Abstract
Conditioning regimens contribute significantly to outcomes following allogeneic stem cell transplantation (allo-SCT). Reduced-intensity conditioning (RIC) regimens provide lower toxicity at the cost of reduced efficacy compared with myeloablative conditioning (MAC) regimens. However, because pre-transplant prognostic variables often determine the conditioning regimen, studies of RIC vs. MAC have been inconclusive. We present a retrospective analysis of 242 acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) patients, 112 of whom were in 56 pairs matched using propensity scores, to account for variation that may confound clinical outcomes. The uniform conditioning regimens consisted of fludarabine with pharmacokinetic (PK)-guided intravenous busulfan (Bu). The RIC and MAC regimens were dosed at the average daily area under the concentration-vs-time curve (AUC) of 4000 µMol min and 5000–6000 µMol min, or total course AUC of 16,000 µMol min and 20,000–24,000 µMol min, respectively; PK-guided dosing removes overlap in systemic Bu exposure. When patients’ data were propensity-matched, there was a trend toward significantly increased full donor chimerism and decreased chronic graft vs. host disease in RIC, and no significant differences in progression free survival and overall survival between RIC and MAC. Our results also elucidate the efficacy of PK-guided-dosing in the setting of allo-SCT for AML and MDS.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Andersson BS, de Lima M, Thall PF, Wang X, Couriel D, Korbling M, et al. Once daily i.v. busulfan and fludarabine (i.v. Bu-Flu) compares favorably with i.v. busulfan and cyclophosphamide (i.v. BuCy2) as pretransplant conditioning therapy in AML/MDS. Biol Blood Marrow Transplant. 2008;14:672–84.
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.
Lee JH, Joo YD, Kim H, Ryoo HM, Kim MK, Lee GW, et al. Randomized trial of myeloablative conditioning regimens: busulfan plus cyclophosphamide versus busulfan plus fludarabine. J Clin Oncol. 2013;31:701–9.
Liu H, Zhai X, Song Z, Sun J, Xiao Y, Nie D, et al. Busulfan plus fludarabine as a myeloablative conditioning regimen compared with busulfan plus cyclophosphamide for acute myeloid leukemia in first complete remission undergoing allogeneic hematopoietic stem cell transplantation: a prospective and multicenter study. J Hematol Oncol. 2013;6:15.
Rambaldi A, Grassi A, Masciulli A, Boschini C, Mico MC, Busca A, et al. Busulfan plus cyclophosphamide versus busulfan plus fludarabine as a preparative regimen for allogeneic haemopoietic stem-cell transplantation in patients with acute myeloid leukaemia: an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2015;16:1525–36.
Russell JA, Savoie ML, Balogh A, Turner AR, Larratt L, Chaudhry MA, et al. Allogeneic transplantation for adult acute leukemia in first and second remission with a novel regimen incorporating daily intravenous busulfan, fludarabine, 400 CGY total-body irradiation, and thymoglobulin. Biol Blood Marrow Transplant. 2007;13:814–21.
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.
Blaise D, Vey N, Faucher C, Mohty M. Current status of reduced-intensity-conditioning allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica. 2007;92:533–41.
Hamadani M, Mohty M, Kharfan-Dabaja MA. Reduced-intensity conditioning allogeneic hematopoietic cell transplantation in adults with acute myeloid leukemia. Cancer Control. 2011;18:237–45.
Shimoni A, Hardan I, Shem-Tov N, Yeshurun M, Yerushalmi R, Avigdor A, et al. Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity. Leukemia. 2006;20:322–8.
Baron F, Storb R, Storer BE, Maris MB, Niederwieser D, Shizuru JA, et al. Factors associated with outcomes in allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning after failed myeloablative hematopoietic cell transplantation. J Clin Oncol. 2006;24:4150–7.
McClune BL, Weisdorf DJ. Reduced-intensity conditioning allogeneic stem cell transplantation for older adults: is it the standard of care? Curr Opin Hematol. 2010;17:133–8.
Corradini P, Zallio F, Mariotti J, Farina L, Bregni M, Valagussa P, et al. Effect of age and previous autologous transplantation on nonrelapse mortality and survival in patients treated with reduced-intensity conditioning and allografting for advanced hematologic malignancies. J Clin Oncol. 2005;23:6690–8.
