title: Treosulfan-based conditioning and hematopoietic cell transplantation for nonmalignant diseases: a prospective multicenter trial.
abstract: Hematopoietic cell transplantation is an effective treatment for patients with nonmalignant diseases and for many is the only known cure. Conventional myeloablative regimens have been associated with unacceptably high early transplant-related mortality (TRM), particularly in patients with comorbid conditions. This prospective multicenter trial was designed to determine the safety and engraftment efficacy of treosulfan-based conditioning in patients with nonmalignant diseases. Thirty-one patients received HLA-matched related (n = 4) or unrelated (n = 27) grafts after conditioning with treosulfan (total dose, 42 g/m(2)), fludarabine (total dose, 150 mg/m(2)), ± thymoglobulin (6 mg/kg; n = 22). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. All patients engrafted. Day-100 TRM was 0%. With a median follow-up of 2 years, the 2-year survival was 90%. Three patients died of GVHD, recurrent hemophagocytic lymphohistiocytosis, and a surgical complication, respectively. The cumulative incidences of grades II to IV and III to IV acute GVHD at day 100 and chronic GVHD at 2 years were 62%, 10%, and 21%, respectively. Patients who received thymoglobulin had a significantly lower incidence of grades III to IV acute GVHD (0% versus 33%; P = .005). These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with low toxicity and improved survival in patients with nonmalignant diseases and support the need for future disease-specific clinical trials.
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington School of Medicine, Seattle, Washington; Seattle Children's Hospital, Seattle, Washington. Electronic address: lburroug@fhcrc.org.
authors.forename: Lauri M
authors.initials: LM
authors.lastname: Burroughs
authors.affiliation: Oregon Health & Science University, Portland, Oregon.
authors.forename: Eneida R
authors.initials: ER
authors.lastname: Nemecek
authors.affiliation: University of Washington School of Medicine, Seattle, Washington; Seattle Children's Hospital, Seattle, Washington.
authors.forename: Troy R
authors.initials: TR
authors.lastname: Torgerson
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington School of Medicine, Seattle, Washington.
authors.forename: Barry E
authors.initials: BE
authors.lastname: Storer
authors.affiliation: Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Julie-An
authors.initials: JA
authors.lastname: Talano
authors.affiliation: Vanderbilt University, Nashville, Tennessee.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Domm
authors.affiliation: Children's Hospital Colorado, Aurora, Colorado.
authors.forename: Roger H
authors.initials: RH
authors.lastname: Giller
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington School of Medicine, Seattle, Washington; Seattle Children's Hospital, Seattle, Washington.
authors.forename: Akiko
authors.initials: A
authors.lastname: Shimamura
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington School of Medicine, Seattle, Washington; Seattle Children's Hospital, Seattle, Washington.
authors.forename: Colleen
authors.initials: C
authors.lastname: Delaney
authors.affiliation: University of Washington School of Medicine, Seattle, Washington; Seattle Children's Hospital, Seattle, Washington.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Skoda-Smith
authors.affiliation: Medical College of Wisconsin, Milwaukee, Wisconsin.
authors.forename: Monica S
authors.initials: MS
authors.lastname: Thakar
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington School of Medicine, Seattle, Washington; Seattle Children's Hospital, Seattle, Washington.
authors.forename: K Scott
authors.initials: KS
authors.lastname: Baker
authors.affiliation: University of Washington School of Medicine, Seattle, Washington; Seattle Children's Hospital, Seattle, Washington.
authors.forename: David J
authors.initials: DJ
authors.lastname: Rawlings
authors.affiliation: University of Washington School of Medicine, Seattle, Washington; Seattle Children's Hospital, Seattle, Washington.
authors.forename: Janet A
authors.initials: JA
authors.lastname: Englund
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington School of Medicine, Seattle, Washington.
authors.forename: Mary E D
authors.initials: ME
authors.lastname: Flowers
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington School of Medicine, Seattle, Washington.
authors.forename: H Joachim
authors.initials: HJ
authors.lastname: Deeg
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington School of Medicine, Seattle, Washington.
authors.forename: Rainer
authors.initials: R
authors.lastname: Storb
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, Washington; University of Washington School of Medicine, Seattle, Washington; Seattle Children's Hospital, Seattle, Washington.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Woolfrey
mesh_terms: D000293:Adolescent; D000328:Adult; D000741:Anemia, Aplastic / Q000401:mortality / Q000628:therapy*; D000961:Antilymphocyte Serum / Q000008:administration & dosage; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage*; D002066:Busulfan / Q000008:administration & dosage / Q000031:analogs & derivatives*; D002648:Child; D002675:Child, Preschool; D005199:Fanconi Anemia / Q000401:mortality / Q000628:therapy*; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D007223:Infant; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage; D019653:Myeloablative Agonists; D011446:Prospective Studies; D016559:Tacrolimus / Q000008:administration & dosage; D019172:Transplantation Conditioning; D061349:Unrelated Donors; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000961:Antilymphocyte Serum; D018906:Antineoplastic Agents, Alkylating; D007166:Immunosuppressive Agents; D019653:Myeloablative Agonists; C018404:treosulfan; C512542:thymoglobulin; D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine; D016559:Tacrolimus; D008727:Methotrexate
keywords: Allo-transplantation; Clinical results in inherited disorders; Conditioning regimen; Nonmalignant diseases; Reduced-intensity conditioning