Treosulfan, fludarabine, and 2-Gy total body irradiation followed by allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome and acute myeloid leukemia.
Allogeneic hematopoietic cell transplantation (HCT) offers curative therapy for many patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). However, post-HCT relapse remains a major problem, particularly in patients with high-risk cytogenetics. In this prospective phase II trial, we assessed the efficacy and toxicity of treosulfan, fludarabine, and 2 Gy total body irradiation (TBI) as conditioning for allogeneic HCT in patients with MDS or AML. Ninety-six patients with MDS (n = 36: 15 refractory cytopenia with multilineage dysplasia, 10 refractory anemia with excess blasts type 1, 10 refractory anemia with excess blasts type 2, 1 chronic myelomonocytic leukemia type 1) or AML (n = 60: 35 first complete remission [CR], 18 second CR, 3 advanced CR, 4 refractory relapse) were enrolled; median age was 51 (range, 1 to 60) years. Twelve patients had undergone a prior HCT with high-intensity conditioning. Patients received 14 g/m(2)/day treosulfan i.v. on days -6 to -4, 30 mg/m(2)/day fludarabine i.v. on days -6 to -2, and 2 Gy TBI on day 0, followed by infusion of hematopoietic cells from related (n = 27) or unrelated (n = 69) donors. Graft-versus-host disease prophylaxis consisted of tacrolimus and methotrexate. With a median follow-up of 30 months, the 2-year overall survival (OS), relapse incidence, and nonrelapse mortality were 73%, 27%, and 8%, respectively. The incidences of grades II to IV (III to IV) acute and chronic graft-versus-host disease were 59% (10%) and 47%, respectively. Two-year OS was not significantly different between MDS patients with poor-risk and good/intermediate-risk cytogenetics (69% and 85%, respectively) or between AML patients with unfavorable and favorable/intermediate-risk cytogenetics (64% and 76%, respectively). In AML patients, minimal residual disease (MRD; n = 10) at the time of HCT predicted higher relapse incidence (70% versus 18%) and lower OS (41% versus 79%) at 2 years, when compared with patients without MRD. In conclusion, treosulfan, fludarabine, and low-dose TBI provided effective conditioning for allogeneic HCT in patients with MDS or AML and resulted in low relapse incidence, regardless of cytogenetic risk. In patients with AML, MRD at the time of HCT remained a risk factor for post-HCT relapse.
Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington School of Medicine, Seattle, Washington. Electronic address: bgyurkoc@fhcrc.org.
Boglarka
B
Gyurkocza
Department of Medicine, University of Colorado, Denver, Colorado.
Jonathan
J
Gutman
Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
Eneida R
ER
Nemecek
Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
Merav
M
Bar
Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
Filippo
F
Milano
Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
Aravind
A
Ramakrishnan
Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
Bart
B
Scott
Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
Min
M
Fang
Medac GmbH, Hamburg, Germany.
Brent
B
Wood
Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
John M
JM
Pagel
Department of Laboratory Medicine, University of Washing School of Medicine, Seattle, WA.
Joachim
J
Baumgart
Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
Colleen
C
Delaney
Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon.
Richard T
RT
Maziarz
Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
Brenda M
BM
Sandmaier
Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
Elihu H
EH
Estey
Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
Frederick R
FR
Appelbaum
Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
Barry E
BE
Storer
Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
Hans Joachim
HJ
Deeg
D000293:Adolescent; D000328:Adult; D002066:Busulfan / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D015470:Leukemia, Myeloid, Acute / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D019653:Myeloablative Agonists / Q000627:therapeutic use; D009190:Myelodysplastic Syndromes / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D018365:Neoplasm, Residual; D011446:Prospective Studies; D012008:Recurrence; D012074:Remission Induction; D016019:Survival Analysis; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014916:Whole-Body Irradiation
D019653:Myeloablative Agonists; C018404:treosulfan; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine
AML; Allogeneic hematopoietic cell transplantation; MDS; Total body irradiation; Treosulfan