Diaconescu R, Flowers CR, Storer B, Sorror ML, Maris MB, Maloney DG, et al. Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors. Blood. 2004;104:1550–8.
Abdul Wahid SF, Ismail NA, Mohd-Idris MR, Jamaluddin FW, Tumian N, Sze-Wei EY, et al. Comparison of reduced-intensity and myeloablative conditioning regimens for allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia and acute lymphoblastic leukemia: a meta-analysis. Stem Cells Dev. 2014;23:2535–52.
Tanaka J, Kanamori H, Nishiwaki S, Ohashi K, Taniguchi S, Eto T, et al. Reduced-intensity vs myeloablative conditioning allogeneic hematopoietic SCT for patients aged over 45 years with ALL in remission: a study from the Adult ALL Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT). Bone Marrow Transplant. 2013;48:1389–94.
Andersson BS, Thall PF, Madden T, Couriel D, Wang X, Tran HT, et al. Busulfan systemic exposure relative to regimen-related toxicity and acute graft-versus-host disease: defining a therapeutic window for i.v. BuCy2 in chronic myelogenous leukemia. Biol Blood Marrow Transplant. 2002;8:477–85.
Slattery JT, Clift RA, Buckner CD, Radich J, Storer B, Bensinger WI, et al. Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation. Blood. 1997;89:3055–60.
Russell JA, Kangarloo SB, Williamson T, Chaudhry MA, Savoie ML, Turner AR, et al. Establishing a target exposure for once-daily intravenous busulfan given with fludarabine and thymoglobulin before allogeneic transplantation. Biol Blood Marrow Transplant. 2013;19:1381–6.
Geddes M, Kangarloo SB, Naveed F, Quinlan D, Chaudhry MA, Stewart D, et al. High busulfan exposure is associated with worse outcomes in a daily i.v. busulfan and fludarabine allogeneic transplant regimen. Biol Blood Marrow Transplant. 2008;14:220–8.
Dix SP, Wingard JR, Mullins RE, Jerkunica I, Davidson TG, Gilmore CE, et al. Association of busulfan area under the curve with veno-occlusive disease following BMT. Bone Marrow Transplant. 1996;17:225–30.
Slattery JT, Sanders JE, Buckner CD, Schaffer RL, Lambert KW, Langer FP, et al. Graft-rejection and toxicity following bone marrow transplantation in relation to busulfan pharmacokinetics. Bone Marrow Transplant. 1995;16:31–42.
Shimoni A, Hardan I, Shem-Tov N, Yerushalmi R, Nagler A. Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: long-term follow-up. Leukemia. 2010;24:1050–2.
Andersson BS, Thall PF, Valdez BC, Milton DR, Al-Atrash G, Chen J, et al. Fludarabine with pharmacokinetically guided IV busulfan is superior to fixed-dose delivery in pretransplant conditioning of AML/MDS patients. Bone Marrow Transplant. 2017;52:580–7.
Tang X, Alatrash G, Ning J, Jakher H, Stafford P, Zope M, et al. Increasing chimerism after allogeneic stem cell transplantation is associated with longer survival time. Biol Blood Marrow Transplant. 2014;20:1139–44.
Keating MJ, Smith TL, Gehan EA, McCredie KB, Bodey GP, Spitzer G, et al. Factors related to length of complete remission in adult acute leukemia. Cancer. 1980;45:2017–29.
Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89:2079–88.
Andersson BS, Valdez BC, de Lima M, Wang X, Thall PF, Worth LL, et al. Clofarabine+/- fludarabine with once daily i.v. busulfan as pretransplant conditioning therapy for advanced myeloid leukemia and MDS. Biol Blood Marrow Transplant. 2011;17:893–900.
Valdez BC, Li Y, Murray D, Champlin RE, Andersson BS. The synergistic cytotoxicity of clofarabine, fludarabine and busulfan in AML cells involves ATM pathway activation and chromatin remodeling. Biochem Pharmacol. 2011;81:222–32.
Przepiorka D, Khouri I, Ippoliti C, Ueno NT, Mehra R, Korbling M, et al. Tacrolimus and minidose methotrexate for prevention of acute graft-versus-host disease after HLA-mismatched marrow or blood stem cell transplantation. Bone Marrow Transplant. 1999;24:763–8.
