–122.
Tutschka PJ, Santos GW, Elfenbein GJ . Marrow transplantation in acute leukemia following busulfan and cyclophosphamide. Haematol Blood Transfus 1980; 25: 375–380.
Santos GW, Kaizer H . Bone marrow transplantation in acute leukemia. Semin Hematol 1982; 19: 227–239.
Santos GW, Tutschka PJ, Brookmeyer R et al. Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide. N Engl J Med 1983; 309: 1347–1353.
Geller RB, Saral R, Piantadosi S et al. Allogeneic bone marrow transplantation after high-dose busulfan and cyclophosphamide in patients with acute nonlymphocytic leukemia. Blood 1989; 73: 2209–2218.
Tutschka PJ, Copelan EA, Klein JP . Bone marrow transplantation for leukemia following a new busulfan and cyclophosphamide regimen. Blood 1987; 70: 1382–1388.
Tutschka PJ, Copelan EA, Kapoor N . Replacing total body irradiation with busulfan as conditioning of patients with leukemia for allogeneic marrow transplantation. Transplant Proc 1989; 21: 2952–2954.
Copelan EA, Biggs JC, Thompson JM et al. Treatment for acute myelocytic leukemia with allogeneic bone marrow transplantation following preparation with BuCy2. Blood 1991; 78: 838–843.
Zapatero A, Martin de Vidales C, Pinar B et al. Prognostic factors affecting leukemia relapse after allogeneic BMT conditioned with cyclophosphamide and fractionated TBI. Bone Marrow Transplant 1996; 18: 591–596.
Blaise D, Maraninchi D, Archimbaud E et al. Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: a randomized trial of a busulfan-cytoxan vs cytoxan-total body irradiation as preparative regimen: a report from the Group d'Etudes de la Greffe de Moelle Osseuse. Blood 1992; 79: 2578–2582.
Ringden O, Ruutu T, Remberger M et al. A randomized trial comparing busulfan with total body irradiation as conditioning in allogeneic marrow transplant recipients with leukemia: a report from the Nordic Bone Marrow Transplantation Group. Blood 1994; 83: 2723–2730.
Ringden O, Labopin M, Tura S et al. A comparison of busulphan vs total body irradiation combined with cyclophosphamide as conditioning for autograft or allograft bone marrow transplantation in patients with acute leukaemia. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 1996; 93: 637–645.
Litzow MR, Perez WS, Klein JP et al. Comparison of outcome following allogeneic bone marrow transplantation with cyclophosphamide-total body irradiation vs busulphan-cyclophosphamide conditioning regimens for acute myelogenous leukaemia in first remission. Br J Haematol 2002; 119: 1115–1124.
Michel G, Gluckman E, Esperou-Bourdeau H et al. Allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: impact of conditioning regimen without total-body irradiation – a report from the Societe Francaise de Greffe de Moelle. J Clin Oncol 1994; 12: 1217–1222.
Frassoni F, Labopin M, Powles R et al. Effect of centre on outcome of bone-marrow transplantation for acute myeloid leukaemia. Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation. Lancet 2000; 355: 1393–1398.
Pino y Torres JL, Bross DS, Lam WC et al. Risk factors in interstitial pneumonitis following allogenic bone marrow transplantation. Int J Radiat Oncol Biol Phys 1982; 8: 1301–1307.
Labar B, Bogdanic V, Nemet D et al. Total body irradiation with or without lung shielding for allogeneic bone marrow transplantation. Bone Marrow Transplant 1992; 9: 343–347.
Simpson DR, Nevill TJ, Shepherd JD et al. High incidence of extramedullary relapse of AML after busulfan/cyclophosphamide conditioning and allogeneic stem cell transplantation. Bone Marrow Transplant 1998; 22: 259–264.
Witherspoon RP, Fisher LD, Schoch G et al. Secondary cancers after bone marrow transplantation for leukemia or aplastic anemia. N Engl J Med 1989; 321: 784–789.
Curtis RE, Rowlings PA, Deeg HJ et al. Solid cancers after bone marrow transplantation. N Engl J Med 1997; 336: 897–904.
