title: Cyclophosphamide conditioning in patients with severe aplastic anaemia given unrelated marrow transplantation: a phase 1-2 dose de-escalation study.
abstract: BACKGROUND
  The optimum preparative regimen for unrelated donor marrow transplantation in patients with severe aplastic anaemia remains to be established. We investigated whether the combination of fludarabine, anti-thymocyte globulin, and total body irradiation (TBI) would enable reduction of the cyclophosphamide dose to less than 200 mg/kg while maintaining engraftment and having a survival similar to or better than that with standard regimens using a cyclophosphamide dose of 200 mg/kg (known to be associated with significant organ toxicity) for unrelated donor transplantation for severe aplastic anaemia. We have previously shown that cyclophosphamide at 150 mg/kg resulted in excess toxicity and its omission (0 mg/kg) resulted in unacceptable graft failure (three of three patients had secondary graft failure). Here we report results for the 50 mg/kg and 100 mg/kg cohorts.
  
  
  METHODS
  In a multicentre phase 1-2 study, patients (aged ≤65 years) with severe aplastic anaemia, adequate organ function, and an unrelated adult marrow donor HLA matched at the allele level for HLA A, B, C, and DRB1 or mismatched at a single HLA locus received bone marrow grafts from unrelated donors. All patients received anti-thymocyte globulin (rabbit derived 3 mg/kg per day, intravenously, on days -4 to -2, or equine derived 30 mg/kg per day, intravenously, on days -4 to -2), fludarabine (30 mg/m(2) per day, intravenously, on days -5 to -2), and TBI (2 Gy). Cyclophosphamide dosing started at 150 mg/kg and was de-escalated in steps of 50 mg/kg (to 100 mg/kg, 50 mg/kg, and 0 mg/kg). The primary endpoint was the selection of the optimum cyclophosphamide dose based on assessments of graft failure (primary or secondary), toxicity, and early death during 100 days of follow-up after the transplant; this is the planned final analysis for the primary endpoint. This trial is registered with ClinicalTrials.gov, number NCT00326417.
  
  
  RESULTS
  96 patients had bone marrow transplant. At day 100, 35 (92%) of 38 patients were engrafted and alive in the cyclophosphamide 50 mg/kg cohort and 35 (85%) of 41 in the 100 mg/kg cohort. Cyclophosphamide 50 mg/kg and 100 mg/kg resulted in posterior means for fatality without graft failure of 0·7% (credible interval 0-3·3) and 1·4% (0-4·9), respectively. Three patients (8%) had graft failure with cyclophosphamide 50 mg/kg and six (15%) with cyclophosphamide 100 mg/kg. Four (11%) patients had major regimen-related toxicity with cyclophosphamide 50 mg/kg and nine (22%) with cyclophosphamide 100 mg/kg. The most common organ toxicity was pulmonary (grade 3 or 4 dyspnoea or hypoxia including mechanical ventilation), and occurred in three (8%) and four (10%) patients given cyclophosphamide 50 mg/kg and 100 mg/kg, respectively.
  
  
  CONCLUSIONS
  Cyclophosphamide at 50 mg/kg and 100 mg/kg with TBI 2 Gy, fludarabine, and anti-thymocyte globulin results in effective conditioning and few early deaths after unrelated donor transplantation for severe aplastic anaemia. These doses of cyclophosphamide provide a framework for further regimen optimisation strategies.
  
  
  BACKGROUND
  US National Heart, Lung, and Blood Institute and National Cancer Institute.
authors.affiliation: University of Texas, MD Anderson Cancer Center, Houston, TX, USA. Electronic address: panderli@mdanderson.org.
authors.forename: Paolo
authors.initials: P
authors.lastname: Anderlini
authors.affiliation: Emmes Corporation, Rockville, MD, USA.
authors.forename: Juan
authors.initials: J
authors.lastname: Wu
authors.affiliation: Emmes Corporation, Rockville, MD, USA.
authors.forename: Iris
authors.initials: I
authors.lastname: Gersten
authors.affiliation: Emmes Corporation, Rockville, MD, USA.
authors.forename: Marian
authors.initials: M
authors.lastname: Ewell
authors.affiliation: University of Minnesota, Minneapolis, MN, USA.
authors.forename: Jakob
authors.initials: J
authors.lastname: Tolar
authors.affiliation: Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Antin
authors.affiliation: Phoenix Children's Hospital, Phoenix, AZ, USA.
authors.forename: Roberta
authors.initials: R
authors.lastname: Adams
authors.affiliation: Stanford Hospital and Clinics, Stanford, CA, USA.
authors.forename: Sally
authors.initials: S
authors.lastname: Arai
authors.affiliation: Cooks Children's Hospital, Fort Worth, TX, USA.
authors.forename: Gretchen
authors.initials: G
authors.lastname: Eames
authors.affiliation: Duke University, Durham, NC, USA.
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Horwitz
authors.affiliation: Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: John
authors.initials: J
authors.lastname: McCarty
authors.affiliation: City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: University of Utah, Salt Lake City, UT, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Pulsipher
authors.affiliation: Hackensack University Medical Center, Hackensack, NJ, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Rowley
authors.affiliation: National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Leifer
authors.affiliation: Emmes Corporation, Rockville, MD, USA.
authors.forename: Shelly L
authors.initials: SL
authors.lastname: Carter
authors.affiliation: National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: DiFronzo
authors.affiliation: Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Mary M
authors.initials: MM
authors.lastname: Horowitz
authors.affiliation: National Marrow Donor Program, Minneapolis, MN, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Confer
authors.affiliation: Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: H Joachim
authors.initials: HJ
authors.lastname: Deeg
authors.affiliation: Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Eapen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000188:drug therapy* / Q000628:therapy; D016026:Bone Marrow Transplantation; D002648:Child; D002675:Child, Preschool; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000627:therapeutic use; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D007223:Infant; D008297:Male; D008875:Middle Aged; D019172:Transplantation Conditioning; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D003520:Cyclophosphamide