Fisher R. On the interpretation of χ2 from contingency tables, and the calculation of P. J R Stat Soc. 1922;85:87–94.
Freeman GH, Halton JH. Note on an exact treatment of contingency, goodness of fit and other problems of significance. Biometrika. 1951;38:141–9.
Randles R, Wolfe D. Introduction to the Theory of Nonparametric Statistics: John Wiley; 1979.
Rosenbaum PR, Rubin DB, Constructing a Control-Group. Using multivariate matched sampling methods that incorporate the propensityscore. Am Stat. 1985;39:33–8.
Ho D, Imai K, King G, Stuart E. MatchIt: nonparametric preprocessing for parametric causal inference; 2007.
Snedecor GW, Cochran WG. Statistical methods. 8th edn. Ames: Iowa State University Press; 1989. p 503.
Kaplan EL, Meier P. Nonparametric estimaion from incomplete observations. J Am Stat Assoc. 1958;53:457–81.
Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966;50:163–70.
Klein JP, Moeschberger ML. Survival analysis: techniques for censored and truncated data. New York: Springer-Verlag; 1997.
Therneau TM, Grambsch PM. Modeling survival data: extending the Cox model. New York: Springer-Verlag; 2000.
Grambsch PM, Therneau TM. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika. 1994;81:515–26.
Scott BL, Pasquini MC, Logan BR, Wu J, Devine SM, Porter DL, et al. Myeloablative versus reduced-intensity hematopoietic cell transplantation for acute myeloid leukemia and myelodysplastic syndromes. J Clin Oncol. 2017;35:1154–61.
Ustun C, Courville EL, DeFor T, Dolan M, Randall N, Yohe S, et al. Myeloablative, but not reduced-intensity, conditioning overcomes the negative effect of flow-cytometric evidence of leukemia in acute myeloid leukemia. Biol Blood Marrow Transplant. 2015;22:669–75.
Sibai H, Falcone U, Deotare U, Michelis FV, Uhm J, Gupta V, et al. Myeloablative versus reduced-intensity conditioning in patients with myeloid malignancies: a propensity score-matched analysis. Biol Blood Marrow Transplant. 2016;22:2270–5.
Kim H, Kim BS, Kim DH, Hyun MS, Kim SH, Bae SH, et al. Comparison between matched related and alternative donors of allogeneic hematopoietic stem cells transplanted into adult patients with acquired aplastic anemia: multivariate and propensity score-matched analysis. Biol Blood Marrow Transplant. 2011;17:1289–98.
Bartelink IH, Lalmohamed A, van Reij EM, Dvorak CC, Savic RM, Zwaveling J, et al. Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis. Lancet Haematol. 2016;3:e526–e36.
Harris AC, Ferrara JL, Levine JE. Advances in predicting acute GVHD. Br J Haematol. 2013;160:288–302.
Kebriaei P, Wilhelm K, Ravandi F, Brandt M, de Lima M, Ciurea S, et al. Feasibility of allografting in patients with advanced acute lymphoblastic leukemia after salvage therapy with inotuzumab ozogamicin. Clin Lymphoma Myeloma Leuk. 2013;13:296–301.
Westin JR, Saliba RM, De Lima M, Alousi A, Hosing C, Qazilbash MH, et al. Steroid-refractory acute GVHD: predictors and outcomes. Adv Hematol. 2011;2011:601953.
Kebriaei P, Cutler C, de Lima M, Giralt S, Lee SJ, Marks D, et al. Management of important adverse events associated with inotuzumab ozogamicin: expert panel review. Bone Marrow Transplant. 2018;53:449–56.
de Witte T, Bowen D, Robin M, Malcovati L, Niederwieser D, Yakoub-Agha I, et al. Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel. Blood. 2017;129:1753–62.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The senior author was previously a consultant to Otsuka Research and Development, Inc.
Supplementary information
Rights and permissions
About this article
Cite this article
Alatrash, G., Kidwell, K.M., Thall, P.F. et al. Reduced intensity vs. myeloablative conditioning with fludarabine and PK-guided busulfan in allogeneic stem cell transplantation for patients with AML/MDS. Bone Marrow Transplant 54, 1245–1253 (2019). https://doi.org/10.1038/s41409-018-0405-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41409-018-0405-0