Blaise D, Maraninchi D, Michallet M et al. Long-term follow-up of a randomized trial comparing the combination of cyclophosphamide with total body irradiation or busulfan as conditioning regimen for patients receiving HLA-identical marrow grafts for acute myeloblastic leukemia in first complete remission. Blood 2001; 97: 3669–3671.
Ringden O, Remberger M, Ruutu T et al. Increased risk of chronic graft-vs-host disease, obstructive bronchiolitis, and alopecia with busulfan vs total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia. Nordic Bone Marrow Transplantation Group. Blood 1999; 93: 2196–2201.
Socie G, Clift RA, Blaise D et al. Busulfan plus cyclophosphamide compared with total-body irradiation plus cyclophosphamide before marrow transplantation for myeloid leukemia: long-term follow-up of 4 randomized studies. Blood 2001; 98: 3569–3574.
Thomas ED, Clift RA, Hersman J et al. Marrow transplantation for acute nonlymphoblastic leukemic in first remission using fractionated or single-dose irradiation. Int J Radiat Oncol Biol Phys 1982; 8: 817–821.
Clift RA, Buckner CD, Appelbaum FR et al. Long-term follow-up of a randomized trial of two irradiation regimens for patients receiving allogeneic marrow transplants during first remission of acute myeloid leukemia. Blood 1998; 92: 1455–1456.
Helenglass G, Powles RL, McElwain TJ et al. Melphalan and total body irradiation (TBI) versus cyclophosphamide and TBI as conditioning for allogeneic matched sibling bone marrow transplants for acute myeloblastic leukaemia in first remission. Bone Marrow Transplant 1988; 3: 21–29.
Blume KG, Kopecky KJ, Henslee-Downey JP et al. A prospective randomized comparison of total body irradiation-etoposide vs busulfan-cyclophosphamide as preparatory regimens for bone marrow transplantation in patients with leukemia who were not in first remission: a Southwest Oncology Group study. Blood 1993; 81: 2187–2193.
Snyder DS, Chao NJ, Amylon MD et al. Fractionated total body irradiation and high-dose etoposide as a preparatory regimen for bone marrow transplantation for 99 patients with acute leukemia in first complete remission. Blood 1993; 82: 2920–2928.
Linker CA, Ries CA, Damon LE et al. Autologous bone marrow transplantation for acute myeloid leukemia using busulfan plus etoposide as a preparative regimen. Blood 1993; 81: 311–318.
Spitzer TR, Cottler-Fox M, Torrisi J et al. Escalating doses of etoposide with cyclophosphamide and fractionated total body irradiation or busulfan as conditioning for bone marrow transplantation. Bone Marrow Transplant 1989; 4: 559–565.
Zander AR, Berger C, Kroger N et al. High dose chemotherapy with busulfan, cyclophosphamide, and etoposide as conditioning regimen for allogeneic bone marrow transplantation for patients with acute myeloid leukemia in first complete remission. Clin Cancer Res 1997; 3: 2671–2675.
Kroger N, Zabelina T, Sonnenberg S et al. Dose-dependent effect of etoposide in combination with busulfan plus cyclophosphamide as conditioning for stem cell transplantation in patients with acute myeloid leukemia. Bone Marrow Transplant 2000; 26: 711–716.
Brown RA, Wolff SN, Fay JW et al. High-dose etoposide, cyclophosphamide, and total body irradiation with allogeneic bone marrow transplantation for patients with acute myeloid leukemia in untreated first relapse: a study by the North American Marrow Transplant Group. Blood 1995; 85: 1391–1395.
Bibawi S, Abi-Said D, Fayad L et al. Thiotepa, busulfan, and cyclophosphamide as a preparative regimen for allogeneic transplantation for advanced myelodysplastic syndrome and acute myelogenous leukemia. Am J Hematol 2001; 67: 227–233.
Ratanatharathorn V, Karanes C, Lum LG et al. Allogeneic bone marrow transplantation in high-risk myeloid disorders using busulfan, cytosine arabinoside and cyclophosphamide (BAC). Bone Marrow Transplant 1992; 9: 49–55.
