A modified busulfan and cyclophosphamide preparative regimen for allogeneic transplantation in myeloid malignancies
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Background Busulfan/cyclophosphamide (Bu/Cy) is commonly used as a standard conditioning regimen without total body irradiation for patients with hematological myeloid malignancies undergoing hematopoietic stem cell transplantation (HSCT). Objective To develop a new myeloablative conditioning regimen incorporating fludarabine (Flu) and cytarabine (Ara-c). Setting A tertiary blood disease hospital in Tianjin, China. Methods A Bu/Cy preparative regimen was used, modified by Flu 90 mg/m2 and Ara-c 6 g/m2 in 57 unselected patients (median age 37 years) with hematological myeloid malignancies. The patients were to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT). Thirteen patients had high-risk leukemia, fifty patients had HLA matched sibling donors while seven patients had HLA mismatched sibling donors. Cy was given 50 mg/kg/day for 2 days while Bu was given 3.2 mg/kg/day intravenously for 3 days. Main outcome measure Post-transplant donor chimerism, relapse tendency and minimal residual disease. Results Extramedullar toxicity was relatively limited; the incidence of treatment-related mortality (TRM) within 100 days was 3.5 %. The incidence of grade II–IV, grade III–IV acute graft versus host disease (GVHD) and chronic GVHD of the evaluable patients were 21.1, 8.8 and 36.4 %, respectively. With a median follow up of 59 (13–96.5) months, TRM and relapse rate (RR) at eight years were 24.1 ± 5.8 and 14.7 ± 4.8 %, respectively. Disease free survival at eight years was 67.9 ± 6.2 % for the entire group, 60.0 ± 8.9 % for patients with AML, 77.3 ± 8.9 % for patients with CML, 70.0 ± 6.5 and 42.9 ± 18.7 % or matched sibling and mismatched sibling HSCT respectively. Conclusion The new regimen was associated with a low relapse rate, low incidence and severity of graft versus host disease and satisfactory survival for patients with myeloid malignancies.
KeywordsBusulfan Conditioning regimen Cytarabine FLAG Fludarabine Graft-versus-host disease Myeloid malignancy Stem cell transplantation
This work was supported by Grants from the National Key Technology Support Program of China (2013BAIO1BO9) and the Key Program of Applied basic Research Foundation of Tianjin (14JCZDJC33000).
Conflicts of interest
The authors have no conflict of interests.
- 2.Ringdén O, Remberger M, Ruutu T, Nikoskelainen J, Volin L, Vindeløv L, et al. Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: long-term results of a randomized trial in allogeneic marrow recipients with leukemia. Nordic Bone Marrow Transplantation Group. Blood. 1999;93:2196–201.PubMedGoogle Scholar
- 3.Hassan M, Ljungman P, Ringdén O, Hassan Z, Oberg G, Nilsson C, et al. The effect of busulphan on the pharmacokinetics of cyclophosphamide and its 4-hydroxy metabolite: time interval influence on therapeutic efficacy and therapy-related toxicity. Bone Marrow Transplant. 2000;25:915–24.PubMedCrossRefGoogle Scholar
- 4.Ringdén O, Ruutu T, Remberger M, Nikoskelainen J, Volin L, Vindeløv L, 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;83:2723–30.PubMedGoogle Scholar
- 8.Kashyap A, Wingard J, Cagnoni P, Jones R, Tarantolo S, Hu W, et al. Intravenous versus 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.Google Scholar
- 10.Nagler A, Rocha V, Labopin M, Unal A, Ben Othman T, Campos A. Allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia in remission: comparison of intravenous busulfan plus cyclophosphamide (Cy) versus total-body irradiation plus Cy as conditioning regimen–a report from the acute leukemia working party of the European group for blood and marrow transplantation. J Clin Oncol. 2013;31:3549–56.PubMedCrossRefGoogle Scholar
- 12.Blaise D, Maraninchi D, Archimbaud E, Reiffers J, Devergie A, Jouet JP, et al. Allogeneic bone marrow transplantation for acute myeloid leukemia in first remission: a randomized trial of a busulfan-Cytoxan versus Cytoxan-total body irradiation as preparative regimen: a report from the Group d’Etudes de la Greffe de Moelle Osseuse. Blood. 1992;79:2578–82.PubMedGoogle Scholar
- 13.Devergie A, Blaise D, Attal M, Tigaud JD, Jouet JP, Vernant JP, et al. Allogeneic bone marrow transplantation for chronic myeloid leukemia in first chronic phase: a randomized trial of busulfan-cytoxan versus cytoxan body irradiation as preparative regimen: a report from the French Society of Bone Marrow Graft (SFGM). Blood. 1995;85:2263–8.PubMedGoogle Scholar
- 18.US National Cancer Institute. Cancer therapy evaluation program common toxicity criteria, version 2.0. Bethesda, MD: DCTD, NCI, NIH, DHHS; 1998.Google Scholar
- 24.Russell JA, Tran HT, Quinlan D, Chaudhry A, Duggan P, Brown C, 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;8:468–76.PubMedCrossRefGoogle Scholar
- 26.de Lima M, Couriel D, Thall PF, Wang X, Madden T, Jones R, et al. Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood. 2004;104:857–64.PubMedCrossRefGoogle Scholar
- 28.Bartelink IH, van Reij EM, Gerhardt CE, van Maarseveen EM, de Wildt A, Versluys B, et al. Fludarabine and exposure-targeted busulfan compares favorably with busulfan/cyclophosphamide-based regimens in pediatric hematopoietic cell transplantation: maintaining efficacy with less toxicity. Biol Blood Marrow Transplant. 2013;20(3):345–53.PubMedCrossRefGoogle Scholar
- 31.Weyman C, Graham-Pole J, Emerson S, August C, Champlin R, Coccia P, et al. Use of cytosine arabinoside and total body irradiation as conditioning for allogeneic marrow transplantation in patients with acute lymphoblastic leukemia: a multicenter survey. Bone Marrow Transplant. 1993;11:43–50.PubMedGoogle Scholar
- 33.Gordon BG, Warkentin PI, Strandjord SE, Abromowitch M, Bayever E, Harper JL, et al. Allogeneic bone marrow transplantation for children with acute leukemia: long-term follow-up of patients prepared with high-dose cytosine arabinoside and fractionated total body irradiation. Bone Marrow Transplant. 1997;20:5–10.PubMedCrossRefGoogle Scholar
- 38.Martino R, Pérez-Simón JA, Moreno E, Queraltó JM, Caballero D, Mateos M, et al. Reduced-intensity conditioning allogeneic blood stem cell transplantation with fludarabine and oral busulfan with or without pharmacokinetically targeted busulfan dosing in patients with myeloid leukemia ineligible for conventional conditioning. Biol Blood Marrow Transplant. 2005;11:437–47.PubMedCrossRefGoogle Scholar