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Prepublished online as a Blood First Edition Paper on April 3, 2003; DOI 10.1182/blood-2002-11-3567.

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Submitted November 26, 2002
Accepted March 29, 2003

Conditioning with fludarabine and targeted busulfan for transplantation of allogeneic hematopoietic stem cells

Martin Bornhauser*, Barry Storer, John T Slattery, Frederick R Appelbaum, H Joachim Deeg, John Hansen, Paul J Martin, George B Mc Donald, W Garrett Nichols, Jerald Radich, Ann Woolfrey, Andreas Jenke, Eberhard Schleyer, Christian Thiede, Gerhard Ehninger, and Claudio Anasetti

Medizinische Klinik und Poliklinik I, University of Dresden, Dresden, Germany
Fred Hutchinson Cancer Research Center, Seattle, WA, USA

* Corresponding author; email: bornhaeuser{at}mk1.med.tu-dresden.

A regimen of busulfan and cyclophosphamide is standard therapy before transplantation of allogeneic hematopoietic stem cells in patients with chronic myelogenous leukemia (CML) or myelodysplastic syndrome (MDS). The clinical trial reported here was undertaken to test the hypothesis that fludarabine can replace cyclophosphamide in this regimen and facilitate donor engraftment with reduced toxicity. The new conditioning regimen consisted of intravenous fludarabine 30 mg/m2 daily from day -9 to day -6, and oral busulfan given at 1 mg/kg x 16 every 6 h from day -5 to day -2, with doses adjusted to target plasma levels of 900±100 ng/ml at steady state. Cyclosporine and methotrexate were used for prophylaxis for graft-versus-host disease. Forty-two patients with high-risk CML (n=4) or MDS (n=38) were enrolled. The median patient age was 52 (range 12-65) years. Mobilized blood stem cells were obtained from HLA-compatible siblings (n=16) or unrelated donors (n=26). Engraftment was achieved in all patients, and the day-100 regimen-related mortality was 7%. With a median follow-up of 18 (range 13-27) months, the probabilities of overall survival, disease-free survival and non-relapse mortality were 42.4%, 34.9% and 24%, respectively. These data indicate that the combination of fludarabine and targeted busulfan is sufficiently immunosuppressive to facilitate engraftment of blood stem cells from HLA-matched siblings and unrelated donors. Based on these encouraging results, further studies of fludarabine and targeted busulfan are warranted in standard risk patients.


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