Crilley P, Topolsky D, Styler MJ et al. Extramedullary toxicity of a conditioning regimen containing busulphan, cyclophosphamide and etoposide in 84 patients undergoing autologous and allogenic bone marrow transplantation. Bone Marrow Transplant 1995; 15: 361–365.
Reske SN, Bunjes D, Buchmann I et al. Targeted bone marrow irradiation in the conditioning of high-risk leukaemia prior to stem cell transplantation. Eur J Nucl Med 2001; 28: 807–815.
Jurcic JG, Caron PC, Nikula TK et al. Radiolabeled anti-CD33 monoclonal antibody M195 for myeloid leukemias. Cancer Res 1995; 55: 5908s–5910s.
Matthews DC, Appelbaum FR, Eary JF et al. Development of a marrow transplant regimen for acute leukemia using targeted hematopoietic irradiation delivered by 131I-labeled anti-CD45 antibody, combined with cyclophosphamide and total body irradiation. Blood 1995; 85: 1122–1131.
Matthews DC, Appelbaum FR, Eary JF et al. Phase I study of (131)I-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome. Blood 1999; 94: 1237–1247.
Bunjes D, Buchmann I, Duncker C et al. Rhenium 188-labeled anti-CD66 (a, b, c, e) monoclonal antibody to intensify the conditioning regimen prior to stem cell transplantation for patients with high-risk acute myeloid leukemia or myelodysplastic syndrome: results of a phase I–II study. Blood 2001; 98: 565–572.
Jurcic JG, Larson SM, Sgouros G et al. Targeted alpha particle immunotherapy for myeloid leukemia. Blood 2002; 100: 1233–1239.
Slattery JT, Sanders JE, Buckner CD et al. Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics. Bone Marrow Transplant 1995; 16: 31–42.
Vassal G, Deroussent A, Hartmann O et al. Dose-dependent neurotoxicity of high-dose busulfan in children: a clinical and pharmacological study. Cancer Res 1990; 50: 6203–6207.
Dix SP, Wingard JR, Mullins RE et al. Association of busulfan area under the curve with veno-occlusive disease following BMT. Bone Marrow Transplant 1996; 17: 225–230.
Ljungman P, Hassan M, Bekassy AN et al. High busulfan concentrations are associated with increased transplant-related mortality in allogeneic bone marrow transplant patients. Bone Marrow Transplant 1997; 20: 909–913.
Chattergoon DS, Saunders EF, Klein J et al. An improved limited sampling method for individualised busulphan dosing in bone marrow transplantation in children. Bone Marrow Transplant 1997; 20: 347–354.
Schuler U, Schroer S, Kuhnle A et al. Busulfan pharmacokinetics in bone marrow transplant patients: is drug monitoring warranted? Bone Marrow Transplant 1994; 14: 759–765.
McDonald GB, Slattery JT, Bouvier ME et al. Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood 2003; 101: 2043–2048.
Andersson BS, Madden T, Tran HT et al. Acute safety and pharmacokinetics of intravenous busulfan when used with oral busulfan and cyclophosphamide as pretransplantation conditioning therapy: a phase I study. Biol Blood Marrow Transplant 2000; 6: 548–554.
Olavarria E, Hassan M, Eades A et al. A phase I/II study of multiple-dose intravenous busulfan as myeloablation prior to stem cell transplantation. Leukemia 2000; 14: 1954–1959.
Schuler US, Renner UD, Kroschinsky F et al. Intravenous busulphan for conditioning before autologous or allogeneic human blood stem cell transplantation. Br J Haematol 2001; 114: 944–950.
Hassan M, Nilsson C, Hassan Z et al. A phase II trial of liposomal busulphan as an intravenous myeloablative agent prior to stem cell transplantation: 500 mg/m(2) as a optimal total dose for conditioning. Bone Marrow Transplant 2002; 30: 833–841.
Kashyap A, Wingard J, Cagnoni P et al. Intravenous vs oral busulfan as part of a busulfan/cyclophosphamide preparative regimen for allogeneic hematopoietic stem cell transplantation: decreased incidence of hepatic venoocclusive disease (HVOD), HVOD-related mortality, and overall 100-day mortality. Biol Blood Marrow Transplant 2002; 8: 493–500.
Russell JA, Tran HT, Quinlan D et al. Once-daily intravenous busulfan given with fludarabine as conditioning for allogeneic stem cell transplantation: study of pharmacokinetics and early clinical outcomes. Biol Blood Marrow Transplant 2002; 8: 468–476.
Ho VT, Soiffer RJ . The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood 2001; 98: 3192–3204.
Young JW, Papadopoulos EB, Cunningham I et al. T-cell-depleted allogeneic bone marrow transplantation in adults with acute nonlymphocytic leukemia in first remission. Blood 1992; 79: 3380–3387.
Soiffer RJ, Fairclough D, Robertson M et al. CD6-depleted allogeneic bone marrow transplantation for acute leukemia in first complete remission. Blood 1997; 89: 3039–3047.
Papadopoulos EB, Carabasi MH, Castro-Malaspina H et al. 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 1998; 91: 1083–1090.
Marmont AM, Horowitz MM, Gale RP et al. T-cell depletion of HLA-identical transplants in leukemia. Blood 1991; 78: 2120–2130.
Aversa F, Terenzi A, Carotti A et al. Improved outcome with T-cell-depleted bone marrow transplantation for acute leukemia. J Clin Oncol 1999; 17: 1545–1550.
Maris M, Woolfrey A, McSweeney PA et al. Nonmyeloablative hematopoietic stem cell transplantation: transplantation for the 21st century. Front Biosci 2001; 6: G13–G16.
McSweeney PA, Niederwieser D, Shizuru JA et al. Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-vs-tumor effects. Blood 2001; 97: 3390–3400.
Devine SM, Sanborn R, Jessop E et al. Fludarabine and melphalan-based conditioning for patients with advanced hematological malignancies relapsing after a previous hematopoietic stem cell transplant. Bone Marrow Transplant 2001; 28: 557–562.
Pawson R, Potter MN, Theocharous P et al. Treatment of relapse after allogeneic bone marrow transplantation with reduced intensity conditioning (FLAG +/− Ida) and second allogeneic stem cell transplant. Br J Haematol 2001; 115: 622–629.
Martino R, Caballero MD, Simon JA et al. Evidence for a graft-vs-leukemia effect after allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes. Blood 2002; 100: 2243–2245.
Feinstein LC, Sandmaier BM, Hegenbart U et al. Non-myeloablative allografting from human leucocyte antigen-identical sibling donors for treatment of acute myeloid leukaemia in first complete remission. Br J Haematol 2003; 120: 281–288.
Djulbegovic B, Seidenfeld J, Bonnell C et al. Nonmyeloablative allogeneic stem-cell transplantation for hematologic malignancies: a systematic review. Cancer Control 2003; 10: 17–41.
Mielcarek M, Martin PJ, Leisenring W et al. Graft-versus-host disease after nonmyeloablative vs conventional hematopoietic stem cell transplantation. Blood 2003; 102: 756–762.
We thank Dr JM Rowe for a careful review of the manuscript and helpful comments. AK holds the Gloria and Seymour Epstein Chair in Cell Therapy and Transplantation at University Health Network and University of Toronto.
About this article
Cite this article
Gupta, V., Lazarus, H. & Keating, A. Myeloablative conditioning regimens for AML allografts: 30 years later. Bone Marrow Transplant 32, 969–978 (2003). https://doi.org/10.1038/sj.bmt.1704285
- conditioning regimen
- total body irradiation
This article is cited by
Improving hematopoietic recovery through modeling and modulation of the mesenchymal stromal cell secretome
Stem Cell Research & Therapy (2018)
Nature Reviews Gastroenterology & Hepatology (2014)
High-dose busulfan, cyclophosphamide, and etoposide does not improve outcome of allogeneic stem cell transplantation compared to BuCy2 in patients with acute myeloid leukemia
Bone Marrow Transplantation (2005)
The role of reduced intensity conditioning allogeneic stem cell transplantation in patients with acute myeloid leukemia: a donor vs no donor comparison